Critical Reviews in Food Science and Nutrition

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A review of the role of inositols in conditions of

insulin dysregulation and in uncomplicated and
pathological pregnancy

Oliver C. Watkins, Hannah E. J. Yong, Neha Sharma & Shiao-Yng Chan

To cite this article: Oliver C. Watkins, Hannah E. J. Yong, Neha Sharma & Shiao-Yng Chan (2022)
A review of the role of inositols in conditions of insulin dysregulation and in uncomplicated and
pathological pregnancy, Critical Reviews in Food Science and Nutrition, 62:6, 1626-1673, DOI:
10.1080/10408398.2020.1845604

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CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION
2022, VOL. 62, NO. 6, 1626–1673
https://doi.org/10.1080/10408398.2020.1845604

REVIEW

A review of the role of inositols in conditions of insulin dysregulation and in

uncomplicated and pathological pregnancy
Oliver C. Watkinsa , Hannah E. J. Yongb , Neha Sharmaa , and Shiao-Yng Chana,b
a
Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore;
b
Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research, Singapore, Singapore

ABSTRACT KEYWORDS
Inositols, a group of 6-carbon polyols, are highly bioactive molecules derived from diet and Diabetes; PCOS; myo-
endogenous synthesis. Inositols and their derivatives are involved in glucose and lipid metabolism inositol; lipid-metabolism;
and participate in insulin-signaling, with perturbations in inositol processing being associated with placenta; fetal development
conditions involving insulin resistance, dysglycemia and dyslipidemia such as polycystic ovary syn-
drome and diabetes. Pregnancy is similarly characterized by substantial and complex changes in
glycemic and lipidomic regulation as part of maternal adaptation and is also associated with
physiological alterations in inositol processing. Disruptions in maternal adaptation are postulated
to have a critical pathophysiological role in pregnancy complications such as gestational diabetes
and pre-eclampsia. Inositol supplementation has shown promise as an intervention for the allevi-
ation of symptoms in conditions of insulin resistance and for gestational diabetes prevention.
However, the mechanisms behind these affects are not fully understood. In this review, we explore
the role of inositols in conditions of insulin dysregulation and in pregnancy, and identify priority
areas for research. We particularly examine the role and function of inositols within the maternal-
placental-fetal axis in both uncomplicated and pathological pregnancies. We also discuss how ino-
sitols may mediate maternal-placental-fetal cross-talk, and regulate fetal growth and development,
and suggest that inositols play a vital role in promoting healthy pregnancy.

Introduction Brautigan, and Thorner 2010; Croze and Soulage 2013;

Inositols are 6-carbon polyols present in all living cells
(Noventa et al. 2016). Humans synthesize approximately 4 g
of inositol a day in the kidney (Clements 1979), but inositols
are also abundant in fruits, grains and nuts, with a typical
North American diet providing about 1 g of inositol a day
(Holub 1986). Inositol and inositol derivatives often act as
both insulin mimics and second messengers (Asplin,
Galasko, and Larner 1993; Greene et al. 1987; Huang et al.
1993; Suzuki et al. 1994; Larner, Brautigan, and Thorner
2010; Cheang et al. 2008; Unfer et al. 2012; Facchinetti et al.
2015; Croze and Soulage 2013) and their complex interac-
tions with both glucose and lipid metabolism are well dem-
onstrated across tissue types and in many species (Larner,
Brautigan, and Thorner 2010; M€ uller et al. 1998; Romero
and Larner 1993; Saltiel 1990; Hansen 2015; Yamazaki,
Zawalich, and Zawalich 2010; Nielson and Rutter 2018;
Kunjara et al. 1999; Tabrizi et al. 2018). In humans, pertur-
bations in inositol synthesis, metabolism and excretion are
associated with metabolic conditions such as polycystic
ovary syndrome (PCOS), diabetes mellitus and metabolic
syndrome (Asplin, Galasko, and Larner 1993; Larner,
Heimark, McAllister, and Larner 2014; Ceriello et al. 1988;
Croze, Gelo€en, and Soulage 2015; Sun et al. 2002), as well as
perinatal disorders including gestational diabetes (GDM)
(Crawford et al. 2015; D’Anna and Santamaria 2018), pre-
eclampsia (D’Oria et al. 2017) and intrauterine growth
restriction (IUGR) (Dessı and Fanos 2013). Alterations are
most prominent in nervous and reproductive tissue, but the
extent and foci of the inositol-related pathophysiology in
insulin resistant conditions and pregnancy complications
remains unclear (Asplin, Galasko, and Larner 1993;
Daughaday and Larner 1954; Kennington et al. 1990).
Several small clinical trials suggest that inositol supple-
mentation could be a useful intervention or preventive
measure for the insulin-related and metabolic abnormalities
in PCOS, GDM and type 2 diabetes (Noventa et al. 2016;
Croze and Soulage 2013; Crawford et al. 2015; Papaleo et al.
2007; D’anna et al. 2012; Gateva, Unfer, and Kamenov 2018;
Colazingari et al. 2013; Bizzarri and Carlomagno 2014;
Unfer and Porcaro 2014; Muscogiuri et al. 2016; Lubin et al.
2016; Brown, Crawford Tineke, and Alsweiler 2015; Farren
et al. 2017; Malvasi et al. 2014; Pintaudi, Di Vieste, and

CONTACT Shiao-Yng Chan obgchan@nus.edu.sg Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of
Singapore, National University Health System, 1E Kent Ridge Road, NUHS Tower Block, Level 12, Singapore 119228, Singapore.
Supplemental data for this article is available online at https://doi.org/10.1080/10408398.2020.1845604.
ß 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/),
which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.

Bonomo 2016; D’Anna et al., 2013; Matarrelli et al. 2013;
Werner et al. 2016; DʼAnna et al. 2015; D’Anna et al., 2013;
Cogram et al. 2002; Cavalli et al. 2011). Inositol supplemen-
tation appears to decrease glycemia and improve insulin
sensitivity, but effects vary depending on the inositol isomer
used, the dose and the population studied (D’anna et al.
2012; Dʼ Anna et al. 2015; D’Anna et al., 2013; Kim et al.
2005; Santamaria et al. 2012; Giordano et al. 2011; Artini
et al. 2013; Genazzani et al. 2012; Santamaria, Di Benedetto,
et al. 2016; Corrado et al. 2011; Fraticelli et al. 2018). Other
small clinical trials have also suggested that inositol supple-
mentation might reduce plasma triglycerides and total and
LDL-cholesterol levels among patients with diabetes mellitus,
hyperinsulinemia, metabolic syndrome and PCOS (Tabrizi
et al. 2018), thereby highlighting a natural compound that
could address the increased risk of atherosclerotic and car-
diovascular diseases associated with these conditions.
Current evidence suggests that each inositol isomer and
derivative affects metabolism in distinct ways (Thomas, Mills,
and Potter 2016). Furthermore, these compounds appear to be
regulated differently in different tissues and in different popula-
tions even within apparently similar clinical phenotypes (Tables
3–7). In this review we will examine how inositol isomers and
derivatives regulate glucose and lipid metabolism, and discuss
how disruptions in inositol synthesis, metabolism or excretion
could be involved in conditions of insulin dysregulation.
Pregnancy is characterized by substantial and complex
changes in glycemic and lipidomic regulation, brought about
by signals released by the fetal-placental unit (Di Cianni et al.
2003). The placenta is situated at the maternal-fetal interface,
where it ensures appropriate fetal nutrition throughout gesta-
tion, by regulating maternal-fetal cross talk and nutritional
transfer (Gallo, Barrett, and Nitert 2017). Dysregulation of
these processes in pregnancy complications such as GDM and
pre-eclampsia cause disordered fetal growth and threaten both
maternal and fetal health (Gallo, Barrett, and Nitert 2017; Uhl
et al. 2015; Herrera and Ortega-Senovilla 2018; Larque et al.
2014; Philipps et al. 2011). Impact on offspring is often long
term because the in-utero environment shapes life-long health
(Developmental Origin of Health and Disease (Barker 2004)).
The fetal-placental unit is rich in inositol, and inositol
concentrations in fetal and neonatal circulations are much
higher than that in adults (Brusati et al. 2005; Toh et al.
1987; Santamaria, Di Benedetto, et al. 2016; Campling and
Nixon 1954; Pereira et al. 1990; Islam, Selvam, et al. 2019;
Pillai et al. 2020; Battaglia et al. 1961). Inositols are thus
postulated to be important in maintaining normal pregnancy
physiology and inositol dysregulation could be a key patho-
logical element in many pregnancy pathologies. In this
review we will therefore investigate how inositols could act
as critical signals in maternal-placental-fetal communications
and how they might regulate fetal nutritional supply,
growth, adiposity and tissue programming.
Review criteria
Overall, this review aimed to examine the current literature on
the biology of inositols in conditions of insulin dysregulation,
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 1627
with a focus on their role within the maternal-placental-fetal
axis. This review was conducted in the Department of
Obstetrics and Gynecology at the National University of
Singapore and includes studies published in English up until
March 2020. Articles were identified manually using Pubmed,
Science Direct and Google Scholar using the key words
described in Supplementary Table S1 and by following relevant
references in articles of interest. Human and animal studies,
clinical, randomized controlled trials (RCTs), cross-sectional
and prospective studies, in-vitro studies, cell studies, genetic
studies, reviews and meta-analyses were all included.
Inositol biology
Inositol stereoisomers and their derivatives
Inositol distribution and content in tissues and fluids
Myo-inositol is the most abundant and well-studied inositol,
but there are seven other natural inositol stereo-isomers: D-
chiro-inositol, L-chiro-inositol, epi-inositol, allo-inositol,
muco-inositol, neo-inositol and scyllo-inositol, and one syn-
thetic stereo-isomer: cis-inositol (Thomas, Mills, and Potter
2016). Only myo-inositol, D-chiro-inositol, L-chiro-inositol,
neo-inositol and scyllo-inositol have so far been found in
mammals (Thomas, Mills, and Potter 2016; Stewart,
Sherman, and Harris 1970). Reported inositol concentrations
in human and mammalian adult and fetal tissues, and in the
circulation are summarized in Table 1.
Many older methods were not able to quantify different
inositol isomers separately (Tables 1A and 1C), whilst newer
techniques such as gas chromatography (GC), high perform-
ance liquid chromatography (HPLC) and nuclear magnetic
resonance (NMR) have enabled the quantification of some
individual isomers (Tables 1B, 1D).
Inositol is ubiquitous in the body, but content is particu-
larly high in the central nervous system (CNS), kidney, and
male and female reproductive organs, suggesting an import-
ant role for inositol in these tissues (Table 1). Several studies
suggest that inositols are critical for nervous system function
(Fisher, Novak, and Agranoff 2002; Thurston et al. 1989) and
inositol is known to play a key role in dopamine, serotonin,
noradrenaline and acetylcholine neurotransmission
(Shaldubina et al. 2007). Indeed, brain inositol dysregulation
has been associated with Down syndrome (Berry et al. 1999),
bipolar disorder (Calker and Belmaker, 2000), schizophrenia
(Shimon et al. 1998), aging (Stokes, Gillon, and Hawthorne
1983), epilepsy (Pascente et al. 2016) and Alzheimer’s disease
(Stokes and Hawthorne 1987). Inositols were also found to be
crucial for testicular and ovarian function, with dysregulation
associated with male and female infertility (Steegers-
Theunissen, Groenen, and Beemster 2002; Condorelli et al.
2017; Unfer et al. 2017; Papaleo et al. 2009).
Isomeric composition of inositols in circulation, urine
and tissues
The amount and isomeric composition of inositol in any
cell, and the consequent biological effects, are influenced by
systemic and local factors. Systemic inositol concentrations
 1628
O. C. WATKINS ET AL.

Table 1A. Unspecified inositols (mmol/ kg wet tissue) analyzed by methods that do not differentiate between inositol isomers.
Ref Method Species Central nervous system Muscle Liver Kidney Heart Intrauterine tissues Other tissues
(Kalra, Kalra, and Sharma 2016) Inositols isolated and weighed Adult Rat 9.1-9.3 Testis: 2.2-3.7,
Epididymis:
11.4-12.3,
Seminal vesicle:
33.9-37.0
(Battaglia et al. 1961) Thin layer chroma-tography Adult Sheep Cortex: 0.8-2.7 2.1-3.9 3.6-10.9 4.6-15.2 Uterine mucosa:
11-11.6, 3.9
15.7
Cerebellum: 11.2-15.5
Fetal sheep Cortex: 12.3, Cerebellum: 15.5 0.3-4.3 0.4-3.3 0-12.7 0-3.22 Chorion: 4.2,
Placenta: 1.0
Adult Goat Cortex: 0-1.7 1.3 3.7-8.5 8.4-11.0 Uterine mucosa:
5.9-9.3, 0.5-3.4,
Cerebellum: 6.9-15.7 Chorion:
1.6-4.1,
Placenta:
0.4-1.0
Fetal goat Cortex: 2.0-4.2 12.7-15.0 2.7-3.9
10.6-14.5,
Cerebellum: 12.9-14.9
Adult Rabbit Brain: 10.3 1.9 1.7 Placenta: 1.7
Adult Rat Brain: 0.2-2.1 2.4 6.9-7.6 0.8-1.7 Uterine mucosa: 3.1,
5.0-6.7 Placenta:
0.7-1.7
Adult Pig Uterine mucosa: Ovaries:
0.4-5.8 3.3-5.3
(Campbell et al. 2004) Microbiological assay method Adult Mice 11.7 (1) 0.32 (0.04) 1.2 (0.2) 8.2 (0.6) 1.4 (0.2) Pancreas:
2.3 (0.2)
(Islam, Selvam, et al. 2019) Enzymatic assay Fetal Human Placenta (Freea):
2.7 (0.3),
Placenta (totalb):
3.5 (0.4)
Ref: Study reference. aFree inositol was extracted with water, bTotal inositol extracted by high temperature acid hydrolysis. Mean with standard deviation (SD) or range stated if available.
Table 1B. Specified inositols in tissues.
Ref Method Species Central nervous system Peripheral nervous system Liver Kidney In utero tissues Other tissue
Myo-inositol in tissues quantified in mmol/ kg wet tissue

(Stokes and Hawthorne 1987) GC Adult Human Cortex: 2.28

(Shimon et al. 1998) GC Adult Human Frontal cortex:
1.20 (0.6),
Occipital cortex:
0.81 (0.5),
Cerebellum:
0.67 (0.5)
(Toh et al. 1987) GC Fetal Human Placenta: 0.53,
Umbilical cord: 0.59
(Stull et al. 2008) GC Adult Rat Freea: 5.31-6.67 Freea: 0-0.32 Freea:
Lipid boundb: Lipid boundb: 2.06-2.55 5.72-6.53,
1.11-1.38 Lipid boundb:
1.02-1.04
(Taguchi et al. 1997) GC Adult Rat Brain: 6.62 (0.96) Sciatic nerve: 0.57 (0.12) 4.51 (0.36)
3.10 (0.34)
(Kennington 1992) GC Adult Rat 3.52 (0.04)
(Larner 2002) GC Adult Female rats Brain: 4.5 (0.29) 1.27 (0.2)
(Sherman, Goodwin, GC Adult Rabbit Cerebral cortex: Sciatic nerve: 2.0 Testis: 5.7,
and Gunnell 1971) 13.0 (0.9), 4.25 (0.19), Spleen: 0.8,
Cerebellar cortex: 13.6 (0.5), Vagus nerve: Lens: 0.3
Optic nerve: 4.26 (0.55)
14.2 (0.3),
White matter:
11.6 (0.7),
Midbrain nuclei:
13.2 (0.7)
Adult Rat Brain: 5.82 (0.29) Sciatic nerve: 6.12 (0.54)
Spinal cord: 7.4 4.06 (0.26)
Neo-inositol in tissues quantified in mmol/ kg wet tissue

(Groenen, Merkus, GC Adult Rat Brain: 1.9-6.5 <0.8 6.2-9.6 Heart: <0.8-3.5,
et al. 2003) Testis: 6.5-4,
Spleen: 1.2-4.4
Scyllo-inositol in tissues quantified in mmol/ kg wet tissue

(Michaelis et al., 1993) GC Adult Rabbit Cerebral cortex: Sciatic nerve: 0.17 Testis: 0.2,
0.53 (0.05), 0.34 (0.04), Spleen: 0.12,
Cerebellar cortex: Vagus nerve: Pancreas: 0.09,
0.07 (0.06), 0.65 (0.17) Lens: 0.59
Optic nerve:
0.63 (0.03),
White matter:
0.46 (0.03)
Midbrain nuclei: 0.57 (0.06)
GC Adult Rat Brain: 0.16 (0.01), Sciatic nerve: 0.45 (0.02)
Spinal cord: 0.18 0.29 (0.02)
(Seaquist and Gruetter 1998 ) NMR Adult Human Brain: 0.43 (0.11)
(Sherman, Stewart, NMR Adult Human Occipital cortex:
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION

Kurien, et al. 1968) 1.4 (0.1)

Ref: Study reference, GC: Gas Chromatography, NMR: Nuclear Magnetic resonance. aFree inositol was extracted with water, bLipid bound inositol was extracted with chloroform methanol (2:1). Mean with standard devi-
ation (SD) or range if available.
1629
1630 O. C. WATKINS ET AL.

Table 1C. Unspecified inositols in fluids (mmol/L) by methods that do not differentiate between inositol isomers.(Garcia-Perez and Burg 1990)Inositols isolated
and weighed Adult Boar Seminal: 110,000-167,000
Ref
(Kalra, Kalra, and Sharma 2016) Inositols isolated
(Battaglia et al. 1961)
(H€aussinger 1998)
(Zheng et al. 2015)
(Campling and Nixon 1954)
(Celentano et al. 2020)
(Pereira et al. 1990)
Ref: Study reference. NAD: Nicotinamide adenine dinucleotide. Mean with standard deviation (SD) or range if available.
Method
and weighed
Thin layer chromatography
Microbiological assay
Microbiological assay
Microbiological assay
þ
NAD myo-inositol
dehydrogenase assay
Enzymatic fluorometric assay
Species (status) Blood Other fluid
Adult Rat Seminal: 52,400-58,900
Adult Sheep Plasma: 0-89
Fetal sheep Plasma: 800-1333 Spinal: 7780, Urine: 17-83,
Allantoic: 555-167,
Amniotic: 300-528
Adult Goat Plasma: 39-89 Spinal: 460
Fetal goat Plasma: 933-1230 Spinal: 3060, Amniotic: 560
Adult Bull Coccygeal vein plasma: 22 (3) Rete testis: 3877 (287),
Cauda epididymidis: 2470
(240),
Seminal: 761 (121)
Adult Human Semen: 3600 (1600)
Human (pregnant, term) Whole blood: 28-44
Human fetus (term) Whole blood: 61-155 Amniotic: 33-89
Human fetus (under 24 weeks) Whole blood: 188.7-888.1 Amniotic: 38.9-521.8,
Plasma: 188.7-621.7 Fetal urine: 144.3-299.7
Sheep (pregnant) Whole blood: 33-150
Sheep fetus Whole blood: 555-1721 Amniotic: 33-1117, Allantoic:
Plasma: 610.6-1465.4 278-1171
Adult monkey (pregnant) Plasma: 44.4
Monkey fetus Plasma: 199.8 Amniotic: 99.9
Adult goat (pregnant) Whole blood: 27.8-194.3
Goat fetus Whole blood: 172.1-1887.2 Amniotic: 138.8-405.2,
Allantoic: 444.0-1182.3
Adult rabbit (pregnant) Whole blood: 44.4-172.1
Rabbit fetus Whole blood: 177.6-910.3 Amniotic: 105.5-1681.8,
Allantoic: 3718.9-10629.4
Adult cat (pregnant) Whole blood: 138.8-188.7
Cat fetus Whole blood: 910.3-1254.4 Amniotic: 455.2,
Allantoic: 1509.8-2919.6
Adult Human Serum: 39 (2) Follicular fluid: 36 (3)
Adult human (post partum) Serum (at birth): 52 (6) Breast milk
(preterm colostrum): 2240
(280),
Breast milk
(term colostrum): 1840
(451),
Breast milk (mature):
1456 (276)
Neonate Preterm neonate serum: 108
(10),
Term neonate serum:
86 (13)

are determined by inositol intake, bioavailability and excre-
tion. Locally, cellular levels are regulated by cellular uptake
and efflux, isomeric conversion, synthesis, catabolism and
metabolism into inositol-containing derivatives (Holub
1986). Myo-inositol comprises 98% of adult human plasma
inositol and 71% of urinary inositol (Kalra, Kalra, and
Sharma 2016). D-chiro-inositol is commonly quoted as the
second most abundant inositol with plasma D-chiro-inositol
being 3% relative to plasma myo-inositol, and urinary D-
chiro-inositol being 21- 29% relative to urinary myo-inositol
(Campbell et al. 2004; Stull et al. 2008). However, this may
not be the case, since most methods used cannot distinguish
between D-chiro-inositol and L-chiro-inositol, and do not
quantify scyllo-inositol or neo-inositol. There is also concern
that the use of acid in some analytical methods may cause
isomerization ex-vivo, leading to an artificial change in the
ratio of different inositol isomers (Taguchi et al. 1997).
Therefore, in many studies inositols may have been missed,
mis-identified or mis-analyzed.
Only a handful of studies have described the relative
abundance of other inositol isomers. In Sprague Dawley
rats, L-chiro-inositol was found in similar concentrations to
D-chiro-inositol in muscle phospholipids (skeletal and
smooth) and heart phospholipids, but D-chiro-inositol was
higher than L-chiro-inositol in fat, liver, brain and kidney
phospholipids (Kennington 1992; Larner 2002). Neo-inositol
meanwhile was found in the brain, heart, kidney, testis, and
spleen of the rat, but was not detected in rat liver (Sherman,
Goodwin, and Gunnell 1971). Scyllo-inositol and epi-inositol
quantified in human plasma were about 100 times less abun-
dant than myo-inositol (Groenen, Merkus, et al. 2003), while
scyllo-inositol in the human brain was about five times less
abundant than myo-inositol (Michaelis et al., 1993; Seaquist
and Gruetter 1998). In rabbit tissue, the myo-inositol to
scyllo-inositol ratio was very high in the spleen, pancreas,
testis (45:1, 30:1, 28:1, respectively) and in the brain (19:1 –
25:1 depending on region), but much lower in the sciatic
nerve, vagus nerve and lens (12:1, 6.6:1, 10:1, respectively)
 CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 1631

Table 1D. Specified isomers in fluids (mmol/L).

Ref Method Species Blood Other Fluids
Myo-inositol

(Formuso, Stracquadanio, and GC Adult human Urine: 454 (738)

Ciotta 2015)
(Ma et al., 2012) GC Adult human Seminal: 1472 (255)
(Ma et al., 2012) GC Adult human Serum: 38 Cerebrospinal: 22-905
(Nozadze et al. 2011) GC Adult human Cerebrospinal: 167-611
(Taguchi et al. 1997) GC Adult rat Serum: 80 (10)
(Kennington 1992) GC Adult rat Serum: 48.6 (4.9)
(Michaelis et al., 1993) GC Adult rat Serum: 71.0 (0.6)
(Bersudsky et al. 1999) GC Adult human Plasma: 19.9 (2.5)
Adult human human 90 min Plasma: 96.5 (16.6)
after myo-inositol oral
ingestion
(100 mg/kg body weight)
(Santamaria, Di Benedetto, GC Adult human Amniotic: 79.0
et al. 2016)
(Einat and Belmaker 2001) GC Human (Non-pregnant) Serum: 24.5
Human (pregnant) Serum: 21.4
Human fetus Cord serum (mid-gestation):
125,
Umbilical artery serum
(term): 60.2,
Umbilical vein serum
(term): 45.4
(Strieleman et al., 1992) GC Adult human Plasma: 34 (6) Urine: 167 (99)
(Brusati et al. 2005) HPLC Human (pregnant) Plasma: 26
Human Fetus Umbilical artery (term): 75
Umbilical vein (term): 64
Other inositol isomers

(Strieleman et al., 1992) GC Adult human Plasma D-chiro-inositol, urine: 50 (35)

(Formuso, Stracquadanio, and
Ciotta 2015)
(Bersudsky et al. 1999)
Ref: Study reference, GC: Gas chromatography, HPLC: high performance liquid chromatography. Mean with standard deviation (SD) or range if available.
D-chiro-inositol: 0.90 (0.24)
GC Adult human D-chiro-inositol, urine: 21 (34)
GC Adult human Plasma
Scyllo-inositol: 0.46 (0.13),
Epi-inositol: 0.19 (0.19)
Adult human 90 min after Plasma
myo-inositol oral ingestion Scyllo-inositol: 1.09 (0.17),
(100 mg/kg body weight) Epi-inositol: 0.38 (0.23)

Table 2. Inositol transport proteins facilitating cellular influx of inositol.

Name/ alternative
Transporter type name Metabolites transferred (ordered by relative affinity) Organs with highest gene expression
Proton (Hþ)/ myo-inositol symporters HMIT/ GLUT13/ Myo-inositol > scyllo-inositol > D-chiro- Brain, adipose tissue and kidneys
SLC2A13 inositol > muco-inositol
Sodium/ myo-inositol transporters SMIT-1/ Myo-inositol ¼ scyllo-inositol > glucose Kidney, brain, placenta, pancreas,
SLC5A3 heart and skeletal muscle
SMIT-2/ Myo-inositol and D-chiro-inositol > L-Chiro-inositol, Heart, skeletal muscle, kidney, liver
SLC5A11 D-glucose, D-manose and D-pinitol and placenta
Note: Data from Guo et al. 1997; Davanzo et al. 2003; Davanzo et al. 2001, Willmroth et al. 2007; Davanzo et al. 2003; Harwood 2005; Davanzo et al. 2003;
Lubrich and van Calker 1999; Calker and Belmaker, 2000.

with similar results seen in rats (Sherman, Stewart, Kurien,
et al. 1968). This may suggest a more important role for
scyllo-inositol in the peripheral nervous system compared
with other tissues. Overall, further studies are required to
clarify the inositol composition in biological systems.
Different actions of inositol isomers
The shape of inositol isomers affects their ability to interact
with enzymes giving them distinct bioactivities (Thomas,
Mills, and Potter 2016) and altering how these molecules are
transported across membranes (Table 2). However, all
inositol isomers have the same effects when shape does not
affect function, such as in osmotic regulation (Thurston
et al. 1989; Garcia-Perez and Burg 1990; H€aussinger 1998).
Inositol isomers are also differently disrupted in various
pathologies (Tables 3–7). The pharmacological effects of
inositol likely depend on the inositol isomer, the dose, and
the population studied. For example, daily inositol supple-
mentation resulted in decreased insulin resistance as
assessed by the Homeostatic Model Assessment of Insulin
Resistance (HOMA-IR) in postmenopausal women with
metabolic syndrome [4000 mg myo-inositol (Santamaria
et al. 2012; Giordano et al. 2011)], in non-pregnant women
1632 O. C. WATKINS ET AL.

Table 3. Case-control studies of inositol concentrations in non-pregnant populations with diabetes compared with controls.
Population Comparison Country/
Ref (as specified in study) (Control) Ethnicity Sample L-chiro-inositol D-chiro-inositol Myo-inositol Method
Type 1 or Insulin-dependent population
(Pugliese et al. 1990) Overweight, Insulin Overweight/ USA Urine (24 h No change Increased Increased GCMS
dependent diabetes obese, output,
Non-diabetic creatinine
normalized)
Plasma No change No change No change GCMS
(Coppey et al. 2002) Normal weight Type Normal weight, Korea Urine – Decreased Increased HPLC
1 diabetes Non-diabetic (24 h
output)
Type 2 or Insulin-independent population
(Daughaday and Poorly Non- diabetic USA Urine Inositol Increased Yeast assay
Larner 1954) controlled diabetes Plasma No change in inositol
(Pugliese et al. 1990) Obese, non-insulin Overweight/ USA Urine No change Increased Increased GCMS
dependent diabetes obese, (24 h
(poorly controlled) Non-diabetic output)
Plasma No change No change No change
(Formuso, Stracquadanio, Overweight, Type Normal weight, Korea Urine – Increased Increased HPLC
and Ciotta 2015) 2 diabetes Non-diabetic
(Kennington et al. 1990) Non-insulin Non-diabetic USA Urine – Decreased Increased GCMS
dependent diabetes (White, (24 h output)
Black)
Non-insulin Non-diabetic USA, – Decreased Increased GCMS
dependent diabetes Pima Indian
(Coppey et al. 2002) Normal weight, Type Normal weight, Korea Urine – Decreased Increased HPLC
2 diabetes Non-diabetic (24 h
output)
(Suzuki et al. 1994) Normal weight, Type Age- matched Japan Urine – Decreased – GCMS
2 diabetes Normal
weight,
Non-diabetic
Ref: Study reference. Inositol levels refer to the non-lipid-bound portion unless otherwise stated.

Table 4. Animal studies of inositol levels in non-pregnant diabetes models.

Ref Species Model of diabetes Control Location D-Chiro-inositol Myo-inositol
(Taguchi et al. 1997) Rat Streptozocin-induced, Untreated, non- Brain, kidney, urine – Increased
long-term mild diabetes diabetic rat Sciatic nerve – Decreased
Brain – Decreased lipid-bound
Streptozocin-induced, Serum, Liver – Increased
acute diabetes Sciatic nerve – Decreased lipid-bound
(Yue et al. 1989) Rat Streptozocin- induced Untreated, non- Peripheral nerve – Decreased
diabetic rat Peripheral nerve – Decreased incorporation
of [3H]-myo-inositol
into
phosphatidylinositol
(Chukwuma, Ibrahim, Rat Streptozocin- induced Untreated, non- Sciatic nerve – Decreased
and Islam 2016) diabetic rat Plasma – Unchanged
(Loy et al. 1990) Rat Streptozocin- induced Untreated, non- Superior – Decreased
diabetic rat cervical ganglion
(Greene et al. 1987) Rat Biobreeding Biobreeding diabetic Sciatic nerve – Decreased
given insulin
(Palmano, Whiting, and Rabbit Alloxan induced Untreated non- Retina – Deceased
Hawthorne 1977) diabetic rabbit
(Zhu and Eichberg 1990) Rabbit Alloxan induced diabetic Kidney – Unchanged
(mild or severe) Left ventricle of
heart,
Atrioventricular
node region,
Aqueous humor,
Retinal
choriocapillaris,
Cornea
Alloxan induced diabetic Aortic myointima – Decreased
(mild, 19
days exposure)
Alloxan induced diabetic – Unchanged
(mild, 2
months exposure)
Alloxan induced diabetic – Increased
(severe, 2
months exposure)
(continued)
 CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 1633

Table 4. Continued.
Ref Species Model of diabetes Control Location D-Chiro-inositol Myo-inositol
Alloxan induced diabetic Retinal – Decreased
(severe diabetes, 2 pigmented
months exposure) epithelium
Alloxan induced diabetic Serum – Decreased
(mild and severe)
(Mayer and Rat Goto-Kakizaki Wistar rat controls Urine Decreased Increased
Tomlinson 1983)
(Greene, De Jesus, and Rhesus monkeys Spontaneously diabetic Non- Urine Decreased –
Winegrad 1975) diabetic monkey
(Kennington et al. 1990) Rhesus monkeys Spontaneously diabetic Urine Decreased Increased
(Solomonia et al. 2010) Rat Streptozocin induced Untreated rat Urine Increased Increased
Mouse db/db mice Wild-type mice Urine Increased Increased
Ref: Study reference. Inositols measured are non-lipid-bound forms unless otherwise stated.

Table 5. Case-control studies of IPGs in non-pregnant diabetes compared with non-diabetic controls.
Ref Type of diabetic Analysis method Location P-IPG A-IPG
(Asplin, Galasko, and Type 2 diabetes PDH phosphatase assay Muscle Decreased –
Larner 1993) of P-IPG fraction Hemodialysate Decreased Unchanged
cAMP dependent Urine (24 h output) Decreased Decreased
protein kinase assay of
A-IPG fraction
D-chiro-inositol and Hemodialysate D-chiro-inositol/ myo-inositol ratio decreased
myo-inositol in P-IPG Muscle D-chiro-inositol/ myo-inositol ratio decreased
fraction by HPLC
(Kennington et al. 1990) Type 2 diabetes Myo-inositol and D- Muscle biopsy before Decrease in D-chiro- Increased in myo-
chiro-inositol content in insulin administration inositol content inositol content
combined P-IPG and A- Muscle biopsy 15 and
IPG fractions analyzed 20 min into
by GC euglycemia
insulinemic
clamp study
(Kunjara et al. 1999) Types 1 and 2 diabetes PDH phosphatase assay Urine Unchanged Increased
of P-IPG fraction
(creatinine
normalized),
Lipogeneses assay of
A-IPG fraction
(creatinine
normalized)
Ref: Study reference.

with PCOS [2000 mg myo-inositol (Artini et al. 2013;
Genazzani et al. 2012)], in obese and overweight pregnant
women [4000 mg (Dʼ Anna et al. 2015; Santamaria, Di
Benedetto, et al. 2016) myo-inositol], and in women with
GDM with no insulin therapy [4000 mg myo-inositol
(Corrado et al. 2011; Fraticelli et al. 2018)]. However, no
change in insulin resistance as assessed by HOMA-IR was
observed among pregnant women with GDM treated with
D-chiro-inositol [500 mg D-chiro-inositol or a combination
of 1100 myo-inositol/27.6 mg D-chiro-inositol (Fraticelli
et al. 2018)]. However, differences in the statistical power of
these studies, and in the methods used, make compari-
sons difficult.
So far, only trials of supplements containing myo-inositol
(without other inositols) suggested efficacy in reducing risk
of GDM (Zheng et al. 2015). Treatment with D-chiro-inosi-
tol [500 mg] alone showed no effect on GDM prevention,
while combined myo-inositol [1100 mg] and D-chiro-inositol
[27.6 mg] treatment has shown no consistent positive effect
(Farren et al. 2017; Celentano et al. 2020).
Unlike in GDM, both myo-inositol and D-chiro-inositol
treatments were able to significantly improve endocrine
and metabolic parameters in non-pregnant overweight
PCOS patients (Formuso, Stracquadanio, and Ciotta 2015)
(vide-infra). Meanwhile, scyllo-inositol and epi-inositol
show promise for neurological function. Scyllo-inositol
showed effectiveness in-vitro and in-vivo as potential
Alzheimer’s disease treatment, decreasing neuronal tox-
icity, cognitive deficits and the aggregation of amyloid b
peptides and increasing long-term potentiation (Ma et al.,
2012; Ma et al., 2012). In rats, scyllo-inositol also showed
anti-convulsive effects and maybe useful in treating epi-
lepsy (Nozadze et al. 2011), while epi-inositol reduced
anxiety (Bersudsky et al. 1999; Einat and Belmaker 2001).
Some inositol isomers may also influence the effects of
other inositols (Strieleman et al., 1992; Wentzel et al. 2001;
Salman et al. 1999; Strieleman and Metzger 1993;
Strieleman et al., 1992). Scyllo-inositol, for example, in the
developing rat conceptus, inhibited myo-inositol uptake
and the synthesis myo-inositol derived phosphoinositide
and phosphoinositide-phosphate (PIP) (Strieleman et al.,
1992; Wentzel et al. 2001; Salman et al. 1999; Strieleman
and Metzger 1993; Strieleman et al., 1992), and these
changes were associated with increased structural abnor-
malities and deceased crown rump length and somite
number (Strieleman et al., 1992).
Table 6. IPGs in pregnant women with and without diabetes. 1634

Ref Pregnant Population Sample (gestational age) Method of assay P-IPG A-IPG
Uncomplicated pregnancy compared with non-pregnant controls

(Suzuki et al. 2014) Non-diabetic pregnancies Urine 24 h output Extraction of IPG fractions followed by Increased compared to –
(26 to 37 weeks) bioactivity assay non-pregnant
Pregnant women with preexisting diabetes (or diabetes not specified) compared with matched non-diabetic pregnant controls of similar gestational age†

(Suzuki et al. 2014) Type 1 diabetes treated with insulin Maternal urine 24 h output Extraction and bioactivity assay Similar to controls Similar to
(31 to 38 weeks) controls
(Sacks et al. 2012) Type 2 diabetes Maternal urine (spot collection any time Polyclonal antibody assay, Increased –
O. C. WATKINS ET AL.

point before 30 weeks) creatinine normalized

Maternal urine Similar to controls –
(spot collection after 30 weeks)
(Scioscia, Gumaa, et al. 2007)
Diabetes Endothelium of term placental vessels Immuno-histochemical staining Decreased –
(type not specified)
Pregnant women with GDM compared with matched non-diabetic pregnant controls of similar gestational age†

(Zeitler, Wu, and GDM Maternal urine 24 h output Extraction of IPG fractions followed Increased –
Handwerger 1991) (30.2 ± 6.3 (SD) weeks) by bioactivity assay
(Sacks et al. 2012) GDM Maternal urine (spot collection 20-35 weeks) Polyclonal antibody assay, Increased –
Maternal urine (spot collection after 35 weeks) creatinine normalized Similar to controls –
(Hayashi, Hasegawa, GDM Maternal urine Extraction of IPG fractions followed – Decreased
and Tomita 1976) (spot collection, gestational age not available) by bioactivity assay, creatinine
normalized
Ref: Study reference. †All studies are cross sectional. GA: Gestational age. GDM: gestational diabetes mellitus. SD: standard deviations.

Table 7. P-IPG in pre-eclampsia (PE) compared to controls with an uncomplicated pregnancy.

Ref Location Gestational age (weeks) Measured by P-IPG in pre-eclampsia
(463) Urine (spot collection) PE: 32.0 ± 4.5, Polyclonal antibody assay, Increased
Control 31.4 ± 3.5 creatinine normalized
(464) Urine (spot collection) Urine collected every 4 weeks Polyclonal antibody assay, Increased
after booking creatinine normalized
(Best et al. 1946) Urine (catheter urine sample At delivery Polyclonal antibody assay Increased
collected at the start of
the cesarean section)
Amniotic fluid Increased
Peripheral vein Extraction and No change
Umbilical vein bioactivity assay No change
Umbilical artery No change
Uterine vein Decreased
(Suzuki et al. 2014) Urine (24 h output) PE: 26 to 37, Extraction and Increased
Placenta Control: 31 to 38 bioactivity assay Increased
(Hegsted et al. 1973) Cultured placenta incubated Post delivery Extraction and Decreased placental P-IPG
with insulin bioactivity assay after insulin exposure
(Chu and Hegsted 1980) Cultured placenta incubated Post delivery Extraction and Decreased placental P-IPG
with insulin bioactivity assay after insulin exposure
Ref: Study reference.
 CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 1635

Figure 1. Synthesis, catabolism, excretion, isomerization and derivatization of inositols.

The synthesis of methylated inositol derivatives has so far only been found in plants and whether this process also occurs in mammals is controversial.

Inositol derivatization Wells 1965). Meanwhile, an enzymatic assay study which

Inositols can be derivatized with lipids, phosphates, sugars,
proteins and other compounds to form a wide range of bio-
active molecules (Figures 1 and 2). A lack of suitable analyt-
ical techniques means that little is known about the relative
abundance of different derivatives. One gas chromatography
study compared water soluble myo-inositol (aqueous extract,
probably mainly underivatized) to lipid-bound inositol
(organic extraction followed by acidic hydrolysis) (Wells,
Pittman, and Wells 1965). This study demonstrated that in
the brain and kidney most inositol was found in the water-
soluble form (83 and 87% respectively), while in the liver
most inositol was lipid-bound (94%) (Wells, Pittman, and
compared water-soluble and total acid hydrolyzable inositol
in human placenta found 77% of the inositol in the water-
soluble form (Islam, Selvam, et al. 2019).
It should be noted that although most quantified water
soluble inositol will originate from underivatized inositol,
some will be due to the cleavage of other water-soluble inosi-
tol derivatives during processing. The degree to which this
occurs is not known, but the amount of cleavage will depend
on the methods used, with the harsher methods used to pre-
pare samples for gas chromatography likely to cause more
cleavage than other methods. The degree of cleavage will also
depend on the inositol derivative involved. For example, the
1636 O. C. WATKINS ET AL.

Figure 2. Inositol metabolism leads to the formation of diverse bioactive derivatives many of which interact with insulin signaling pathways. Inositol derivatives
containing lipids are shown in gold while those that do not are shown in green. Other compounds are shown in black. Blue arrows and descriptions show selected
signaling or metabolic processes affected by inositol or inositol derivatives. Abbreviations: Arachidonic acid (AA), Diacylglycerol (DAG), Glycosyl-phosphatidyl-inosi-
tols (GPI), Inositol phosphoglycans (IPGs), Lysophosphatidic acid (LPA), lyso-phosphotidyl inositol (LPI), Phosphoinositide phosphates (PIPs).

phosphate-ester bond in inositol phosphates will be more sen-
sitive to cleavage than the ether bond of pinitol (D-chiro-
inositol-O-methyl ether) or the glycosidic bonds of inositol
glycans and inositol phosphoglycans (IPGs). Thus, the
amount of inositol quantified will depend on extraction, proc-
essing and quantification methods used and results cannot
easily be compared between studies.
Labeled myo-inositol and D-chiro-inositol injected into rats
generally remained as free underivatized inositols (94% and 83.4%
respectively), with substantially les s incorporated into inositol
phosphates (1.8% and 16.4%), or phospholipids (3.2% and 0.2%),
when assessed in all tissues combined after 72 h, suggesting inosi-
tol derivatization is isomer dependent (Pak et al. 1998).
Inositol synthesis, iomerism and catabolism
Myo-inositol synthesis
Myo-inositol can be endogenously synthesized from glucose
by inositol-3-phosphate synthase (ISYNA1) and inositol-1-
monophosphatase (IMPA1) (Noventa et al. 2016; Holub
1986) (Figure 1). These enzymes are relatively specific to
inositol metabolism, although IMPA1 can also hydrolyze gal-
actose 1-phosphate (an intermediate of galactose metabolism)
to form galactose (Parthasarathy, Parthasarathy, and Vadnal
1997). ISYNA1 is found in all eukaryotes, while IMPA1 is
found in all Animalia (Zerbino et al. 2018). Although both
are ubiquitously expressed in mammalian tissues, ISYNA1 is
particularly highly expressed in human placenta and testis,
while IMPA1 is especially highly expressed in the testis
(Fagerberg et al. 2014; Guan, Dai, and Shechter 2003).
Despite such expression patterns, the kidneys remain the pre-
dominant site of myo-inositol synthesis (approximately 4 g/
day in humans (Clements Jr 1979)), with appreciable amounts
also synthesized by the brain [30 mmoles/kg wet weight/h
(Stewart, Sherman, and Harris 1970)] and testis [316 mmoles/
kg wet weight/hr (Stewart, Sherman, and Harris 1970;
Eisenberg and Bolden 1963; Middleton and Setchell 1972;
Voglmayr and White 1971; Hauser and Finelli 1963)], con-
sistent with these tissues’ high inositol content (Table 1).
Myo-inositol epimerization to D-chiro-inositol
Myo-inositol is thought to be converted into D-chiro-inositol
by myo-inositol-D-chiro-inositol-1-epimerase. Epimerization
was evaluated in-vivo via the conversion of injected radio-iso-
tope-labeled [3H]-myo-inositol into [3H]-D-chiro-inositol in
non-diabetic rats (Pak et al. 1992). The relative amount of

isotope label found as D-chiro-inositol varied between tissues,
ranging from 0.7% in the heart, to 2.2% in liver. Much higher
relative amounts of D-chiro-inositol were observed in urine
(36%) and blood (60.4%) (Pak et al. 1992), which reflect the
combined whole body tissue conversion rates. Labeling of
other inositol isomers including scyllo-inositol, neo-inositol,
epi-inositol, and mucoinositol was less than 0.06%.
Myoinositol epimerase activity appears altered in several
conditions of insulin resistance, but the direction of change
depends on the condition and tissue studied. Ovarian thecal
cells from patients with PCOS showed decreased myo-inosi-
tol:chiro-inositol ratios, and increased in-vitro epimerase
activity (Heimark, McAllister, and Larner 2014; Carlomagno,
Unfer, and Roseff 2011). In contrast, the muscle, liver, and
fat of Goto-Kakizaki diabetic rats showed increased in-vivo
myo-inositol:chiro-inositol ratios and decreased in-vivo epi-
merase activity (Sun et al. 2002; Pak et al. 1998).
We cannot rule out that differences between these studies
could possibly be due to methodological issues, but this does
not seem likely. In both cases, in-vivo epimerase activity was
quantified by measuring the conversion of myoinositol to chiro-
inositol by HPLC. The ovarian study measured the conversion
of non-labeled isotopes using an Ag/AgCl electrochemical
detector, with peak identity confirmed by GCMS and by com-
parison to known standards of myo-inositol and D-chiro-inosi-
tol. In contrast, the rat study measured the conversion of
radiolabeled inositols using a radiolabel detector, a more sensi-
tive technique which automatically adjusts for recovery losses.
Peak identity was confirmed by GCMS and by comparison to
known standards of myo-inositol, D-chiro-inositol, scyllo-inosi-
tol, neo-inositol, epi-inositol, and mucoinositol.
It is more likely that the observed differences are due to
the tissues and disorder studied. Treatment with intramus-
cular insulin increased epimerase activity in the livers of
Sprague Dawley rats suggesting that epimerase activity likely
depends on insulin availability and insulin sensitivity (Sun
et al. 2002; Pak et al. 1998). The muscle, liver, and fat of
Goto-Kakizaki diabetic rats are likely more insulin resistant
than controls, which could lead to decreased epimerase
activity. In contrast, in PCOS the ovaries, unlike other tis-
sues do not become insulin resistant, but are still exposed to
increased insulin leading to increased epimerase activity
(Carlomagno, Unfer, and Roseff 2011).
Insulin treatment also increased the conversion of total
[3H]myo-inositol to [3H]chiro-inositol in a rat fibroblast cell
line that expressed the human insulin receptor (Pak et al.
1993). However, the increase in radio-label incorporation was
mainly observed in the acid hydrolyzed lipid fraction, suggest-
ing either that epimerization occurred in phospholipids rather
than free inositol or that the insulin-promoted increase in
newly synthesized D-chiro-inositol was rapidly converted into
lipids. However, these results may be artefacts brought about
by acid treatment and further research is needed.
Controversy about epimerase activity
One study has proposed that the function of the myoinositol
epimerase in the previously described rat, ovarian and fibro-
blast studies had been misidentified, due to the mis-
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 1637
identification of the inositols involved (Lin, Ma, Gopalan,
et al. 2009). This hypothesis was based on research which
suggested that mice cannot convert myo-inositol into D-
chiro-inositol and instead rely on dietary D-chiro-inositol
(Lin, Ma, Gopalan, et al. 2009). D-chiro-inositol was found
to fall rapidly in the plasma, stools and urine of mice fed a
myo-inositol containing, but pinitol and D-chiro-inositol
deficient diet (Lin, Ma, Gopalan, et al. 2009). Moreover,
mice fed the deficient diet who were fed deuterium-labeled
water or injected intraperitoneally with [2H6]-myoinositol
produced urine that contained deuterium-labeled myo-inosi-
tol, but no deuterium labeled D-chiro-inositol.
However, such evidence alone is not strong enough to sug-
gest that the myoinositol epimerase has been mis-identified.
Instead these results could also be explained by low endogen-
ous D-chiro-inositol synthesis compared to dietary intake, the
sensitivity limits of stable isotope based analysis, differences
in mouse inositol metabolism compared to other species, or
to the metabolic consequences a pinitol and D-chiro-inositol-
deficient diet for 15 weeks prior to the measurement of the
outcome of interest. However, further research on the activity
of this epimerase in different tissues and conditions is needed
before strong conclusions can be drawn.
The synthesis of other inositol isomers
Myo-inositol is converted into scyllo-inositol by myo-ino-
sose-2 (Sherman, Stewart, Kurien, et al. 1968; Sherman,
Stewart, Kurien, et al. 1968; Hipps, Holland, and Sherman
1977; Hipps, Ackermann, and Sherman 1982). Myo-inosose-
2 is expressed in a variety of rat and rabbit tissues, but is
particularly high in brain, testis and kidneys (Sherman,
Stewart, Kurien, et al. 1968; Sherman, Stewart, Kurien, et al.
1968), suggesting an important role for scyllo-inositol in
these tissues. However, whether this is also the case in
humans remains to be established. Neo-inositol is synthe-
sized from D-mannose 6-phosphate, but the process is not
well understood (Sherman, Goodwin, and Gunnell 1971).
Myo-inositol catabolism and excretion
Myo-inositol is catabolized by myo-inositol oxygenase
(MIOX) into D-glucuronic acid (Charalampous 1959; Arner
et al. 2001). D-glucuronic acid can then be converted into
D-xylulose 5-phosphate, which enters the pentose phosphate
pathway (Charalampous 1959; Arner et al. 2001). The kid-
ney is the primary organ for myo-inositol catabolism
(Holub 1986), with proximal tubular epithelial cells being
the main site of MIOX expression (Arner et al. 2006). The
kidneys play a major role in regulating inositol excretion
with about 95% of filtered inositol being reabsorbed in iso-
lated perfused dog kidney (Troyer et al. 1986). Patients with
chronic renal failure demonstrate a systemic build-up of
inositol which resolves following renal transplantation,
showing that healthy kidney function is required for inositol
excretion (Clements Jr 1979). Nervous tissue can also catab-
olize myo-inositol and MIOX is highly expressed in the sci-
atic nerve, pigmented epithelium and lens epithelium
suggesting that local inositol content needs to be closely
regulated for optimal nervous function (Arner et al. 2006).
1638 O. C. WATKINS ET AL.
Inositol transport proteins
Inositol is hydrophilic and requires transporters to cross
membranes. Intracellular inositol concentrations are there-
fore dependent on the expression and activity of transport-
ers. The high levels of inositol in the brain and the female
reproductive organs are thought to be due to high inositol
import, rather than high local inositol synthesis (Thomas,
Mills, and Potter 2016; Berry et al. 1999; Lewin et al. 1982; Di
Daniel et al. 2009; Bourgeois, Coady, and Lapointe 2005;
Michaelis et al., 1993; Frej, Otto, and Williams 2017). Sodium/
Myo-Inositol Transporters (SMIT) are expressed in multiple
tissues among Animalia (Zerbino et al. 2018; Schneider 2015),
while proton (Hþ)/Myo-Inositol symporters (HMIT) are found
in all living organisms and are closely related to the GLUT
family of sugar transporters (Schneider 2015; Mueckler and
Thorens 2013). SMIT and HMIT are symporters, which
require a sodium or proton gradient respectively to pump
inositol into cells. The affinity of different inositol isomers to
each transporter is summarized in Table 2.
Regulation of inositol transport is important for maintaining
cell osmolality. SMIT-1 is upregulated by intracellular hyperton-
icity and downregulated by hypotonicity (Schneider 2015).
Inositol transport is also affected by volume sensitive organic
osmolyte anion channels, but the underlying mechanisms are
poorly understood (Strange et al. 1994; Isaacks et al. 1999;
Jackson and Strange 1993). Other inositol transporters are
found in plants, fungi and yeasts, but these have not yet been
described in animals and humans (Schneider 2015).
Competition between inositol isomers and other saccha-
rides for inositol transporters affects the relative uptake of
each inositol isomer. For example, the uptake of myo-inosi-
tol by SMIT-1 is inhibited by scyllo-inositol in isolated
bovine cardiac sarcolemmal vesicles (Rubin and Hale 1993),
and by scyllo-inositol and a range of other saccharides in
human embryonic HEK293 kidney cell-line (Fenili 2010).
This raises the possibility that a divergence from a normal
ratio of inositol isomers and glucose in the circulation or
renal filtrate could impact local inositol uptake and supply.
Inositol transport in pathological conditions
Disrupted inositol transport has been observed in multiple
pathological conditions, mostly involving the central nervous
system. For example, particular single nucleotide polymor-
phisms within HMIT are associated with Parkinson’s disease
(Satake et al. 2009; Gao et al. 2012). Meanwhile, the SMIT-1
gene, found on chromosome 21 (Berry et al. 1995) and
likely over-expressed in Down syndrome (trisomy 21)
(Schneider 2015; Berry et al. 1995; Fruen and Lester 1991;
Guo et al. 1997), may contribute to inositol elevation in
brain, cerebrospinal fluid, and amniotic fluid (Berry et al.
1999; Lamar et al. 2011; Santamaria et al. 2014) and an
increased risk of Alzheimer’s disease (Lamar et al. 2011).
Depressive symptoms are associated with decreased
myo-inositol in the frontal cortex of the brain (Willmroth
et al. 2007; Frey et al. 1998; Moore et al. 1999; Moore et al.
2000; Silverstone, McGrath, and Kim 2005; Coupland et al.
2005), while increased inositol in the cingulate cortex was
observed in children with mania (Davanzo et al. 2003;
Davanzo et al. 2001). Neutrophils in bipolar I disorder, but
not bipolar II disorder, expressed higher SMIT mRNA than
controls (Willmroth et al. 2007). These findings suggest
specific regional changes in inositol transport rather than
general physiological deficiency in mood disorders
(Willmroth et al. 2007; Frey et al. 1998; Moore et al. 1999;
Moore et al. 2000; Silverstone, McGrath, and Kim 2005).
Mood stabilizers lithium, valproate and carbamazepine
inhibit SMIT activity in astrocyte cultures, and decrease
brain inositol levels in bipolar disorder, suggesting a possible
mode of action for these medications (Calker and Belmaker,
2000; Silverstone, McGrath, and Kim 2005; Harwood 2005;
Lubrich and van Calker 1999; Calker and Belmaker, 2000;
Wolfson et al. 2000).
In the diabetic rat model of acute stage streptozocin-
induced hyperglycemia SMIT expression increased in the
hippocampus, while SMIT-1 knockout mice display reduced
inositol in the frontal cortex and hippocampus (Yamashita
et al. 1998). During human pregnancy, protein expression of
SMIT2 and HMIT in the placenta were downregulated with
increasing maternal glycemia and this is thought to contrib-
ute to lower placental inositol in GDM compared to controls
(Pillai et al. 2020). Such changes may be directly attributable
to glucose since glucose treatment of placental explants in-
vitro downregulated SMIT2 mRNA expression (Pillai et al.
2020). Understanding the regulation of transporter activity
is therefore important for understanding inositol-related
pathology and potential side-effects of inositol supplements
outside the target tissue.
Oral intake and absorption of inositols
Inositol hexaphosphate (phytate) is an important dietary
source of myo-inositol found in cereals and legumes
(Schlemmer et al. 2009). High fiber diets are rich in phytates
and it has been suggested that the health benefits of such
diets may be due to inositol (Prynne et al. 2010). Phytate is
broken down by intestinal microbes to release underivatized
inositol, which is then taken up by inositol transporters in
the small intestine (Grases et al. 2001; Steer and Gibson
2002). Experiments in rats have suggested that SMIT-2 in
particular maybe involved in intestinal inositol uptake
(Aouameur et al. 2007). Some studies hypothesized that
mammals may also absorb phytate directly, but more recent
work in HeLa cells suggests that most physiological phytate
is synthesized in-situ (Letcher, Schell, and Irvine 2008).
Phytate was classically thought to decrease the dietary bio-
availability of zinc, iron and copper ions, but recent studies
suggest that phytate does not usually affect mineral status in
humans (Grases et al. 2001). Dietary phytate confers protec-
tion against kidney stones, colon, lung and mammary can-
cer, and has both anti-oxidant and hypocholesterolaemic
effects (Grases et al. 2001). However, it is unclear whether
these effects are due to phytate itself or due to increased
inositol availability (Grases et al. 2001). Dietary inositol may
also originate from lipid-bound inositols, pinitol or 6-
b-galactinol (Holub 1986; Croze and Soulage 2013). Lipid-
bound inositols are particularly important, making up 56%

Figure 3. The availability of phosphoinositides (PI), phosphoinositide phosphates (PIP) and inositol phosphates, and therefore the activity of many signaling proc-
esses, is tightly regulated by metabolism. Phosphates may be selectively and specifically added to PI by kinases, or removed by phosphatases, to produce PIP such
as PIP1 and PIP2. These PIPs are cleaved by lipases to form inositol phosphates and diacylglycerol (DAG).
of the inositol in a typical American diet (Holub 1986;
Croze and Soulage 2013).
Inositol derivatives
Phosphoinositides (PI)
Inositols can be derivatized with phosphoglycerol and either
one or two fatty acids to form lyso-phosphoinositides (LPI;
also known as lyso-phosphatidylinositols) and phosphoinosi-
tides (PI; also known as phosphatidylinositol) respectively
(Traynor-Kaplan et al. 2017).
PIs are generally found at relatively low concentrations
making up only 2–12% of the total phospholipids in mam-
malian tissues (White 1973; D’Souza and Epand 2014), but
these lipids are vitally important in maintaining cell archi-
tecture, membrane function and dynamics (Di Paolo and De
Camilli 2006; Shewan, Eastburn, and Mostov 2011).
PI species are enriched in poly-unsaturated fatty acids
(PUFA), particularly at the SN2 position and 70% of all PI
species contain both arachidonic acid (an important
omega-6 PUFA) and oleic acid (Traynor-Kaplan et al.
2017; D’Souza and Epand 2014). PI metabolism therefore
regulates the cellular storage and availability of PUFA and
the synthesis of PUFA derived signaling molecules such as
eicosanoids (Traynor-Kaplan et al. 2017; D’Souza and
Epand 2014). Myo-inositol, D-chiro-inositol, scyllo-inositol
and muco-inositol have all been found in PI in mammals,
but the relative abundance of each isomer in such lipids
and the biological importance of this variation remains
unknown (Fenili et al. 2007; Freedman et al. 2014; Behuria
et al. 2018).
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 1639
Phosphoinositide phosphates (PIP) and inositol
phosphates
Phosphoinositide phosphates (PIPs) and inositol phosphates
are influential and highly energetic signaling compounds
that regulate diverse processes (Croze and Soulage 2013;
Balla 2013; Bitsanis et al. 2005). The availability of these
transient compounds is rapidly and tightly controlled by the
activity of kinases, phosphatases and lipases (illustrated for
PIP1 and PIP2 in Figure 3), enabling cells to rapidly
respond to constantly changing environments (Farese 1983).
PIPs are produced when the inositol component of PI and
LPI lipids is phosphorylated by kinases (Hansen 2015; Czech
2000). Multiple phosphates may be selectively and specifically
added in a variety of configurations and the phosphate moi-
eties of PIPs can be further phosphorylated to form high
energy pyro-phosphates (Hansen 2015; Czech 2000). PIPs can
be hydrolyzed by phospholipase C (PLC) to produce a wide
range of inositol phosphates, pyro-phosphates and diacylgly-
cerols (DAG), (Hansen 2015; Czech 2000). Inositol phos-
phates can also be produced by direct phosphorylation of
inositol (as evident in slime molds and plants) (Letcher,
Schell, and Irvine 2008), or from the further phosphorylation
of existing inositol triphosphates (in all organisms) (Letcher,
Schell, and Irvine 2008; Shears 2015). The relative amount of
PIPs and inositol phosphates compared to PI in biological
systems is difficult to quantify, because these molecules occur
at very low concentrations and are very susceptible to degrad-
ation during processing (Wenk et al. 2003; Fukami and
Takenawa 1989; Pettitt et al. 2006).
PIPs and inositol phosphates act as powerful and versatile
signals that mediate processes as varied as cell proliferation,
1640 O. C. WATKINS ET AL.
apoptosis, metabolism and motility (Hansen 2015; Balla
2013; Berridge and Irvine 1989). Individual PIPs and inositol
phosphates, have distinct bioactivities, but most provide
phosphate-ester based energetic currency for kinases (Shears
2015) and many regulate Ca2þ signaling pathways (Hansen
2015; Czech 2000). Cleavage of PIP2 for example forms
inositol 1,4,5- trisphosphate (IP3), which stimulates protein
kinase C, inducing a cascade of kinase regulated changes
(Van Sande et al. 2006; Sayers and Hanyaloglu 2018;
Berridge 2009). Interestingly, scyllo-inositol phosphates were
found to act as agonists for myo-inositol-IP3 receptors, sug-
gesting that inositol phosphates containing different isomers
might have different, or even antagonistic activities (Wilcox
et al. 1998; Brautigan et al. 2005; Lampe and Potter 1993).
Many PIPs and inositol phosphates act as second messen-
gers in hormone signaling pathways (Yamazaki, Zawalich,
and Zawalich 2010; Blazer-Yost and Nofziger 2005; Manna
and Jain 2013). For instance, the binding of insulin to tyro-
sine kinase receptors activates phosphoinositide 3 kinase
(PI3K), that phosphorylates PIP2 to form PIP3 which acti-
vates protein kinase B (PKB) causing a cascade of kinase
regulated effects (Lizcano and Alessi 2002).
Inositol phosphates may show contrasting effects on insu-
lin pathways as part of homeostatic regulation. For example,
diphosphoinositol pentakisphosphate (IP7) increases insulin
secretion, but impairs insulin signaling (Rajasekaran et al.
2018; Barker and Berggren 2013; Nagamatsu and Ohara-
Imaizumi 2007). In pancreatic b-cells, glucose increases the
synthesis of IP7 by hexakisphosphate kinase1(IP6K1) from
phytate (IP6). Increased IP7 then increases insulin secretion
enabling IP7 to regulate first phase insulin release
(Rajasekaran et al. 2018; Barker and Berggren 2013;
Nagamatsu and Ohara-Imaizumi 2007). However, IP7 itself
appears to suppress PKB activity, resulting in reduced insu-
lin signaling (Kim et al. 2019). Indeed a reduction in the
amount of IP7 via the knockdown of IP6K1 resulted in an
increase in PKB signaling in many in-vitro experiments,
while a total knockout of IP6K1 in mice was associated with
reduced insulin resistance and a phenotype resistant to
high-fat diet-induced obesity and diabetes (Kim et al. 2019;
Mackenzie and Elliott 2014). This creates an in-built auto-
crine homeostatic mechanism where the direct effects of IP7
on suppressing PKB counter-balances those of IP7-induced
insulin secretion which would induce PKB activation and
ensures responses are timely, transient and highly sensitive
to changes in the environment.
Glycosylphosphatidylinositols (GPIs)
Glycans can be attached to PIs containing myo-inositol or
D-chiro-inositol to form glycosylphosphatidylinositols
(GPIs) (Balla 2013; Tsai, Liu, and Seeberger 2012; Pak and
Larner 1992). GPIs impact diverse cellular processes and can
interact with intracellular targets, or be transported across
the cell membrane by transporters such as Glut2 to act as a
“hormone” at a distance (Mariggi o et al. 2006). GPIs can be
attached to proteins which enables these proteins to be
anchored into membranes (Paulick and Bertozzi 2008).
GPIs and GPI-anchored proteins are particularly import-
ant in signal transduction and vesicular trafficking (Paulick
and Bertozzi 2008). At a cellular level, membrane GPIs in
lipid rafts and caveolae are important for lipid raft function,
potocytosis and the regulation of Kþ and Ca2þ transport
(Reeves, Thomas, and Smart 2012; Noble, Zhang, and Wray
2006), while cleavage of GPI-anchored proteins by phospho-
lipases releases a range of signaling proteins (Low 2000).
GPIs are also involved in many key physiological functions
of the body, as well as pathophysiological processes. GPIs in
sperm are essential for egg fertilization, while GPIs synthe-
sized by macrophages modulate immune cell function
(Kondoh et al. 2005; Patrussi et al. 2013). During infection,
GPIs produced by protozoan parasites such as Plasmodium
and Trypanosoma, induce the pathological production of
cytokines, chemokines and nitric oxide (NO) by the host
eliciting clinical symptoms such as hypoglycemia, acidosis or
anemia (Debierre-Grockiego and Schwarz 2010). Several
GPIs are also currently under investigation as malaria vac-
cine candidates (Malik et al. 2020). The generation of abnor-
mal GPI-anchored proteins has also been observed in prion
disease (Simons and Ehehalt 2002).
Inositol phosphoglycans (IPGs) and inositol glycans
The lipid moiety of GPIs may be cleaved off by phospholip-
ase C or D (PLC, PLD) to form inositol phosphoglycans
(IPGs) and inositol glycans (Huang et al. 1993; Larner,
Brautigan, and Thorner 2010; Croze and Soulage 2013;
Kunjara et al. 1999; Nestler and Unfer 2015). Historically it
has been difficult to differentiate between IPGs and inositol
glycans, and these classes are often not distinguished in pub-
lished work. IPGs and inositol glycans commonly act as
insulin second messengers, but they can also act as insulin
mimics independently from insulin, whilst also having non-
insulin related effects (Larner, Brautigan, and Thorner 2010;
M€ uller et al. 1998). These molecules are thought to regulate
enzymes by acting as catalytic chelators, coordinating the
traffic of Mn2þ and Zn2þ within cells, enabling them to
control kinase activity and a cascade of downstream effects
(McLean et al. 2008).
As well as having local effects, IPGs and inositol glycans
may be released into the circulation as signals to other tis-
sues (McLean et al. 2008; Alvarez et al. 1991; Turner,
Chakraborty, and d’Alarcao 2005). The origin of IPGs and
inositol glycans in the circulation is still unclear, but the
process appears to be regulated by insulin (Scioscia 2017;
Scioscia et al. 2013; Kunjara, Greenbaum, et al. 2000).
Glucose consumption was associated with a spike in circu-
lating IPG (Baillargeon et al. 2006), while IPG release into
muscle could be induced by the administration of insulin
during euglycemic-hyperinsulinemic-clamp studies
(Kennington et al. 1990). Furthermore, IPG release by cul-
tured placental trophoblast microvillous membranes could
be induced by the addition of insulin to culture media
(Scioscia et al. 2006; Scioscia et al. 2008).
Insulin activates phospholipase C and D, so it has been
suggested that increases in IPG and inositol glycans are due
to increased cleavage of GPI, enabling IPGs to act as an

insulin second messenger (Kennington et al. 1990; Pak et al.
1993; Goel and Azev 2009; Nascimento et al. 2006).
However, IPG availability will likely also be regulated by
GPI availability, IPG transport and IPG metabolism and lit-
tle is known about how these processes are altered by insu-
lin. Experiments in primary rat hepatocytes demonstrated
that radiolabeled IPGs can be transported into cells through
an energy-dependent IPG transporter, but nothing else is
known about the transport of these molecules (Alvarez et al.
1991). IPGs may also affect cellular function by interacting
with external cell surface receptors, with fluorescently-
labeled IPG stimulating lipogenesis in a rat adipocyte cell
line, despite an inability to enter the cell (Turner,
Chakraborty, and d’Alarcao 2005).
P-IPGs and A-IPGs
The structure of most IPGs and inositol glycans is unknown
(Larner, Brautigan, and Thorner 2010; M€ uller et al. 1998) so
these molecules are classified based on their biochemical prop-
erties and our ability to separate them into two fractions. The
first fraction (P-IPGs) elutes at pH 2.0 and activates pyruvate
dehydrogenase (an enzyme that links the glycolysis metabolic
pathway to the citric acid cycle via the production of acetyl-
CoA), while the second fraction (A-IPGs) elutes at pH 1.3 and
inhibits protein kinase A (an enzyme that modulates glucose
and lipid metabolism) (Larner, Brautigan, and Thorner 2010).
These IPG fractions likely contain both IPGs and inositol gly-
cans, but little is known about the relative amounts of each.
Generally, the levels of P-IPG and A-IPG have been quantified
by testing these fractions using enzymatic assays (e.g. for pyru-
vate dehydrogenase activation activity), or by measuring the
amount of inositol in these fractions by techniques such as Gas
Chromatography Mass Spectrometry (GCMS) (Paine et al.
2006). An antibody-mediated assay is also available, but only
for a pregnancy-specific P-IPG, and this test only works in
urine and not plasma or serum samples (Paine et al. 2003).
Hence, the development of more discriminatory tests are sorely
needed to better characterize IPGs and inositol glycans.
P-IPGs and A-IPGs were classically thought to contain D-
chiro-inositol and myo-inositol respectively, but current evi-
dence suggests that both classes contain a range of inositol
and inositol phosphate isomers bound to a range of glycans
and phosphoglycans, and that many of these compounds
have different effects even when they are from the same
fraction (Asplin, Galasko, and Larner 1993; Elased et al.
2001). P-IPG fractions from human hemodialysate have a D-
chiro-inositol:myo-inositol ratio of 1.19, whilst those from
skeletal muscle extracts have a ratio of 9.42 (Asplin, Galasko,
and Larner 1993) suggesting that IPG composition varies
between biological fluids and tissue types.
The composition and structures of some IPGs have been
investigated more closely. For instance, one compound named
INS-2 was isolated from the P-IPG fraction of bovine liver and
was found to contain galactosamine, pinitol and Mn2þ
(Larner, Brautigan, and Thorner 2010; Larner et al. 2003)).
The structure of this molecule was subsequently confirmed by
the synthesis of an analogue with identical biological properties
(Larner, Brautigan, and Thorner 2010; Larner et al. 2003).
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 1641
Methylated inositol derivatives such as pinitol, sequoyitol and
bornesitol are well known plant secondary metabolites
(Owczarczyk-Saczonek et al. 2018), but the origin of mamma-
lian pinitol is uncertain and could be dietary or endogenously
synthesized (Lin, Ma, Gopalan, et al. 2009).
Another compound extracted from a malarial parasite P-
IPG fraction was found to contain myo-inositol, phos-
phorus, galactosamine, glucosamine, and glucose (Elased
et al. 2001). Meanwhile the makeup of A-IPGs is particularly
unclear with some appearing to contain myo-inositol, glu-
cosamine, galactose and ethanolamine (Larner, Brautigan,
and Thorner 2010).
IPGs influence glucose and lipid metabolism
IPGs alter glucose and lipid metabolism in similar ways to
insulin, leading these molecules to be classified as insulin
mimics. For example, both P-IPG and A-IPG fractions and
INS-2 (a synthetic P-IPG) stimulated the incorporation of
labeled glucose into glycogen in rat diaphragm muscles,
hepatoma cells, erythroleukemia cells and rat primary adipo-
cytes (Huang et al. 1993; Larner et al. 2003; Lazar et al.
1994; Lawrence, Guinovart, and Larner 1977). Furthermore,
P-IPG fractions purified from human plasma or bovine liver
and synthetic INS-2 stimulated glucose oxidation and lipo-
genesis in a variety of model systems (Larner, Brautigan,
and Thorner 2010; Kunjara, Greenbaum, et al. 2000; Elased
et al. 2001; Larner et al. 2003; Galasko et al. 1996).
Moreover, the A-IPG fraction tested in a variety of assays
also increased lipid synthesis by decreasing the amount of
fatty acids directed toward b oxidation by activating acetyl-
CoA carboxylase (ACC) (Huang et al. 1993; Kunjara et al.
1999) and lowered lipolysis by activating cAMP-phospho-
diesterase (Larner, Brautigan, and Thorner 2010; Kunjara
et al. 1999; Scioscia 2017; Caro et al. 1997; Scioscia, Gumaa,
and Rademacher 2009; Witters and Kemp 1992).
P-IPG can also stimulate the activity of several other
regulatory molecules within the insulin signaling pathway
including Phosphatidyl Inositol 3-Kinase (PI3K), Protein
Kinase B (PKB) and Insulin Receptor Substrate (IRS) pro-
teins (Larner, Brautigan, and Thorner 2010; Kunjara et al.
1999; Scioscia 2017; Varela-Nieto, Le on, and Caro 1996;
Burton, Scioscia, and Rademacher 2011) and thus could
potentially enhance insulin actions, as well as act as insulin
mimics in their own right. INS-2, for example was just as
effective as insulin in stimulating testosterone production by
human ovarian thecal cells in-vitro, and the effect of insulin
could be blocked by an anti-INS-2 polyclonal antibody sug-
gesting that INS-2 is critical to this signaling pathway
(Nestler et al. 1998).
IPGs can also show anti-insulin-like effects. For example
the A-IPG fraction was found to inhibit adenylate cyclase
(which is normally activated by insulin) and protein kinase
A (which normally stimulates insulin secretion) in multiple
assays (Larner, Brautigan, and Thorner 2010; Kunjara et al.
1999; Scioscia 2017; Caro et al. 1997; Scioscia, Gumaa, and
Rademacher 2009; Villalba, Kelly, and Mato 1988; Scioscia,
Gumaa, et al. 2007). The A-IPG fraction could also decrease
glucose oxidation by antagonizing the in-vitro stimulation of
1642 O. C. WATKINS ET AL.
the PDH phosphatase by P-IPG (Kunjara et al. 1999;
Kunjara, Greenbaum, et al. 2000). IPGs also modulate the
actions of other hormones besides insulin, with A-IPG
inhibiting leptin release from cultured non-pregnant rat adi-
pocytes (Kunjara, Greenbaum, et al. 2000). IPGs are there-
fore important regulators of both glucose and lipid
metabolism through insulin-dependent and independent
mechanisms (Nestler et al. 1998).
Synthetic GPIs and IPGs and the relationship between
structure and function
Since the isolation and structural elucidation of natural IPGs
has been difficult, chemists have produced a range of syn-
thetic GPIs, IPGs and inositol glycans in order to better
understand structure-function relationships and identify pos-
sible drug candidates (Larner, Brautigan, and Thorner 2010;
Goel and Azev 2009; Suzuki et al. 2014). While many of
these candidates showed insulin mimetic activity in various
assays, the strength of the effect, and whether the effect was
on glucose, glycogen or lipid metabolism varied by molecu-
lar structure (Larner, Brautigan, and Thorner 2010; Goel
and Azev 2009; Suzuki et al. 2014). These effects were
reviewed by Goel et.al. (Goel and Azev 2009), who found
that high insulin-like activity was more often found for
compounds containing a cyclic phosphate on the inositol, an
unacylated amino group on the second sugar, and a
phosphonate, phosphate or sulfate on one or more of the
mannose residues (Goel and Azev 2009). Hence, it seems
likely that natural GPIs and IPGs will play a wide range of
roles in glucose and lipid metabolism and insulin signaling.
However, these will not be fully understood until the effects
of individual IPGs rather than broad class effects can be reli-
ably quantified.
Inositols influence lipid metabolism, transport
and storage
Inositol and its derivatives regulate lipid mobilization, trans-
port and storage, but effects vary depending on the organ
and model studied. There is some evidence that myo-inosi-
tol supplementation reduces circulating triglycerides, and
total and LDL cholesterol levels in patients with metabolic
diseases such as diabetes, GDM, PCOS and metabolic syn-
drome (Tabrizi et al. 2018). Myo-inositol supplementation
appears to alter body wide lipid distribution and, in general,
causes more lipids to be stored in adipose tissue and less to
be stored ectopically in the liver and other areas, but this
varies depending on the model studied as discussed below
(Hayashi et al. 1978).
Lipid storage and myo-inositol in animal models
Various animal models have been utilized to examine myo-
inositol’s effect on lipid storage and body-wide distribution.
Myo-inositol deficiency in gerbils caused a decrease in
plasma lipids and lipoproteins, but increased lipid storage in
large lipid droplets in intestinal mucosal cells leading to the
development of intestinal lipodystrophy (Hegsted et al. 1973;
Chu and Hegsted 1980). In many rat experiments, myo-
inositol deficiency was associated with increased adipose tis-
sue lipid mobilization and increased hepatic triacylglycerol
(TAG) and cholesterol ester (CE) accumulation while myo-
inositol supplementation reversed these effects (Hayashi
et al. 1978; Andersen and Holub, 1980; Burton and Wells
1976; Best et al. 1946; Gavin and McHenry 1941).
Alterations to lipid metabolism appeared fatty acid specific,
and in rats fed inositol-deficient diets liver phospholipids
contained less linoleic acid whilst TAGs contained more pal-
mitoleic acid (Andersen and Holub 1976; Andersen and
Holub, 1980). Increased lipid storage in adipose tissue,
rather than ectopically in liver, muscle or other organs is
known to associate with decreased cardiometabolic adversity,
suggesting that this myo-inositol effect may be beneficial
(Hayashi et al. 1978; Gaggini, Saponaro, and Gastaldelli
2015). However, overall increased obesity could itself lead to
negative outcomes and even alter responses to myo-inositol.
Differential lipid storage responses to myo-inositol
with obesity
The effects of myo-inositol on adipose tissue appear to be
opposite in obese rodent models compared to non-obese
models. Myo-inositol supplementation of a non-pregnant
high fat diet obese adult mouse model was associated with
reduced fat accretion in white adipose tissue and a partial
normalization of plasma leptin concentrations (Croze,
Gelo€en, and Soulage 2015). Similarly, myo-inositol supple-
mentation in obese PCOS patients, was found to signifi-
cantly decrease body mass index (BMI) and circulating
leptin concentrations (Gerli et al. 2007). However, it is
unclear whether this reduction in adipose tissue fat accretion
is protective (from obesity-related pathology), or whether it
is harmful (by increasing ectopic lipid accretion). It is not
known why obesity alters the effect of myo-inositol on adi-
pose tissue. Adipocytes from obese populations tend to be
more insulin resistant and have low liposynthetic capacity
and high lipolytic capacity (Zhang and Zhang 2010), and
thus might be less likely to respond to insulin-dependent
inositol effects while being more likely to release free fatty
acids. Adipose tissue in obese populations also shows more
pro-inflammatory activity (Zhang and Zhang 2010), which
may be altered by inositols. Indeed other studies have sug-
gested a role for inositol in many immune and inflammatory
processes (Krystal 2000; Miller, Chamberlain, and Cooke
2008). Hence, obesity modifies the responses of adipose tis-
sue to myo-inositol, and understanding how this occurs will
enable the development of strategies to enhance the benefits
of myo-inositol supplementation in obese populations.
Myo-inositol status and lipid mobilization during preg-
nancy and lactation
Myo-inositol and lipid mobilization have also been specific-
ally investigated in the context of pregnancy and lactation.
Rats given a myo-inositol deficient diet during pregnancy
until 49 days after the birth, developed fatty liver only dur-
ing lactation and these changes were reversed by treatment

with inositol or by the cessation of lactation (Burton and
Wells 1977). This suggests that myo-inositol deficiency is
more dangerous during periods of massive lipid mobiliza-
tion from adipose tissue, such as during lactation (Oben
et al. 2010; Vernon 2005). The livers of these myo-inositol-
deficient lactating rats showed increased numbers of intra-
cellular lipid droplets, which were larger and contained
more cholesterol-ester and TAG, but less cholesterol and PI
(Burton and Wells 1977). Interestingly, no difference in lip-
ids was seen in kidney or intestinal tissues, suggesting a
liver-specific effect (Burton and Wells 1977). Lactating rats
supplemented with inositol and given radiolabeled palmitic
acid showed decreased radiolabeled liver TAG, but increased
radiolabeled serum TAG compared to animals given an
inositol-deficient diet (Burton and Wells 1979). Together
these findings again suggest inositol selectively modulates
lipid transfer and storage around the body producing differ-
ent effects in different organs and different effects depending
on the population studied.
Mechanisms of myo-inositol regulation of lipid mobiliza-
tion and distribution
Myo-inositol-deficient rats showed increased hepatic fatty
acid synthetase and acetyl-CoA carboxylase (ACC) activity,
which could explain the increase in hepatic lipogenic activity
(Beach and Flick 1982). Myo-inositol deficiency in yeasts
also increased ACC activity, resulting in an accumulation of
neutral lipids and this effect was reversed when the defi-
ciency was rectified by myo-inositol treatment (Hayashi,
Hasegawa, and Tomita 1976). In contrast, mouse adipocyte
cells treated with myo-inositol in-vitro showed increased
lipid accumulation due to increased fatty acid synthase
expression and reduced lipolysis (Kim, Han, and Kim 2014).
Collectively, these studies suggest that myo-inositol may
potentially reduce ectopic fat deposition by mobilizing lipid
stores in the liver, which is an ectopic site, and increasing
adipose tissue stores, although this needs to be validated in
further studies.
In addition, myo-inositol effects may interact with the auto-
nomic nervous system. Plasma adrenalin levels were higher in
myo-inositol-deficient rats, suggesting that myo-inositol may
affect the autonomic nervous system and hormonal regulation
(Hayashi et al. 1978). Moreover, administration of sympathetic
nervous system blockers to myo-inositol-deficient rats inhibited
hepatic lipid deposition and increased serum free fatty acids
(Holub 1986; Hayashi et al. 1978), indicating that sympathetic
nervous activity also modulates myo-inositol effects.
Inositol may also impact cholesterol and lipoprotein metab-
olism (Hayashi et al. 1978; Burton and Wells 1977). Myo-inosi-
tol-deficient rats showed increased plasma hormone-sensitive
lipase activity in epididymal adipose tissues, which would
increase the local breakdown of circulating lipoproteins and
increase lipid uptake (Hayashi et al. 1978). Myo-inositol defi-
cient rats also showed reduced plasma lecithin–cholesterol acyl-
transferase (LCAT) activity suggesting decreased cholesterol
ester and lipoprotein formation (Burton and Wells 1977; Wells
and Hogan 1968). Additionally, intravenous injection of PI
into rabbits inhibited the transfer of hepatocyte cholesteryl
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 1643
esters into the blood stream and increased hepatic uptake of
plasma cholesterol and cholesterol biliary secretion (Burgess
et al. 2003; Stamler et al. 2000). Plasma from rabbits treated
with PI also showed lower LCAT activity within 10 minutes of
PI injection. Since PI will not be converted into myo-inositol
in this short period, it seems likely that PI, rather than unes-
terified inositol, is responsible for altered cholesterol metabol-
ism. Inositols also appear to regulate the synthesis and
hydrolysis of PI (Strieleman et al., 1992; Wentzel et al. 2001;
Salman et al. 1999). Scyllo-inositol for example inhibited the
incorporation of myo-inositol into PI and the hydrolysis of
PIP into myo-inositol phosphates in the developing rat concep-
tus (McPhee, Downes, and Lowe 1991). D-chiro-inositol mean-
while, was found to be a potent inhibitor of mycobacterial PI
synthase (Salman et al. 1999). Overall, how inositols and their
derivatives are involved in lipid metabolism in different species,
metabolic conditions, tissue types, and various stages of devel-
opment is still not well understood and further research is
necessary. The effects of inositol supplementation on lipid
metabolism in GDM pregnancy will be discussed in section
“Inositol and fetal development.”
The anti-oxidant effects of inositol
Inositols can act as anti-oxidants and reactive oxygen species
(ROS) scavengers (Valluru and Van den Ende 2011; Hu,
Chen, and Lin 1995). In Jian carp, myo-inositol was shown to
increase enzymatic anti-oxidant capacity by altering the activ-
ity of catalase, glutathione peroxidase and glutathione reduc-
tase superoxide dismutase and glutathione-S-transferase (Jiang
et al. 2009). Furthermore one small study also suggested that
there is an increase in thiol oxidation and oxidative stress in
the follicular fluid of patients with PCOS compared to con-
trols and that this oxidation was reduced by the administra-
tion of D-chiro-inositol (De et al. 2012; Dona et al. 2012).
Uncomplicated pregnancy, pre-eclampsia, diabetic pregnancy,
GDM and diabetes in non-pregnant populations are also all
associated with increased oxidative stress in general (Wentzel
et al. 2001; Burton and Jauniaux 2004; Jenkins et al. 2000;
Eriksson and Borg 1991; Eriksson and Borg 1993; Wentzel,
Welsh, and Eriksson 1999; Trocino et al. 1995; Newsholme
et al. 2007), but further research is needed to determine how
this is related to inositol dysregulation.
Inositols are important for male fertility, testicular func-
tion and spermatogenesis (Steegers-Theunissen, Groenen,
and Beemster 2002; Condorelli et al. 2017) and a small clin-
ical study showed that myo-inositol supplementation could
be used to treat idiopathic male infertility (Calogero et al.
2015). The biology behind this is not yet known, but it has
been suggested that the anti-oxidant effects of inositol may
play an important role (Colone et al. 2010). In particular,
in-vitro myo-inositol treatment of spermatozoa reduced ROS
activity and mitochondrial cristae damage and reduced the
number of spermatozoa covered with amorphous fibrous
material, which gives an excessive viscosity to the seminal
fluid that increases subfertility (Colone et al. 2010).
1644 O. C. WATKINS ET AL.
Inositol in diabetes mellitus
Inositol bioavailability is altered in diabetes
Circulating and urinary D-chiro-inositol and myo-inositol
levels are altered in adult type 1 and type 2 diabetes popula-
tions compared with non-diabetic controls (Table 3), with
most studies reporting decreased urinary D-chiro-inositol
and increased urinary myo-inositol in both types of diabetes.
However, two studies on overweight and obese populations
found an increase in both urinary D-chiro-inositol and
myo-inositol (Ostlund et al. 1993; Jung et al. 2005). This dif-
ference was discussed by Larner et.al. 2010, who noted that
D-chiro-inositol excretion also increased with increasing
obesity and insulin resistance in PCOS. A similar increase is
also observed in GDM as discussed in section “Maternal
inositols in an uncomplicated pregnancy and lactation.”
Taken together, it appears that diabetes, obesity and PCOS
may each have different and independent associations with
circulating and urinary inositol concentrations.
Obesity alters the relationship between inositols and dia-
betes. The differences in systemic inositol concentrations
between obese and normal weight diabetes populations is also
apparent in animal studies (Table 4). Studies using rodent mod-
els of diabetes associated with obesity such as streptozocin-
treated rats and db/db mice, showed increased urinary D-chiro-
inositol and myo-inositol compared with non-diabetes controls
(Kawa, Przybylski, and Taylor 2003). In contrast, those from
the non-obese Goto-Kakizaki diabetic rat model showed
decreased urinary D-chiro-inositol and increased myo-inositol
compared with controls (Suzuki et al. 1991). These findings fur-
ther support the idea that obesity may modify the associations
of inositol dysregulation with the diabetic state.
However, most previous human and animal studies did
not adequately adjust for BMI or bodyweight as a covariate,
nor use weight-matched controls. Many studies also defined
their study populations by insulin-dependence which makes
it difficult to discern the associations of inositol alterations
with different subtypes of diabetes or treatments. Many of
the patients were also taking oral hypoglycemic agents, with
or without insulin, but these populations were not analyzed
separately. Further research will be necessary to determine
how inositol bioavailability and action is altered in diabetes
in different patient populations, the direction of causality
and to determine whether urinary or circulatory inositols
could be used as a tool to screen for, monitor treatment and
assess progression of diabetes.
Inositol correlations with degree of insulin resistance.
Changes in systemic and local inositol levels in diabetes are
strongly correlated with disease severity and insulin resist-
ance. For example, in spontaneously diabetic rhesus mon-
keys, the urinary D-chiro-inositol excretion rate is directly
correlated with insulin-mediated glucose disposal rates and
glucose tolerance (Ortmeyer, Huang, et al. 1993). Urinary
D-chiro-inositol was also correlated with increased glycogen
synthetase activity in skeletal muscle and adipose tissue, and
decreased activity in glycogen phosphorylase in skeletal
muscle (Ortmeyer, Huang, et al. 1993). This suggests D-
chiro-inositol itself could be involved in the regulation of
glycogen synthesis, which is known to be impaired in type 2
diabetes (Ashcroft et al. 2017; Cline et al. 1999). In humans,
urinary D-chiro-inositol was also strongly correlated with
fasting plasma glucose, glycated hemoglobin and urinary
glucose, and the urinary increase in D-chiro-inositol with
diabetes was reversed by insulin treatment (Ostlund et al.
1993). Although this suggests that increased D-chiro-inositol
excretion may cause or be caused by insulin deficiency or by
hyperglycemia, it does not exclude the possibility that
increased D-chiro-inositol excretion is an adaptive or pro-
tective response against diabetes-induced complications or
could result from diabetes-related secondary pathology.
Tissue inositol content in diabetes. In humans, how tissue
inositol content is changed with diabetes is not known. A
few studies (Asplin, Galasko, and Larner 1993; Kennington
et al. 1990) measured the myo-inositol and D-chiro-inositol
content in IPG fractions in human muscle tissue (see Table
5), but IPGs represent only a small fraction of the total
inositol present in cells and biological systems, and IPG
quantification cannot show if diabetes is associated with
general tissue inositol deficiency. In animal studies strong
evidence for myo-inositol depletion in diabetes is only pre-
sent for nervous tissue (Table 4). Further studies are needed
to determine how inositol metabolism is changed in both
type 1 and type 2 diabetes and how this is altered by insulin,
oral hypoglycemic or lifestyle/dietary treatments. Findings
will depend on how well inositol isomers are separately
quantified and what inositol derivatives are included in the
extraction and analysis methods.
IPGS and diabetes
IPGs are a diverse group of compounds, which can regulate
glycemic and lipidomic pathways (Larner, Brautigan, and
Thorner 2010), and are altered in diabetes (Table 5).
Urinary and tissue P-IPGs are generally decreased in type 2
diabetes (Asplin, Galasko, and Larner 1993; Kunjara et al.
1999; Kennington et al. 1990), whilst urinary and tissue A-
IPGs are increased, but findings varied depending on the
population studied and the analysis method (Table 5). In
one study, the urinary P-IPG:A-IPG ratio was decreased in
diabetes and the ratio was negatively correlated with a rise
in systolic blood pressure, BMI and hemoglobin-A1c
(HbA1c), which are all markers of worsening metabolic syn-
drome (Kunjara et al. 1999). P-IPG has insulin-like effects
(Kunjara et al. 1999; Scioscia 2017; Scioscia, Gumaa, and
Rademacher 2009), so a decrease in P-IPG may promote
diabetogenic effects. A-IPG in contrast, may direct metabol-
ism away from glucose oxidation and toward energy conser-
vation and lipid storage promoting a diabetic phenotype
(Kunjara et al. 1999; Scioscia 2017; Kunjara, Greenbaum,
et al. 2000; Scioscia, Gumaa, and Rademacher 2009).
However, P-IPG and A-IPG fractions both contain many
different myo-inositol, D-chiro-inositol and pinitol

containing IPGs with a range of bioactivities. Until these
can be separately analyzed, and their individual effects quan-
tified, it will be difficult to deepen our understanding of the
role of these molecules in diabetes.
IPG concentrations display sex differences. Urinary A-
IPG is five-fold higher in healthy female urine than healthy
male urine samples and there is a decrease in the P-IPG:A-
IPG ratio in women compared with men (Kunjara,
Greenbaum, et al. 2000), yet most studies do not take these
sex differences into account. Further studies accounting for
sex, type of diabetes, diabetic treatment and BMI are needed
to understand how IPGs are altered in different tissues and
bodily fluids in type 1 and type 2 diabetes.
Alterations in inositols in diabetes: pathological
or adaptive?
Although inositols participate in numerous insulin, glucose
and lipid metabolic pathways, (Yamazaki, Zawalich, and
Zawalich 2010; Manna and Jain 2013; Coustan 2013) it is
not known if these inositol perturbations have an etiological
role in any diabetic features, or if they are a consequence of
the pathology. These inositol-related changes could even be
protective. For example, myo-inositol-derived PIP3 enhances
the transport of glucose into cells by stimulating the trans-
location of GLUT4 to the cell membrane (Paul and Brady
2015). One simple perspective is that a decrease in tissue
myo-inositol and consequently PIP3 could therefore
decrease glucose uptake and promote hyperglycemia, contri-
buting to diabetes pathology. However, a decrease in tissue
myo-inositol could also result in lower intracellular glucose
levels, protecting specific cells from glucose overload in the
context of hyperinsulinemic hyperglycemia. The association
between inositol perturbations and diabetes is also likely tis-
sue-specific and influenced by many factors such as type of
diabetes, BMI or ethnicity.
Inositols as treatment for diabetes in humans
In general, inositol supplementation appears to reduce gly-
cemia and increase insulin sensitivity, suggesting that inosi-
tol supplementation could suppress diabetic features even in
the absence of inositol deficiency. A systematic review and
meta-analysis that included 20 RCTs with a total of 1239
subjects with different types of insulin resistant conditions,
which studied the effects of inositol on glucose homeostasis,
showed that inositol treatment decreased fasting plasma glu-
cose (mean difference [MD]
0.44 mmol/l, 95% CI
0.65,

0.23), 2 h plasma glucose after a 75 g oral glucose load
(MD
0.69 mmol/l, 95% CI
1.14,
0.23), the incidence of
abnormal glucose tolerance (relative risk [RR] 0.28, 95% CI
0.12, 0.66), fasting insulin (MD
38.49 pmol/l, 95% CI

52.63,
24.36) and the Homeostatic Model Assessment of
Insulin Resistance (HOMA-IR) (MD
1.96, 95% CI
2.62,

1.30) (Mi~ nambres et al. 2019). However, this review
included an extremely heterogeneous set of studies and did
not analyze the effects of inositol in diabetes separately from
the effects of other insulin resistant conditions such as
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 1645
PCOS. Furthermore, this review did not adequately differen-
tiate between the use of different types of inositol interven-
tions, although most utilized myo-inositol.
Trials including D-chiro-inositol supplementation are
scarce. One small trial involving twenty men with type 2
diabetes showed that the administration of both myo-inosi-
tol and D-chiro-inositol in combination for three months,
lowered fasting blood glucose and HbA1c levels compared
to pretrial baseline (Pintaudi, Di Vieste, and Bonomo 2016).
A separate 24 weeks’ long RCT involving 26 overweight
patients with type 1 diabetes tested the effect of D-chiro-
inositol (1 g, plus 400 mcg folic acid daily) compared to a
folic acid control (Maurizi et al. 2017). A significant reduc-
tion in HbA1c level was seen in the treated group compared
with control, but no significant reduction in BMI or insulin
requirements was observed (Maurizi et al. 2017).
Several studies of patients with type 2 diabetes (Kim et al.
2005; Kang et al. 2006; Kim et al. 2012; Kim et al. 2007) and
non-diabetic adults (Hernandez-Mijares et al. 2013), sug-
gested that pinitol (3-O-methyl-D-chiro-inositol) can also
improve glycemic control. However, small studies in non-
diabetic older subjects (66 ± 8 years) (Campbell et al. 2004)
and non-diabetic obese subjects (Davis et al. 2000), sug-
gested that pinitol treatment had no impact on fasting glu-
cose, insulin-mediated glucose disposal, or plasma lipids.
Therefore, whilst these initial small studies show promise
and whilst there has been no mention of serious adverse
effects, larger randomized controlled double-blind trials are
required to determine whether treatment with any inositol
isomer or inositol derivative could be used to reduce dia-
betes risk, or to complement current established treatments
for diabetes and other conditions of insulin dysregulation.
Inositols as treatment for diabetes in animal models
and possible mechanisms of action
D-chiro-inositol treatment lowered postprandial glycemia in
streptozocin-induced hyperglycemic rats, wild-type rats and
rhesus monkeys with varying degrees of spontaneous insulin
resistance (Ortmeyer, Huang, et al. 1993; Hansen and
Bodkin 1986). Furthermore, in obese insulin-resistant mon-
keys, myo-inositol or D-chiro-inositol supplementation
decreased postprandial plasma glucose concentrations, while
myo-inositol also decreased urinary glucose (Ortmeyer
1996). Meanwhile, the supplementation of streptozotocin
and high fat diet induced diabetic rats with myo-inositol
decreased fasting glycemia, HOMA-IR and plasma insulin
compared with diabetic controls (Antony et al. 2017).
Supplementation of diabetic rats with myo-inositol has
also been associated with an improvement in several other
diabetic-associated changes including glomerular filtration
rate, serum urea, creatinine and arachidonic acid, urinary
albumin, IgG excretion, endoneural blood flow and motor
nerve conduction velocity (Antony et al. 2017; Carlomagno
and Unfer 2011; Pugliese et al. 1990; Coppey et al. 2002;
Solomonia et al. 2010; Mayer and Tomlinson 1983; Yue
et al. 1989). In obese insulin-resistant monkeys, neither D-
chiro-inositol nor myo-inositol altered post-prandial
1646 O. C. WATKINS ET AL.
circulating insulin levels, suggesting that inositol may have
an effect on downstream insulin pathways (Ortmeyer 1996).
In streptozotocin and high fat diet induced diabetic rats,
myo-inositol treatment increased the adipose tissue expres-
sion of PPARc and significantly upregulated GLUT4 and
insulin receptor signaling molecules, leading to the sugges-
tion that myo-inositol acts as a PPARc agonist (Antony
et al. 2017).
Injected intravenously, both A-IPG and P-IPG fractions
from various natural sources (Elased et al. 2001; Larner
et al. 2003) and synthetic INS-2 (Larner et al. 2003) could
also dose-dependently reduce hyperglycemia in streptozocin-
induced diabetic rats (Larner et al. 2003), db/db mice, and
ob/ob mice (Elased et al. 2001), suggesting that IPGs may be
partly responsible for the insulin like effects of inosi-
tol treatment.
Myo-inositol may also decrease glycemia by reducing
dietary glucose absorption in rats (Chukwuma, Ibrahim, and
Islam 2016). Myo-inositol was found to inhibit duodenal
glucose absorption, reduce post-prandial glucose excursions,
delay gastric emptying and accelerate intestinal transit in
both normal and diabetic (fructose-fed and streptozocin-
injected) rats (Chukwuma, Ibrahim, and Islam 2016). These
effects were observed both in ex-vivo studies where isolated
rat jejunum were treated with increasing concentrations of
myo-inositol and in-vivo in rats given oral myo-inositol co-
administrated with glucose (Chukwuma, Ibrahim, and
Islam 2016).
Proposed mechanisms underlying inositol dysregulation
in diabetes
Myo-inositol depletion by increased excretion. It has been
suggested that systemic myo-inositol deficiency could result
from increased urinary inositol excretion due to increased
competition with glucose for transporters during renal tubu-
lar reabsorption of the glomerular filtrate (Daughaday and
Larner 1954; Kennington et al. 1990; Baillargeon et al.
2006), resulting in reduced inositol reabsorption (Asplin,
Galasko, and Larner 1993; Thomas, Mills, and Potter 2016;
Bourgeois, Coady, and Lapointe 2005). However, hypergly-
cemia is not always associated with increased urinary inosi-
tol excretion, nor with systematic inositol deficiency or
universally decreased tissue inositol (Table 4), and there is
variation between isomers, suggesting alterations in circulat-
ing inositols in diabetes are due to more complex processes
(Loy et al. 1990).
Strong evidence for myo-inositol depletion in diabetes is
so far only evident for nervous tissue (Table 4). Myo-inositol
is consistently depleted in the nervous tissue of diabetic rats
and rabbits across studies (Greene et al. 1987; Loy et al.
1990; Palmano, Whiting, and Hawthorne 1977; Zhu and
Eichberg 1990; Greene, De Jesus, and Winegrad 1975;
Greene and Mackway 1986), while human retinal pigment
epithelial cells incubated in high glucose showed decreased
myo-inositol content and decreased PI synthesis (Thomas
et al. 1994; Thomas et al. 1993; Del Monte et al. 1991;
Nakamura et al. 1992). However, since inositol synthesis
(Stewart, Sherman, and Harris 1970), catabolism (Arner
et al. 2006) and transport (Berry et al. 1999) processes are
particularly active in nervous tissue, this tissue is unlikely to
be representative of changes occurring in other tissues
in diabetes.
Altered transporter protein activity. Tissue inositol content
is regulated by inositol transporter proteins with varying
affinities for different inositol isomers. These transporters’
different isomeric specificity (Table 2) may partly explain
the different D-chiro-inositol and myo-inositol profiles in
diabetes. Meanwhile, at a systemic level, altered intestinal or
kidney transport could lead to altered inositol absorption
and excretion, and hence, systemic inositol concentrations.
Skeletal muscle SMIT-2 activity is upregulated by insulin, as
evidenced by an 18-fold increase in D-chiro-inositol trans-
port in insulin-treated rat skeletal muscle cells that were
transiently transfected with human SMIT-2 (Lin, Ma,
Gopalan, et al. 2009). In contrast, tumor necrosis factor a
(TNFa), a critical factor in the pathophysiology of diabetes
mellitus (Navarro-Gonzalez et al. 2009), caused a decrease in
SMIT-1 mRNA expression and activity in adipocytes (Yorek,
Dunlap, and Lowe 1998). Differential alterations in locally
regulated inositol transporter activity could therefore lead to
varying disruptions in inositol content in tissues.
Dysregulated inositol metabolism. Inositol concentrations in
diabetes are locally controlled by the relative balance of
inositol synthesis, epimerization, derivatization and catabol-
ism. Glucose increased ISYNA1 expression in HepG2
(human liver-derived) cell line, suggesting that diabetes may
increase hepatic myo-inositol synthesis (Guan, Dai, and
Shechter 2003). Furthermore, myo-inositol catabolism
appears to be promoted by upregulation of MIOX in human
and porcine kidney cells (HK-2 or LLC-PK1) treated with
high glucose (Zhan et al. 2015; Xie et al. 2010), and by
increased MIOX expression in the kidneys of mice fed a
high fat diet (Tominaga et al. 2016). The production of
many IPGs could also be increased in diabetes, since the
hydrolysis of membrane proteins, including GPI-anchored
proteins from which IPGs are released, by phospholipase C
is activated by transforming growth factor (TGF)-b, a factor
which is over-expressed in diabetes (Ziyadeh 2004; Vivien
et al. 1993).
Myo-inositol to D-chiro-inositol epimerase is insulin sen-
sitive with evidence of diminished conversion in-vivo in the
insulin resistant Goto-Kakizaki (GK) rat model of type 2
diabetes, resulting in increased myo-inositol, but decreased
D-chiro-inositol in insulin sensitive tissues such as the liver,
fat, muscle and blood, but not in the non-insulin-sensitive
spleen, kidney, intestine, heart and brain (Sun et al. 2002;
Pak et al. 1998). It has been proposed that a deficit of D-
chiro-inositol could impair the synthesis of IPGs containing
D-chiro-inositol, explaining the observed D-chiro-inositol-
IPG deficiency in skeletal muscle, hemodialysate and urine
of patients with type 2 diabetes (Asplin, Galasko, and Larner
1993). However, it is unclear whether D-chiro-inositol

availability is the rate limiting factor in D-chiro-inositol
IPG synthesis.
PI/PIP/Inositol-phosphate signaling pathways, which
regulate many insulin-dependent processes, are also dysregu-
lated in diabetes. SHIP-2 for example, inhibits peripheral
insulin signaling, by catalyzing the conversion of PIP3 to
PIP2 (Soeda et al. 2010) and SHIP-2 knockout mice showed
increased liver and skeletal muscle insulin sensitivity (Soeda
et al. 2010). SHIP-2 protein is significantly increased in the
quadriceps muscle, epididymal fat tissue and brain, but not
in the liver, of diabetic db/db mice relative to controls
(Soeda et al. 2010; Hori et al. 2002). Furthermore, mutations
in SHIP-2 are associated with diabetes and the metabolic
syndrome in population studies (Ishida et al. 2006; Kagawa
et al. 2005; Marion et al. 2002), which may explain why
some individuals have increased susceptibility to develop-
ing diabetes.
Other mechanisms. Receptors and effectors of inositol com-
pounds and their derivatives are also dysregulated in dia-
betes. For example, insulin-induced activation of glycerol-3-
phosphate acyltransferase by D-chiro-inositol-containing
IPGs appeared defective in the adipocytes of type II diabetic
Goto-Kakizaki rats and was associated with altered lipid syn-
thesis (Farese et al. 1994). Meanwhile, renal type I inositol-
1,4,5-trisphosphate receptor expression was reduced in the
kidneys of diabetic rats and mice (Sharma et al. 1999) and a
polymorphism in this gene was found to be a risk factor for
type 1 diabetes in a genetic mapping study (Swedish cohort)
(Roach et al. 2006).
Polycystic ovary syndrome
Polycystic ovary syndrome (PCOS) afflicts 6-10% of women
worldwide and is the most common endocrine disorder in
young women (Goodarzi et al. 2011). PCOS is characterized
by amenorrhea or oligomenorrhoea, ovulatory dysfunction,
hyper-androgenism and polycystic ovaries (Ehrmann 2005).
Women with PCOS are more insulin resistant than matched
controls (Ehrmann et al. 1999) and have an increased risk of
obesity, hirsutism, cardiovascular disease, type 2 diabetes,
GDM, obstetric complications and infertility (Unfer et al.
2017). The role of inositol in PCOS has been reviewed by
others (Unfer et al. 2017; Carlomagno, Unfer, and Roseff
2011; Nestler and Unfer 2015; Regidor et al. 2018), so this
review will focus on how inositol may influence insulin sen-
sitivity and glucose and lipid metabolism in PCOS.
Treatment of PCOS with inositol supplements
Myo-inositol and D-chiro-inositol supplementation separ-
ately and in combination have been shown to improve insu-
lin sensitivity, glycemia and androgen status, circulating
lipid profiles, blood pressure, and anthropometry in PCOS
(Unfer et al. 2012; Facchinetti et al. 2015; Unfer et al. 2017;
Pundir et al. 2018; Formuso, Stracquadanio, and Ciotta
2015; Cianci et al. 2015; Lagana, Barbaro, and Pizzo 2015;
Nestler et al. 1999; Iuorno et al. 2002).
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 1647
A meta-analysis of nine RCTs involving 496 women with
PCOS (Unfer et al. 2017) showed that inositol treatment
(myo-inositol or chiro-inositol) significantly decreased fasting
insulin (Standardized Mean Difference (SMD)
1.021 mU/mL,
95% CI:
1.791 to
0.251, P ¼ 0.009) and HOMA-IR
(
0.585,
1.145 to
0.025, P ¼ 0.041). Interestingly, in obese
PCOS patients, myo-inositol administration appeared more
effective in reducing insulin resistance (area under the curve
of OGTT) in those with higher fasting plasma insulin levels,
suggesting that inositol treatment may be most effective in
those who are more insulin resistant (Genazzani et al. 2012).
Meanwhile, a separate meta-analysis of ten RCTs involv-
ing 362 women with PCOS showed that inositol supplemen-
tation (myo-inositol or D-chiro-inositol) was associated with
significantly improved ovulation rate and increased fre-
quency of menstruation compared with placebo (Pundir
et al. 2018). Favorable effects of myo-inositol on ovaries and
gametes could also potentially improve assisted reproduction
technology outcomes (Nestler and Unfer 2015; Bevilacqua
et al. 2015) and supplementation reduced the likelihood of
PCOS mothers developing GDM in one small study (D’anna
et al. 2012). Some studies have also suggested that combined
D-chiro-inositol and myo-inositol treatment may be more
effective than myo-inositol alone (Colazingari et al. 2013;
Nordio and Proietti 2012). However, more definitive studies
are needed before clinical recommendations can be made.
Inositol dysregulation in polycystic ovary syndrome
In PCOS, urinary D-chiro-inositol was inversely correlated
with insulin sensitivity (assessed using multiple methods)
and was found to be a strong independent predictor of per-
ipheral insulin resistance (Baillargeon et al. 2006; Baillargeon
et al. 2010). However, this association with insulin resistance
is unlikely to be unique to PCOS, since in a study on Greek
women, urinary D-chiro-inositol was found to be correlated
with hyperinsulinemia, even after correction for BMI and
waist-to-hip ratio regardless of PCOS status (Baillargeon
et al. 2008). It is not yet clear whether plasma and urinary
inositols deviate from normal in PCOS. The same study on
Greek women, showed no significant differences in plasma
and urinary D-chiro-inositol or myo-inositol between PCOS
patients and controls (Baillargeon et al. 2008). Meanwhile, a
separate study on American women by the same group,
showed that obese PCOS patients had higher urinary con-
centrations and lower plasma concentrations of D-chiro-
inositol compared with non-obese non-PCOS women, while
myo-inositol does not appear altered (Baillargeon et al.
2006). However, these changes in inositol content were not
significant when adjusted for BMI and/or insulin sensitivity
again suggesting that they may be related to differences in
BMI or insulin sensitivity rather than PCOS itself. Follicular
fluid and serum concentrations of myo-inositol were corre-
lated with oocyte quality and ovulatory activity in women
undergoing IVF suggesting that myo-inositol deficiency
could lead to impaired fertility (Chiu et al. 2002). Overall,
these findings suggest that inositol dysregulation in PCOS
could be involved in the insulin resistance and infertility
1648 O. C. WATKINS ET AL.
issues associated with the syndrome. However, further work
is required to untangle how inositol is linked with PCOS,
insulin resistance and BMI.
Inositol and IPG regulation in PCOS. The precise mecha-
nisms of inositol involvement in regulating insulin sensitiv-
ity in PCOS remains poorly understood. In non-PCOS
women, glucose consumption is associated with a spike in
circulating P-IPG thought to be caused by an insulin-
induced cleavage of GPIs (Baillargeon et al. 2006). Several
studies have shown that patients with PCOS show reduced
glucose-stimulated release of P-IPG into the circulation and
that this reduction has been correlated with decreased insu-
lin sensitivity (Cheang et al. 2008; Baillargeon et al. 2006;
Baillargeon et al. 2010; Baillargeon et al. 2008). Since P-IPG
acts as an insulin second messenger and insulin mimic,
decreased P-IPG release likely contributes to insulin resist-
ance and obesity in these women. However, these studies do
not adequately control for variance in obesity status and fur-
ther research is necessary to draw conclusions. Interestingly,
although metformin therapy decreased post-prandial serum
insulin concentrations in obese women with PCOS, gly-
cemia-induced release of P-IPG was not altered (Baillargeon
et al. 2004). This finding may suggest that P-IPG secretion
is regulated by factors that do not overlap with those
affected by metformin and raises the prospect of synergism
in metformin and inositol combination therapy in PCOS.
It was initially hypothesized that the increased urinary
excretion of D-chiro-inositol led to reduced systemic D-
chiro-inositol and D-chiro-inositol containing P-IPG
(Nestler et al. 1999). If this was true it would suggest oral
D-chiro-inositol supplementation could restore reduced D-
chiro-inositol-containing P-IPGs availability in women with
PCOS and improve some clinical features (Nestler et al.
1999). However, D-chiro-inositol supplementation in women
with PCOS did not increase glucose-stimulated release of P-
IPG (Cheang et al. 2008). Furthermore, there is no evidence
that increased urinary D-chiro-inositol excretion results in
systemic D-chiro-inositol deficiency, or that D-chiro-inositol
availability is the limiting factor in P-IPG production.
At the local tissue level, ovarian thecal cells from women
with PCOS show increased chiro-inositol:myo-inositol ratios
and increased epimerase activity compared to controls, sug-
gesting that in PCOS an overactive ovarian epimerase con-
verts more myo-inositol into D-chiro-inositol (Heimark,
McAllister, and Larner 2014). Increased D-chiro-inositol
excretion in PCOS could therefore be due to increased ovar-
ian synthesis and such possibilities need to be investigated
to ensure that supplementation studies do not worsen a pos-
sible D-chiro-inositol oversupply.
Future studies also need to consider the effects of D-
chiro-inositol supplementation on pinitol containing IPGs.
Treatment with INS-2, a pinitol containing P-IPG (Larner,
Brautigan, and Thorner 2010; Larner et al. 2003), increased
testosterone synthesis in PCOS thecal cells, suggesting that
an increase in pinitol based P-IPGs could contribute to the
hyperandrogenism seen in PCOS (Nestler et al. 1998).
However, although pinitol is synthesized from D-Chiro-
inositol in plants (Vernon and Bohnert 1992), there is not
yet evidence that this occurs in animals (Lin, Ma, Gopalan,
et al. 2009). It is therefore not yet known whether an
increase in D-chiroinositol caused by supplementation or
increased epimerase activity could increase pinitol contain-
ing P-IPGs.
Inositols and their derivatives clearly play important roles
in various aspects of the pathophysiology of PCOS, but fur-
ther research is necessary to disentangle these details. In
particular, most studies did not examine the effects of BMI
and a lack of suitable controls means it is unclear whether
effects are due to obesity, insulin resistance or PCOS.
Inositol in pregnancy
Pregnancy is associated with increasing maternal insulin
resistance as gestation progresses, reducing uptake of glucose
and lipids by maternal tissues and mobilizing resources to
promote fetal nutritional supply, especially in the latter half
of pregnancy (Napso et al. 2018). To drive such maternal
adaptation to pregnancy, pro-diabetic biological signals
including hormones, adipocytokines and exosomes are
released into the maternal circulation from the placenta,
with some originating from the fetus (Scioscia 2017;
Kunjara, Greenbaum, et al. 2000; Jayabalan et al. 2017). Our
understanding of these processes remains incomplete, but
inositol appears to play an important role (Scioscia 2017;
Kunjara, Greenbaum, et al. 2000; Jayabalan et al. 2017).
Maternal inositols in an uncomplicated pregnancy
and lactation
To date, we know very little about how maternal inositols
change during gestation and after delivery. One older study
reported that the maternal serum concentration of myo-
inositol remains stable across gestation and is similar to that
in non-pregnant women, at around 21–26 mmol/L (Quirk
and Bleasdale 1983). However, this study would not have
captured all the different derivatives of inositol nor all inosi-
tol stereoisomers in the circulation. In urine, there is a two-
fold increase in P-IPGs in the third trimester of uncompli-
cated pregnancies compared with non-pregnant controls
(Kunjara, Greenbaum, et al. 2000), and at least one of these
P-IPGs is unique to the pregnant state (Paine et al. 2003). A
cross-sectional study showed that urinary P-IPGs rise
between the 18th and 42nd week of pregnancy (Scioscia,
Gumaa, et al. 2007), suggesting that IPGs could play a role
in mediating the changes in glucose and lipid metabolism
that occur over this time period (Scioscia, Gumaa, et al.
2007). Moreover, urinary P-IPG levels are highest prior to
delivery and are significantly higher during labor than in
non-laboring women, suggesting that P-IPGs may also be
associated with labor onset and progress (Paine et al. 2003).
Unfortunately, IPG research in pregnancy is hindered by
limitations in analytical techniques for measuring different
IPGs. Currently, IPGs can be quantified by separating the
A-IPG and P-IPG fractions and testing fractions for enzym-
atic activity or for inositol content (Paine et al. 2006), but

this is laborious, nonspecific and will only quantify some
and not all IPGs. There is an antibody-mediated P-IPG
assay that is specific for one pregnancy-specific P-IPG, but
it works for urine samples and doesn’t work well for plasma
or serum samples (Paine et al. 2003).
Human breast milk contains a very large amount of un-
derivatized inositol (Table 1), but this falls over the first
6 weeks after birth (Pereira et al. 1990). However, whether
this decrease reflects declining maternal inositol after preg-
nancy, or decreasing infant need for inositol is not known.
Thus, overall, the changes in maternal inositol biology
across gestation and after delivery remain poorly
characterized.
Placental and fetal inositols in pregnancy
Placental inositol. The amount of measured inositol in
human placental tissue is influenced by the method of
extraction, sample processing and the assay method. By gas
chromatography, the human placenta was found to contain
0.53 mmol/kg of un-derivatized inositol (Toh et al. 1987)
and by enzymatic assay, to contain 2.7 mmol/kg of un-deriv-
atized and 3.5 mmol/kg total acid hydrolyzable inositol,
which includes all un-derivatized and derivatized forms
(Islam, Selvam, et al. 2019) (Table 1). These amounts are
similar to those reported in rat placenta (0.7–1.7 mmol/kg
(Battaglia et al. 1961)) and rat liver (0.57 mmol/kg
(Palmano, Whiting, and Hawthorne 1977)), but much lower
than rat brain or kidney (Table 1) (Palmano, Whiting, and
Hawthorne 1977). Little is known about the types or pro-
portions of inositol isomers in placenta, but current studies
suggest myo-inositol is the predominant form (Islam,
Selvam, et al. 2019).
Fetal inositol. Substantial synthesis and metabolism of myo-
inositol occurs in fetal tissues suggesting an important role
for inositol in fetal development. In sheep and goats, fetal
circulating inositol is substantially higher than that of adults
(Table 1D), whilst fetal CNS, kidney and skeletal muscle
inositol levels are at the upper end of corresponding adult
tissues, whereas fetal liver and heart inositol levels are gener-
ally lower than in adults (Table 1A).
The human fetal lung and liver also showed high IMPA1
activity (myo-inositol synthesis) (Quirk and Bleasdale 1983)
and in rabbit fetal kidney both ISYNA1 (myo-inositol syn-
thesis) and MIOX (myo-inositol catabolism) were highly
expressed (Bry and Hallman 1991). This is consistent with
the possibility of important roles for inositol in fetal devel-
opment. Relatively high inositol concentrations were also
found in human second trimester amniotic fluid (79.0 mM,
GCMS), suggesting that the fetal kidney can excrete inositol
(Santamaria, Di Benedetto, et al. 2016). The presence of
inositol synthesis, metabolism and excretion indicates that
the fetus can to some extent regulate fetal inositol availabil-
ity. The inositol content of cranial and spinal neuroectoder-
mal tissue in rat embryos was found to double between day
11 and 12, but little else is known about how fetal tissue
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 1649
inositol is altered or regulated as gestation progresses
(Sussman and Matschinsky 1988).
Inositol transfer and transport. There was a consistently
higher inositol concentration reported in term umbilical
artery blood (75 mM (HPLC) (Brusati et al. 2005)) that flows
from the fetus to the placenta, compared with term umbil-
ical venous blood (64 mM), which flows from the placenta
back to the fetus (Toh et al. 1987; Santamaria, Di Benedetto,
et al. 2016; Campling and Nixon 1954), which is highly sug-
gestive of fetal to placental transfer of inositol.
Moreover, a stable isotope transport study, involving the
maternal administration of 2H6-inositol 2 hours prior to
cesarean delivery, indicated that only a small fraction (10%
or less) of fetal circulating myo-inositol was derived from
transplacental maternal supply in late pregnancy (Staat et al.
2012). Since, the concentration of inositol in both venal and
arterial cord blood is much higher than maternal blood
(26 mM (Brusati et al. 2005)), this suggests that the fetus syn-
thesizes substantial amounts of inositol and that there is net
fetal inositol export to the placenta.
Inositol concentrations in umbilical cord blood obtained
by cordocentesis at mid-gestation (125 mM (Quirk and
Bleasdale 1983)) and from neonates born preterm (108 mM),
was significantly higher than at term (86 mM) (Pereira et al.
1990) suggesting a decline in fetal circulating inositol with
advancing gestation. In rabbits and kittens circulating inosi-
tol falls rapidly in the first month post-delivery reaching
equilibrium after 28 days (Campling and Nixon 1954).
Taken together, these studies suggests that the fetus may
export declining amounts of inositol to the placenta with
advancing gestation. It is not known whether this decline is
due to inositol being more important for fetal-placental
development early in pregnancy or whether this decrease
acts as an important regulatory signal in maternal-placental-
fetal communication.
Inositol transporters SMIT-1 (Berry et al. 1995), SMIT-2
(Roll et al. 2002) and the SMIT signal transcription factor
TonEBP are highly expressed in the placenta (Shin et al.
2012; Trama et al. 2000), suggesting placental inositol trans-
port between the maternal-placental-fetal compartments is
important. Naþ concentrations are generally higher outside
the cell than inside the cell due to the action of the Na/K-
ATPase, so SMIT (a sodium-inositol symporter) likely trans-
ports inositol into the placental syncytiotrophoblast cell bar-
rier from both maternal and fetal compartments (Schneider
2015; Johansson, Jansson, and Powell 2000). The proton gra-
dient between the maternal-placental-fetal compartments is
not constant throughout gestation, and in the presence of
other inositol efflux transporters, the net directionality of
inositol transport through HMIT (a proton-inositol sym-
porter) remains unclear (Schneider 2015; Strange et al. 1994;
Isaacks et al. 1999; Jackson and Strange 1993Ganapathy
et al., 2000). Overall, it would appear that the placenta is
able to both synthesize and import inositol, suggesting an
important role for inositol in placental function (see section
“Placental and fetal inositols in pregnancy”). Interestingly,
1650 O. C. WATKINS ET AL.
SMIT mRNA expression was very high in the brains of rat
embryos, but was gradually down-regulated nearer to birth
and after birth suggesting that myo-inositol and its trans-
porter play an important role in early CNS development
(Guo et al. 1997). In contrast, SMIT mRNA expression in
kidney was very weak in the embryonic stages, but increased
significantly after birth in the rat (Guo et al. 1997), a period
of development that is equivalent to the in-utero develop-
ment occurring in the third trimester of human pregnancy.
This suggests that myo-inositol plays a key role in the devel-
oping fetus, particularly the CNS and kidneys, but that role
might change as gestation progresses.
Inositol and fetal development
Inositol appears critical for healthy fetal development. Myo-
inositol levels were increased in the urine of both large-for-
gestational-age (LGA; birthweight above 90th percentile)
and small-for-gestational-age (SGA; birthweight below 10th
percentile) human newborns (Marincola et al. 2015;
Barberini et al. 2014) and increased in intrauterine growth
restricted (IUGR) piglets (Nissen et al. 2011), which suggests
that inositol dysregulation is associated with both extremes
of the fetal growth spectrum. However, the mechanistic
pathways linking LGA and SGA with inositol dysregulation
remains speculative. Excessive urinary inositol excretion
could be a sign of inositol over production in the fetus, or
conversely, reflect a pathological inositol depletion through
increased excretion. Since inositols are important regulators
of glucose and lipid metabolism, one could speculate that
fetal modulation of its own endogenous inositol production
and bio-availability could therefore be used as a signaling
mechanism to tailor nutritional access from the maternal
and placental compartments. In cases of LGA and SGA such
inositol-mediated mechanisms are postulated to either be
malfunctioning leading to pathology, or used as a compensa-
tory mechanism to try and optimize nutritional supply in
the presence of pathology, such as placental insufficiency or
hyperglycemia.
For example, we postulate that alterations in inositol sig-
nals to the placenta may regulate transplacental supply of
fatty acids and lipids for growth. Myo-inositol treatment of
human placental explants in-vitro alters the processing of
fatty acids into lipids, with myo-inositol displaying fatty
acid-specific effects (Watkins et al. 2019). In particular,
myo-inositol increased the incorporation of isotope-labeled
oleic acid into triacylglycerols, phosphatidylcholines, phos-
phatidylethanolamines and decreased the incorporation of
docosahexaenoic acid (DHA) into triacylglycerols in placen-
tal explants (Watkins et al. 2019). This is of importance,
because the amount of each fatty acid available for fetal sup-
ply will depend on the balance between the different lipid
forms incorporating the fatty acid; more ready supply if the
fatty acid is found in transportable forms (e.g. non-esterified
and lysophospholipid), or in labile and accessible storage
forms (e.g. glycolipids), but less fetal supply if in longer
term storage (e.g. structural phospholipids). Since placental
lipid processing is key to regulating transplacental fatty acid
fetal supply (Lewis, Wadsack, and Desoye 2018), myo-inosi-
tol actions in placenta likely have a significant impact on
fetal growth and development.
Inositol may also affect fetal growth through the facilita-
tion of IGF-1 and IGF-2 signaling, which utilizes PI/PIP/
inositol phosphate signaling pathways (Siddle 2011).
Maternal and fetal circulating IGF-1 and IGF-2 are strongly
associated with the promotion of placental nutrient trans-
port and fetal size (Jansson et al. 2013; Baumann et al.
2014). Increases in birthweight occur with increasing glucose
and amino acid transport to the fetus, and this is likely
mediated by IGF-1, since IGF-1 treatment was associated
with increased placental glucose and amino acid transporter
(GLUT1, SNAT2) expression in multiple placental in-vitro
models (Jansson et al. 2013; Baumann et al. 2014). However,
IGF also decreased lipoprotein lipase activity in placental vil-
lous explants in-vitro (Magnusson-Olsson et al. 2006), which
could lead to decreased maternal to fetal fatty acid transfer
if the same occurred in-vivo. Dysregulation in inositol con-
tent or metabolism would be expected to alter IGF signaling
and could therefore have significant impact on fetal growth,
with the direction of growth-change dependent on which
nutritional supply pathways are most impacted.
Inositol derivatives also affect the placental secretion of
hormones that modulate fetal growth. In particular, inositol
phosphates are involved in inducing the release from placental
syncytiotrophoblasts of human placental lactogen (hPL; see
section “Placental phosphoinositides”), which has anti-insulin
properties (Zeitler and Handwerger 1985; Zeitler, Wu, and
Handwerger 1991; Zeitler, Markoff, and Handwerger 1983;
Handwerger and Freemark 2000) and is one of the key hor-
mones involved in maternal adaptation to pregnancy. As pre-
viously discussed (section “Inositols influence lipid
metabolism, transport and storage”), both A-IPG and myo-
inositol appear to decrease adipocyte leptin release in non-
pregnant in-vitro and in-vivo rat models (Croze, Gelo€en, and
Soulage 2015; Kunjara, Greenbaum, et al. 2000). If a similar
effect of reduced leptin release from the placenta and adipose
tissue occurs in pregnancy, it could potentially suppress
mobilization of glucose, amino acids and lipids to the fetus
for growth (Tessier, Ferraro, and Gruslin 2013). Inositol also
appears to be important for CNS development. Maternal cir-
culatory myo-inositol in the lowest decile has also been associ-
ated with spina bifida in humans (Groenen, Merkus, et al.
2003), although no association was seen with amniotic fluid
inositol levels (Groenen, Merkus, et al. 2003). There are also
several studies reporting associations between myo-inositol
deficiency and dysmorphogenesis in rodents (Cogram et al.
2002; Steegers-Theunissen, Groenen, and Beemster 2002;
Copp and Greene 2010; Baker et al. 1990) which will be dis-
cussed in detail in section “Placental phosphoinositides.”
Hypothesis: Inositol acts as a communication signal
across the maternal-placental-fetal axis to regulate fetal
growth and development
We postulate that levels of inositol in pregnancy, whether of
maternal, fetal or placental origin, act as biological signals
that can regulate maternal and placental glucose and lipid
 CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 1651

Figure 4. Hypothesis: Inositol, acts as a communication signal across the maternal-placental-fetal axis to regulate maternal glycemia and lipidemia, placental func-
tion and fetal physiology and therefore fetal growth and development. We also suggest that much of this inositol is of fetal origin and is likely regulated by factors
such as fetal growth potential and growth velocity, forming a feedback loop and enabling the fetus to control its nutritional supply according to its needs, to regu-
late its own size/growth and development. However, inositol regulation becomes dysfunctional in pregnancies complicated by disorders such as GDM leading to
disorders of fetal growth and maternal insulin resistance. 1 Increased excretion into the amniotic fluid decreases fetal inositol. 2 Increased excretion into maternal
urine decreases maternal inositol. 3 Placental inositol impacts placental function. In particular, inositol and inositol derivatives alter the balance of placental nutri-
ent import, metabolism, storage and export and therefore fetal nutrient supply. Inositol derivatives also affect placental signaling since they act as second messen-
gers for hormones such as insulin and insulin like growth factor (IGF) and impact the synthesis and secretion of bioactive lipid mediators and hormones such as
human placental lactogen. 4 Inositol regulates maternal lipidemia by altering the balance of lipid mobilization between different types of adipose tissue, but the
direction of this inter-adipose-depot redistribution appears strongly affected by BMI. 5 Inositol and its derivatives can regulate maternal glycemia directly or by
affecting maternal insulin sensitivity.

metabolism, endocrine activity and fetal nutrient supply. As
a result, inositol and its derivatives are able to regulate fetal
growth and development. Details of the direction of inositol
exchange between the maternal, placental and fetal compart-
ments and the main foci of inositol action in maternal and
fetal tissues, and whether maternal inositol supplementation
can address defects in these physiological mechanisms
remain to be established. How defects in these processes
may lead to macrosomia in GDM is addressed in section
“Dysregulated maternal-placental-fetal lipid metabolism, adi-
posity and fetal growth in gestational diabetes” and in
Figure 4.
Placental and fetal IPGs
Healthy human placenta contains more P-IPG than any
other studied organ (25-fold more than liver), but contains
no or little detectable A-IPG (Scioscia 2017; Scioscia et al.
2013; Kunjara, Greenbaum, et al. 2000). P-IPG holds a crit-
ical role in the placenta and is involved in the regulation of
glycogen, glucose and lipid metabolic pathways, which in
other organs are mainly regulated by insulin (Larner,
Brautigan, and Thorner 2010; Kunjara et al. 1999; Scioscia
2017). Uniquely, the placenta is not reliant on insulin for
glucose uptake, a feature that preserves continuous rapid
maternal-fetal transfer of glucose, which is essential for fetal
survival (Lager and Powell 2012). The role of IPGs in facili-
tating anaerobic glycolysis is probably particularly important
early in gestation, to provide an alternative to aerobic glu-
cose oxidation in a low oxygen environment prior to deep
trophoblast invasion, which begins at the end of the first tri-
mester, and prior to development of an effective hemocho-
rial placenta for optimal oxygen and nutrient transfer to the
fetus (Scioscia et al. 2011). Later on in pregnancy, P-IPGs
may play an important physiological role in the regulation
of insulin resistance in order to maintain optimal fetal nutri-
tional supply (Larner 2002; Kunjara, Greenbaum, et al. 2000;
Scioscia, Gumaa, and Rademacher 2009). Placental P-IPG
could alter placental function locally, or be released into the
maternal or fetal circulation where it could alter maternal or
1652 O. C. WATKINS ET AL.
fetal metabolism (Scioscia et al. 2008; , Schofield, and
Rademacher 2003).
Even though placental P-IPGs can regulate placental
functions without insulin involvement, insulin may still pro-
mote placental P-IPG actions by effecting P-IPG synthesis
and transport. For example, in-vitro studies showed that
insulin stimulation caused more P-IPGs to be released by
maternal-facing syncytiotrophoblast microvillous membrane
isolates (Scioscia et al. 2008). This increase in P-IPG is
thought to be due to the insulin induced activation of pla-
cental GPI-specific phospholipase D (GPI-PLD) which
cleaves IPG from precursor GPIs (Scioscia et al. 2008;
Deborde, Schofield, and Rademacher 2003).
However, IPG synthesis will also be affected by the avail-
ability of GPI precursors and GPI-PLD and nothing is
known about how this may be affected by insulin.
Even though placental syncytiotrophoblast microvillous
membranes contain active GPI-PLD enzyme (Deborde,
Schofield, and Rademacher 2003), no GPI-PLD mRNA has
been found in BeWo cells (trophoblast-like cell line) or in
two placental cDNA libraries (Deborde, Schofield, and
Rademacher 2003). This suggests GPI-PLD is not synthe-
sized by the placenta and is instead of maternal or fetal ori-
gin (Deborde, Schofield, and Rademacher 2003). Large
amounts of GPI-PLD are exported into the circulation by
the liver outside of pregnancy, suggesting that placental GPI
cleavage maybe regulated by the maternal or fetal liver
(Low 2000).
We do not know if placental GPI is of maternal, placental
or fetal origin. However, Deborde et al. has suggested that
the structure of placental syncytiotrophoblast may regulate
how easily GPI-PLD can access GPIs stored in caveolae
membrane invaginations and that this may alter IPG avail-
ability in various pregnancy complications (Deborde,
Schofield, and Rademacher 2003; Parpal, Gustavsson, and
Strålfors 1995; Anderson et al. 1992).
Although some IPGs appear to be synthesized by the pla-
centa, one pregnancy-specific P-IPG which can be detected
by an antibody assay appears to be formed by the fetus. In
uncomplicated pregnancies, this pregnancy-specific P-IPG
was found to be several hundred times more concentrated
in amniotic fluid than in maternal urine (Scioscia 2017;
Paine et al. 2006; Scioscia et al. 2011). Furthermore in pla-
centa, this pregnancy-specific P-IPG was predominantly
localized in the syncytiotrophoblast, endothelium of placen-
tal vessels and extravillous trophoblast in the basal plate,
with only a little immunostaining within the villous stroma
(Scioscia et al. 2013). If this pregnancy specific P-IPG is of
fetal origin, it could potentially act as a signal to the mother
by which the fetus can regulate its own nutritional supply
according to its needs. However, evidence for this postula-
tion is still scarce and needs to be explored further.
Interestingly amniotic fluid P-IPG was decreased in the third
trimester compared to earlier in pregnancy (Scioscia,
Gumaa, et al. 2007) possibly suggesting that this P-IPG is
more important early in pregnancy, or that a decrease in
this P-IPG is an important signal in late pregnancy.
Placental Phosphoinositides
Phosphoinositide (PI) lipids act as important signaling mole-
cules in the placenta and are a major store of essential poly-
unsaturated fatty acids (PUFA) within the fetal-placental
unit (Bayon et al. 1993). A placental phosphatidylinositol
synthase (CDIPT) has previously been isolated and charac-
terized, suggesting that the placenta can synthesize phos-
phoinositide lipids (Antonsson 1994). Arachidonic acid (AA,
an omega-6 fatty acid; 20:4) for example, comprises 33% of
the fatty acids held in placental PI (Bitsanis et al. 2005).
Such storage reservoirs are important, because the fetal-pla-
cental unit cannot synthesize PUFA due to a lack of desatur-
ase enzymes (Bayon et al. 1993). PUFAs can be released
from placental phospholipids by phospholipase A (PLA)
(Schrey et al. 1992; Schrey, Read, and Steer 1987; Petit et al.
1989), a process vital for fetal PUFA supply and brain devel-
opment (Crawford 2000), and for the synthesis of many
PUFA-derived signaling molecules essential for fetal and pla-
cental development and labor such as prostaglandins and
leukotrienes (Holub 1986; Walsh and Parisi 1986; Boone,
Currie, and Leung 1993).
Inositol and arachidonic acid in dysmorphogenesis. Myo-inosi-
tol’s role in preventing fetal anomalies appears to be par-
tially mediated via its effect on AA metabolism and
prostaglandin synthesis. It is well-established that dysmor-
phogenesis, particularly fetal neural tube defects, are associ-
ated with poorly controlled preexisting diabetes in humans
(Wentzel and Eriksson 2020). Similar defects are also
observed in streptozocin-induced diabetic pregnant rat and
mouse embryos incubated with excess glucose (Wentzel
et al. 2001; Sussman and Matschinsky 1988; Baker et al.
1990; Hashimoto et al. 1990). Such embryos also displayed
an associated decrease in inositol content, particularly in the
neuroectoderm (Steegers-Theunissen, Groenen, and
Beemster 2002; Wentzel et al. 2001; Sussman and
Matschinsky 1988; Baker et al. 1990; Hashimoto et al. 1990),
and indeed, the addition of either prostaglandin E2 or myo-
inositol prevented the neural tube defects (Zeitler, Wu, and
Handwerger 1991; Baker et al. 1990). Separately, in the non-
diabetic curly tail mice model, D-chiro-inositol and myo-
inositol supplementation in-vitro was found to reduce the
frequency of spina bifida (Cogram et al. 2002).
The protective effect of myo-inositol was reversed in-vivo
by the addition of compounds that inhibited the synthesis of
prostaglandins from AA (Baker et al. 1990). This suggests
that inositol plays an important role by providing adequate
AA for prostaglandin synthesis necessary for healthy CNS
development although the nature of this role is not known
(Cogram et al. 2002; Baker et al. 1990).
Inositol might increase the availability of AA by acting as
a structural base for greater AA storage in the form of PI.
Alternatively, inositol might influence the metabolism and
release of AA from a range of phospholipids through regu-
lating lipid synthesis and lysis. For example, cleavage of
inositol containing PIP2 stimulates protein kinase C and
activates PLA2, the phospholipase that cleaves PUFA from

phospholipids (Wentzel et al. 2001). Inositol could also
affect the downstream synthesis of prostaglandins. However,
further studies are needed to confirm the inositol-related
mechanisms on AA release and prostaglandin synthesis.
Rat embryos incubated in high glucose concentrations
and rat embryos from mothers with streptozocin-induced
diabetes showed decreased expression of cytosolic PLA2
(Wentzel et al. 2001) and cyclooxygenase COX-2 (the
enzyme catalyzing the synthesis of prostaglandins from AA;
(Wentzel, Welsh, and Eriksson 1999)) compared with
respective controls on embryonic day E10 but not E11 of
gestation. This suggests a narrow gestational window for
phospholipid cleavage, AA release and prostaglandin synthe-
sis to impact CNS development. However, this change has
yet to be linked to inositol. If it is, then the timing of inosi-
tol supplementation in pregnancy to prevent defects would
be critical.
Interestingly, incubation of mouse embryos with scyllo-
inositol caused similar defects as incubation with glucose,
which suggests that scyllo-inositol competes as a ligand with
myo-inositol in early development to disrupt the important
role played by myo-inositol (Steegers-Theunissen, Groenen,
and Beemster 2002; Wentzel et al. 2001; Baker et al. 1990).
Interactions of inositol derivatives and lipids in maternal-
placental-fetal physiology. The inter-relationships between
placental inositol derivatives, AA availability, maternal endo-
crine regulation by the placenta and fetal growth are com-
plex. In-vitro AA treatment in various models of placental
explants, dispersed placental cells and cultured term human
syncytiotrophoblast, stimulated the hydrolysis of PIPs by
phospholipase C (Zeitler and Handwerger 1985; Zeitler, Wu,
and Handwerger 1991; Zeitler, Markoff, and Handwerger
1983Petit et al., 1989). This caused the release of placental
inositol phosphates, which then induced a rapid release of
human placental lactogen (hPL) (Zeitler and Handwerger
1985; Zeitler, Wu, and Handwerger 1991; Zeitler, Markoff,
and Handwerger 1983Petit et al., 1989). This process is
important especially in the third trimester of pregnancy,
because hPL changes the metabolic state of the mother to
facilitate mobilization of glucose and fatty acids for fetal
nutrition (Zeitler, Wu, and Handwerger 1991; Handwerger
and Freemark 2000). Inositol phosphates are also crucial in
regulating placental lipid metabolism. For example, PIP2
activates placental phospholipase D, which hydrolyzes phos-
pholipids to produce phosphatidic acid, a bioactive lipid
which modulates kinase signaling (Vinggaard and Hansen
1995; Liscovitch et al. 2000; Wang et al. 2006).
Thus, in pregnancy, inositols, PI lipids, PIPs and inositol
phosphates play critical roles in regulating paracrine, endo-
crine, intracellular and intercellular signaling, to influence
maternal and fetal physiology, and fetal nutritional provi-
sion. Given the diversity of inositol involvement in various
biological pathways of maternal-placental-fetal physiology,
some form of inositol dysregulation is likely involved in the
pathophysiological processes of pregnancy complications,
and conversely, great potential for inositol-related interven-
tions to aid in preventing or managing these complications.
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 1653
Gestational diabetes
Gestational diabetes (GDM) is glucose intolerance first rec-
ognized during pregnancy, which is associated with
increased risk of short term and long term adverse outcomes
for both mother and child (Sacks et al. 2012). Both hyper-
glycemia and lipid dysregulation are postulated to be
involved in its pathophysiology (Gallo, Barrett, and Nitert
2017). GDM is associated with increased risk of hypertensive
disorders of pregnancy, preterm delivery and cesarean sec-
tion delivery and babies are at risk of numerous negative
consequences including neonatal hypoglycemia, jaundice
and perinatal death (Metzger et al. 2008; Crowther et al.
2005; Mitanchez et al. 2015). GDM is also associated with
fetal macrosomia which is linked with increased risk of
shoulder dystocia and birth trauma (Metzger et al. 2008;
Crowther et al. 2005; Mitanchez et al. 2015). In the longer
term offspring are at an increased risk of major chronic
health conditions including obesity, type 2 diabetes, meta-
bolic syndrome and cardiovascular disease later in life, while
women who had GDM are 7 times more likely to later
develop type 2 diabetes than controls (Mitanchez et al. 2015;
Bellamy et al. 2009; Ruchat, Hivert, and Bouchard 2013; Ma
et al. 2015).
Pregnancy is a pro-diabetogenic state and is associated
with rising maternal insulin resistance, increased maternal
glucose intolerance and an elevation of circulating non-
esterified fatty acids, most prominently in the third trimester
(Scioscia 2017; Kunjara, Greenbaum, et al. 2000; Jayabalan
et al. 2017). These changes are essential for providing the
fetus with adequate nutrients, but individual hereditary and
environmental vulnerabilities can lead to accentuated
changes that result in GDM and related complications in
some women. It has been postulated that women who are
already sub-clinically metabolically challenged preconception
may be unable to mount an adequate insulin response in
pregnancy, resulting in GDM (Catalano et al. 2003). Since
inositols play an influential role in pregnancy and in dia-
betes, it is important to understand the interactions between
GDM and inositol metabolism and action, in order to fully
exploit inositol’s potential as an intervention in this context.
Relationship between gestational diabetes and inositol
Alterations in the level of inositols in biological fluids are
apparent many weeks prior to the clinical detection of
hyperglycemia and GDM diagnosis (Murphy et al. 2016).
When assessed during early pregnancy, women who would
subsequently manifest the signs of GDM later in pregnancy
displayed increased first trimester urinary D-chiro-inositol
and myo-inositol (Murphy et al. 2016) and increased second
trimester amniotic fluid myo-inositol (Santamaria, Di
Benedetto, et al. 2016), compared to women who did not
subsequently develop GDM. Such findings suggest that dys-
regulated inositol metabolism and excretion in the mother
or the fetal-placental unit predates the development of
hyperglycemia, and may be involved in the generation of
pathological events leading to GDM development. Since
similar increases in urinary D-chiro-inositol and myo-
1654 O. C. WATKINS ET AL.
inositol were also observed in non-pregnant overweight and
obese diabetic adults (Ostlund et al. 1993; Hong et al. 2012),
and in obese diabetic rodent models (Table 3), it has been
postulated that a similar pathological pathway of inositol
dysregulation may be shared by GDM and adult diabetes
that is driven by obesity.
Currently, there is little evidence to suggest how inositol
content and actions in the maternal and fetal tissues, are
altered in GDM, nor how they may alter the risk of GDM
development. Our data suggests that placental inositol con-
tent is significantly reduced in GDM pregnancies compared
with non-GDM cases (Pillai et al. 2020) and work is cur-
rently on-going to establish the underlying mechanisms for
this difference. However, the concurrent rise of both amni-
otic fluid and maternal urinary inositol during pregnancy
suggests that GDM does not conform to the theory of a gen-
eral diabetic inositol deficiency caused by increased urinary
inositol excretion. More SMIT-1 protein was found in GDM
placenta compared to non-GDM placenta, with expression
changes localized to the trophoblast suggesting that
increased inositol transport into the placenta occur in GDM
(Mejia, Reynolds, and Arroyo 2016). In contrast, our studies
showed a decline in IMPA1 (myo-inositol synthesis), SMIT-
2 and HMIT expression, associated with reductions in pla-
cental inositol content, with increasing maternal fasting gly-
cemia (Pillai et al. 2020). However, many other inositol-
related factors are likely altered in GDM, and further work
is needed to understand how inositol alterations within the
maternal-placental-fetal axis relates to GDM
pathophysiology.
P-IPGs in pregnancy and GDM. P-IPGs may play an
important physiological role in the regulation of insulin
resistance in pregnancy (Larner 2002; Kunjara, Greenbaum,
et al. 2000; Scioscia, Gumaa, and Rademacher 2009).
Urinary P-IPGs measured by PDH assay were found to
physiologically increase with increasing gestation among
non-diabetic women (Kunjara, Greenbaum, et al. 2000;
Scioscia, Gumaa, and Rademacher 2009). Since insulin
resistance also rises in late pregnancy, and because of the
link between urinary IPGs and insulin resistance in the non-
pregnant state, it has been suggested that P-IPGs are likely
involved in the development of insulin resistance in the
pregnant state (Larner 2002; Kunjara, Greenbaum, et al.
2000; Scioscia, Gumaa, and Rademacher 2009).
Urinary P-IPGs in women with preexisting type 2 dia-
betes and those who subsequently developed GDM, were
elevated in the first two trimesters of pregnancy compared
with non-diabetic pregnancy (Kunjara, Greenbaum, et al.
2000; Scioscia, Gumaa, and Rademacher 2009). Furthermore,
in one small study of women with GDM, urinary P-IPG lev-
els were found to correlate with antenatal glycemia in the
third trimester and with birthweight, but these correlations
were not observed in the control group (Scioscia, Gumaa,
et al. 2007). However, the amount of P-IPG in maternal tis-
sues and plasma in pregnancies complicated by diabetes
compared to uncomplicated pregnancies is not known.
Increased urinary P-IPG may either reflect an adaptive
systematic increase in P-IPG to try to counter insulin resist-
ance, or reflect pathological increased urinary excretion,
which could in turn reduce systemic P-IPG and promote
insulin resistance.
Even though early pregnancy urinary P-IPGs are higher
in diabetic pregnancies, women with preexisting type 2 dia-
betes and GDM do not show the normal ontogenic rise in
urinary P-IPG with advancing gestation (Kunjara,
Greenbaum, et al. 2000; Scioscia, Gumaa, and Rademacher
2009). Therefore, by the late third trimester, urinary P-IPG
levels in diabetic and non-diabetic groups are similar (Table
6) (Kunjara, Greenbaum, et al. 2000; Scioscia, Gumaa, and
Rademacher 2009). This could suggest that GDM pregnan-
cies go through the P-IPG and glycemic-related metabolic
adaptations associated with later pregnancy at much earlier
gestations. If true, this could increase fetal nutritional supply
over a longer period and possibly contribute to excessive
fetal growth and adiposity in GDM (Scioscia et al. 2011;
Scioscia, Gumaa, and Rademacher 2009).
A-IPGs in pregnancy and GDM. In the third trimester,
urinary A-IPG was found to be lower in GDM than in non-
GDM controls and correlated negatively with glycemic con-
trol, but positively with BMI (Scioscia, Gumaa, et al. 2007).
This study also found a trend suggestive of an association
between urinary A-IPG and birth weight. Since A-IPG in-
vitro influences many glucose, lipid and insulin-related
metabolic processes, in particular stimulating the synthesis
of lipids and glycogen, while lowering lipolysis (D’Anna and
Santamaria 2018; D’Oria et al. 2017; Malvasi et al. 2014;
Pintaudi, Di Vieste, and Bonomo 2016; D’Anna et al., 2013;
Matarrelli et al. 2013), it is plausible that A-IPG may play a
role in the pathophysiology of glucose intolerance and fetal
macrosomia. However, in-vivo mechanistic studies are lack-
ing and we cannot exclude the possibility that A-IPG may
only be an associated indicator of glucose intolerance.
Furthermore, since tissue A-IPG has not yet been quantified
in GDM we cannot tell whether low maternal urinary
A-IPG reflects low systemic A-IPG or decreased excretion.
A-IPGs have been reported to inhibit leptin release from
adipocytes, increase lipid synthesis and decrease the oxida-
tive disposal of glucose in a variety of cell types (Kunjara,
Greenbaum, et al. 2000; Scioscia, Gumaa, et al. 2007;
Kunjara, Greenbaum, et al. 2000). However, the action of A-
IPGs in pregnancy remains unknown and it is difficult to
predict how these molecules may be involved in GDM.
Ipgs as biomarkers of GDM. Whether urinary or serum ino-
sitols or inositol derivatives such as IPGs could represent
useful biomarkers to identify in early pregnancy women
who are at significant risk of developing GDM later in preg-
nancy remains to be explored. Examining if inositol bio-
markers could improve predictive power on top of that
provided by conventional clinical risk assessments using fac-
tors such as previous history of GDM, previous fetal macro-
somia, high BMI and family history of diabetes. Preventive
measures could be instituted early and targeted at those who
are most likely to benefit.

Prevention and treatment of gestational diabetes
with inositols
Inositol supplementation is a promising intervention for the
prevention and treatment of GDM. A recent meta-analysis
(Zhang et al. 2019) of 5 RCTs (Farren et al. 2017; D’Anna
et al., 2013; Matarrelli et al. 2013; Dʼ Anna et al. 2015;
Santamaria, Di Benedetto, et al. 2016) with a total of 927
pregnant women with metabolic risk factors, found that the
daily supplementation of pregnant women with 2
4 g myo-
inositol from early pregnancy reduced the incidence of
GDM (RR 0.43, 95%CI 0.21–0.89), and preterm delivery
(RR 0.36, 0.17–0.73). Other meta-analyses of these studies
generally agreed with these findings (Crawford et al. 2015;
Zheng et al. 2015; Santamaria et al. 2018; Vitagliano et al.
2019). These RCTs were mainly conducted in Caucasian
women who had risk factors for developing GDM namely
obesity/overweight (Dʼ Anna et al. 2015; Santamaria, Di
Benedetto, et al. 2016), a family history of type 2 diabetes
(D’Anna et al., 2013), or an impaired fasting glucose in the
first trimester (Matarrelli et al. 2013), with supplementation
with myo-inositol mostly beginning from the late first tri-
mester onwards. In a separate study, myo-inositol treatment
starting preconception in women with PCOS (n ¼ 83) was
also found to reduce the risk of developing GDM (17.45%
vs 54%, odds ratio 2.4, 95% CI, 1.3–4.4) and this difference
remained significant even after adjusting for covariates (age,
BMI, parity, family history of diabetes) (D’anna et al. 2012).
Two studies have looked at the effects of D-chiro-inositol
combined with myo-inositol. One small randomized control
trial on non-obese Italian pregnant women (n ¼ 157) with
elevated fasting glucose in the first or early second trimester,
who were supplemented with either myo-inositol (4000 mg),
D-chiro-inositol (500 mg), combined myo- and D-chiro-
inositol (1100/27.6 mg) or placebo, showed that all the inosi-
tol treatments significantly decreased fasting and post-pran-
dial glycemia and reduced the risk of developing GDM
(Celentano et al. 2020). Non-inferiority analysis demon-
strated the largest benefit was found in the myo-inositol
group, although dosage differences make comparison diffi-
cult (Celentano et al. 2020). In contrast, another study in
Irish women (n ¼ 240) with a family history of diabetes
found that a combination of myo-inositol 1100 mg and D-
chiro-inositol 27.6 mg/day did not lower GDM incidence
compared to controls (Farren et al. 2017).
One meta-analysis (Zhang et al. 2019) showed that myo-
inositol had no substantial impact on the OGTT 2-h post-
glucose load response or on neonatal birthweight and mac-
rosomia risk (birthweight >4 kg). However, the meta-ana-
lysis was likely underpowered to demonstrate modulation of
fetal size because of the low prevalence of macrosomia
(Zhang et al. 2019). In contrast, the Santamaria et al. (2018)
meta-study which focused only on a subset of three RCTs in
an Italian population at risk of GDM (high BMI or family
history of type 2 diabetes n ¼ 595), showed that myo-inositol
significantly decreased GDM diagnosis, fasting and post-
prandial glycemia, preterm birth and macrosomia. The effect
of myo-inositol on insulin resistance in these Italian studies
appears to be population dependent with HOMA-IR
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 1655
significantly decreased in overweight and obese pregnant
women (DʼAnna et al. 2015; Santamaria, Di Benedetto, et al.
2016), but not those with a family history of type 2 diabetes
(D’Anna et al., 2013). However, these studies were open
label and were all conducted by the same research group on
a homogeneous population. Thus, it remains uncertain if
findings can be generalized to other populations.
One study also analyzed the effect of myo-inositol treat-
ment on lipids in pregnancy (Malvasi et al. 2014). In this
small trial (24 treatment, 24 control), the combination of
myo-inositol, D-chiro-inositol, folic acid and manganese
given to non-obese pregnant women was associated with
reduced glycemia, as well as total cholesterol, low-density
lipoproteins (LDL), high-density lipoproteins (HDL), and
triglycerides compared with control. However, it is unclear
whether these changes are due to inositol or to other treat-
ment components.
Despite these promising findings, all reviews to date have
concluded there is insufficient data to properly evaluate
whether the use of myo-inositol during pregnancy is effica-
cious in reducing the risk of GDM development. In particu-
lar, the populations studied were too small and lacked
diversity, and many studies were open-label (unblinded) and
thus exposed to bias. Furthermore, there is a lack of data on
neonatal outcomes including perinatal mortality and serious
infant morbidity and longer-term offspring health. Also,
there is insufficient data to determine whether myo-inositol
is a better treatment option than D-chiro-inositol or inositol
combinations, or whether these molecules have interactive
effects (Celentano et al. 2020).
Further evaluation in large-scale, multicentre, double-
blinded RCTs are necessary to prove the efficacy of inositols
in reducing the risk of GDM, macrosomia and preterm
delivery. Furthermore, these trials will need to include preg-
nant women of different ethnicities and more varied risk
factors, with examination of different doses of myo-inositol
and other inositol isomers in comparison with placebo. An
example of such a trial is the NiPPeR study (Godfrey et al.
2017) (clinicaltrials.gov NCT02509988) which included
women of multiple ethnicities with both low and high meta-
bolic risks from UK, Singapore and New Zealand. The inter-
vention is a nutritional formulation containing myo-inositol,
probiotics and additional micronutrients, commenced prior
to conception and continued throughout pregnancy, and
results are expected to be published later in 2020. There is
also another smaller on-going clinical trial in the UK
(EMmY study, ISRCTN48872100) (Amaefule et al. 2018) of
myo-inositol supplementation starting in early pregnancy in
women at high risk of GDM development. With completion
of these trials a clearer picture will emerge on the efficacy of
inositol supplementation in reducing pregnancy risks, the
safety of the intervention, and whether specific subgroups
would benefit more than others.
Inositol use after GDM diagnosis. Upon the diagnosis of
GDM, maternal hyperglycemia can be controlled by a var-
iety of interventions, usually starting with diet control, exer-
cise and lifestyle changes, then adding in therapies such as
1656 O. C. WATKINS ET AL.
metformin and/or insulin if required (Falavigna et al. 2012;
Sweeting et al. 2016). Two randomized open-label trials
have tested the effect of inositol in women already diag-
nosed with GDM. One trial on 69 women with GDM found
that myo-inositol (4000 mg) improved insulin resistance
(lower HOMA-IR) and increased circulating adiponectin
(Corrado et al. 2011). Another trial (n ¼ 80) tested the effect
4000 mg myo-inositol or 500 mg D-chiro-inositol or 1100/
27.6 mg myo/D-chiro-inositol (Fraticelli et al. 2018). This
study found that insulin resistance was significantly
decreased in women given myo-inositol, and that groups on
myo-inositol-containing interventions (but not the chiro-
inositol alone group) were less likely to require insulin
therapy, and delivered newborns with significantly lower
birthweights. A third observational study also found that
women with GDM treated with 1.2 g myo-inositol were less
likely to require insulin treatment later in pregnancy but
lacked a contemporaneous control group for valid compari-
son (Lubin et al. 2016). Collectively, these studies suggest
that myo-inositol could potentially be considered as first
line GDM therapy, or as adjuvant therapy with insulin to
reduce insulin dosage and reduce the risk of hypoglycemia
associated with this treatment, although this remains to be
clinically evaluated.
Dysregulated maternal-placental-fetal lipid metabolism,
adiposity and fetal growth in gestational diabetes
According to Pederson, fetal macrosomia is a result of the
anabolic and lipogenic effect of fetal hypersecretion of pan-
creatic insulin, which is stimulated by increased maternal-
fetal glucose transfer in maternal diabetes (Pedersen 1952).
However, GDM cases with apparently satisfactory glycemic
control, still show an increased risk of fetal macrosomia,
and neonates even if appropriately-grown-for-gestational-age
as judged by birthweight, still show increased neonatal adi-
posity in body composition measures (Poston et al. 2015;
Zhuo, Wang, and Yu 2014). Furthermore, maternal circulat-
ing TAGs and free fatty acids, have been positively corre-
lated with neonatal weight and fat mass in well-controlled
GDM, but not in non-GDM pregnancies (Schaefer-Graf
et al. 2008; Schaefer et al. 2011). Hence, it has been postu-
lated that dysregulated lipid metabolism across the mater-
nal-placental-fetal axis, on top of glycemia, may contribute
to the development of excessive fetal growth and adiposity
in GDM (Herrera and Ortega-Senovilla 2010). Furthermore,
it is already well documented that in GDM there is reduced
maternal-placental-fetal transfer of the essential long chain
(LC)-PUFAs (Herrera and Ortega-Senovilla 2018; Larque
et al. 2014; Delhaes et al. 2018; I et al. 2002; Fraser et al.
1990; Schwartz et al. 1994) and it is likely that further
abnormalities of lipid regulation will be described with on-
going research.
Inositol treatment of animal models of GDM appears to
alter maternal lipid metabolism, but effects vary depending
on the model studied. Myo-inositol treatment in the genetic-
ally-modified db/þ mouse model of GDM reduced maternal
intra-abdominal, gonadal and perirenal adiposity, but had
no apparent effect on fetal size (Plows et al. 2017). In con-
trast, in a high fat diet mouse model of GDM, myo-inositol
treatment did not affect maternal glycemia or fat accretion
(Plows et al. 2020), but did increase maternal adipose tissue
mRNA expression of Ir, Irs1, Akt2, and Pck1, which are all
key members of the insulin signaling pathway, and demon-
strated an associated decrease in offspring birthweight
(Plows et al. 2020). This suggests that inositol might have a
pro-insulin or an insulin-like effect in adipose tissue result-
ing in decreased maternal lipid mobilization and lipid trans-
fer for fetal growth. Myo-inositol may also alter lipid supply
to the fetus by affecting placental lipids metabolism as dis-
cussed in section “Inositol and fetal development.”
Current management of GDM does not involve lipid
monitoring nor treatment of dyslipidemia, and lipid lower-
ing drugs are generally contraindicated in pregnancy. Myo-
inositol and its derivatives, as naturally-occurring com-
pounds, are promising candidates to address this metabolic
dysfunction in GDM since they can alter both glucose and
lipid metabolism. This venture must firstly involve develop-
ment of a much deeper understanding of how inositols
influence lipid metabolism in maternal tissues and the pla-
centa, and how they may influence maternal-fetal lipid
transfer. Then, further clinical studies focusing on lipid and
adiposity outcomes in pregnancy are necessary to determine
whether myo-inositol or any other inositol isomers or deriv-
atives could be an effective treatment for the anomalous lipi-
domic features of GDM.
Postulated actions of inositol in gestational diabetes
The mechanisms by which myo-inositol supplementation
may reduce the risk of GDM and fetal macrosomia are not
understood (Coustan 2013). Diabetes is classically hypothe-
sized to be a condition of myo-inositol deficiency (see above
4.5). However, there has been no clear evidence for a gen-
eral systemic inositol deficiency in GDM women that would
require correction (Table 6, section “Relationship between
gestational diabetes and inositol”). Current findings instead
suggest a complex situation where inositol perturbations
may be caused by ill-defined alterations in synthesis, trans-
port and metabolism, and may possibly differ between tissue
types. Furthermore, these alterations could be either patho-
logical leading to the development of GDM, or be an adap-
tive response to the GDM condition to minimize its impact.
Therefore, there is not yet a full picture of how these various
processes would be affected by maternal inositol supplemen-
tation and what the net effects would be in different individ-
uals. However, here we have drawn together threads of our
current understanding (Figure 4) upon which new know-
ledge can be added.
Myo-inositol supplementation has been shown to
improve insulin resistance and glycemic and lipid status in
various metabolic conditions in the non-pregnant state and
may, in theory, also act on maternal tissues during preg-
nancy to improve maternal metabolic health (Croze and
Soulage 2013; Coustan 2013; Zhang et al. 2019). However,
pregnancy involves not just the mother, but also the

placenta and the fetus, and any intervention needs to con-
sider the potential risks and benefits on all three.
Inositol and inositol derivatives are thought to play a role
in the action or release of many hormones that affect mater-
nal metabolism including insulin, thyroid stimulating hor-
mone, leptin and human placental lactogen (Van Sande
et al. 2006; Sayers and Hanyaloglu 2018; Berridge 2009;
Zeitler et al., 1991; Handwerger and Freemark 2000; Perez-
Perez et al. 2016; Hauguel-de Mouzon, Lepercq, and
Catalano 2006). We postulate that alterations in placental
inositol content, could alter fetal nutritional supply by
releasing endocrine signals that affect maternal metabolism
or by directly changing placental glucose, lipid and amino
acid metabolism and transport. Observational data from the
GUSTO mother-offspring cohort (Chu et al. 2020) and from
a separate smaller study (Pillai, et al. 2020) showed that a
high placental inositol content is associated with a suppres-
sion of the fetal growth-promoting and pro-adipogenic
effects of maternal glycemia.
Whether maternal inositol supplementation can increase
placental inositol content to favorably modulate fetal growth
and adiposity remains to be established.
If myo-inositol supplementation can lower maternal
blood glucose and suppress mobilization of lipids to the
fetus, then this could reduce excessive nutrient transfer to
the fetus, reducing macrosomia risk, but if taken to an
extreme this may possibly result in fetal nutritional insuffi-
ciency and growth restriction. Furthermore, fetal poly-unsat-
urated fatty acid (PUFA) supply is already decreased in
GDM and this may be worsened if general fatty acid transfer
is decreased further.
Myo-inositol supplementation may also alter how the pla-
centa metabolizes and transports nutrients. For example,
inositol availability will impact IGF signaling, which requires
the conversion of PIP2 into PIP3 (Section “Inositol and fetal
development”). Increased IGF signaling in GDM is thought
to increase placental glucose and amino acid transport and
therefore fetal growth (Jansson et al. 2013; Baumann et al.
2014; Stanirowski et al. 2017). However, it is not clear
whether inositol supplementation would increase or decrease
IGF signaling, since whilst increased PIP2 would increase
IGF signaling, increased PIP3 would decrease IGF signaling.
Our studies of labeled fatty acid uptake by human pla-
cental explants from non-GDM pregnancies showed that
myo-inositol treatment in-vitro reduced the incorporation of
the LC-PUFA, DHA, into lipids, but increased the incorpor-
ation of the mono-unsaturated fatty acid, oleic acid, into lip-
ids (Watkins et al. 2019). This suggests that myo-inositol
acts differently on PUFA compared to non-PUFA. In a best-
case scenario, reduced incorporation of PUFA into placental
lipids could make available more un-esterified PUFA to be
transported to the fetus to alleviate fetal PUFA deficiency.
By the same logic, increased incorporation of non-PUFA
into lipids could decrease the transport of non-PUFA and
decrease the risk of GDM-associated macrosomia. However,
further studies are needed to investigate the response of
non-GDM and GDM placenta to inositol treatment and to
explore how this may impact fetal growth.
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 1657
Another consideration is how concurrent insulin treat-
ment, during GDM management, may influence the effects
of on-going inositol supplementation. In-vitro, insulin can
stimulate cultured non-GDM placental trophoblast microvil-
lous membranes to release the insulin mimic P-IPGs
(Scioscia et al. 2008), potentially promoting further insulin-
like actions in placenta and mother. In insulin-treated
GDM, there are more insulin receptors in trophoblasts
found at the end of pregnancy than in diet-treated GDM.
Therefore, insulin treatment could potentially increase both
placental P-IPG-insulin-mimic release and increase placental
responsivity to insulin/insulin mimics through receptor up-
regulation, in addition to the direct effects of insulin treat-
ment on maternal tissues to lower glycemia (Scioscia et al.
2008; Desoye and Hauguel-de Mouzon 2007).
How these different actions of inositol and inositol deriv-
atives, and the actions of various hormones interact and
work together to bring about maternal adaptations to preg-
nancy and optimize fetal growth is not well studied to date.
Neither is it understood how inositol supplementation and
pathological states like GDM alter these actions.
Another important consideration is that myo-inositol
supplementation is currently being proposed as a preventive
measure for GDM. Such a strategy would involve myo-inosi-
tol exposure of many pregnancies which would not ultim-
ately develop GDM. Thus, any potential regulatory changes
or harms brought about by inositol treatment during preg-
nancy needs to be properly evaluated and understood in
both uncomplicated and at-risk pregnancies, before wide-
spread implementation of programs for GDM prevention
and treatment with myo-inositol supplementation.
Pre-eclampsia
Pre-eclampsia is characterized by the onset of new hyperten-
sion or exacerbation of preexisting hypertension, accompa-
nied by significant proteinuria or multi-system disorder
during pregnancy, with the pathophysiology arising from
abnormal placental implantation and endothelial dysfunction
(Cheng and Wang 2009). It is a major cause of maternal
mortality and morbidity worldwide and is associated with
intrauterine growth restriction (IUGR) and long-term health
issues for both mother and baby (Cheng and Wang 2009;
Ghulmiyyah and Sibai 2012). Pre-eclampsia is also a state of
heightened insulin resistance, and patients with pre-eclamp-
sia show many similar metabolic changes to those with
GDM (Cheng and Wang 2009; Ghulmiyyah and Sibai 2012).
In addition, women previously exposed to a pre-eclamptic
pregnancy carry an increased risk of future diabetes and car-
diovascular disease, while the associated hyperinsulinemia
and hyperandrogenism of pregnancy may persist for up to
17 years after delivery (Kaaja et al. 1999; Sampson et al.
2004; Seely and Solomon 2003).
Inositol regulation and processing are also altered in pre-
eclampsia, although inositol’s possible role in pre-eclampsia
etiology remains unclear (Table 7 and 8). Compared with
control placentas, placentas from pre-eclamptic pregnancies
showed higher inositol content, reduced expression of
1658 O. C. WATKINS ET AL.

#Urine
SMIT-1 protein and increased expression of the SMIT signal

A-IPG
transcription factor TonEBP (Lee et al. 2014). The former
two alterations in pre-eclampsia-affected placenta are in
contrast to those reported in GDM-affected placentas, hint-
ing at pathophysiological divergence, despite the apparent

the circulation
Insulin induced
metabolic similarities of the two conditions described earlier.

P-IPG release

the placenta
# Release from
# Release into
Like GDM, however, maternal urinary, placental and amni-
otic fluid P-IPGs are higher in pre-eclampsia cases than in
uncomplicated pregnancies (Paine et al. 2006; Williams et al.
2007; Dawonauth et al. 2014). Furthermore, maternal urin-
ary P-IPG rises steeply in the weeks prior to the clinical
onset of signs of pre-eclampsia, and this increase was linked
with exacerbated insulin resistance (Williams et al. 2007;

#Hemo-dialysate

"Amniotic fluid
Paine et al. 2010), just as in GDM. Nevertheless, longitu-

P-IPG
dinal studies measuring maternal urinary P-IPG from the

"Placenta,
#Placenta
#muscle

"Urine,
#Urine

"Urine

"Urine

"Urine
first trimester onwards (spot urine collection, normalized to
creatinine) (Scioscia et al. 2011; Paine et al. 2010) showed P-
IPG levels could not reliably predict pre-eclampsia, because
healthy women also had brief sporadic episodes of increased
P-IPG excretion for unknown reasons. It is to be noted that

D-Chiro-inositol
glucose consumption is known to cause a spike in circulat-
ing P-IPG in the non-pregnant state (Baillargeon et al. 2006)

#Plasma
"Urine,

"Ovary
#Urine

"Urine
and it seems likely that the P-IPG content of individual
urine or plasma samples will be influenced by previous food
consumption. If this is the case, the brief sporadic episodes
of increased P-IPG excretion seen in the study described
above could be caused by dietary factors and future studies

"Placenta inositol
# Nervous tissue

" Amniotic fluid

should take this into account, or set out to perform assess-
Myo-inositol

ments in the fasting state.

# Placenta
# Ovary

A key limitation of existing studies lies in the quantifica-

" Urine

"Urine

"urine
tion methods for P-IPG. The increase in urinary P-IPG is
larger when quantified by an antibody assay that detects
Table 8. Overview of inositol dysregulation associated with conditions involving insulin resistance.

only the pregnancy-specific P-IPG (Paine et al. 2006;

Williams et al. 2007; Dawonauth et al. 2014), than when
using the (less specific) PDH phosphatase activity assay that
Myo-inositol !

epimerase

measures a variety of P-IPGs (Kunjara, Greenbaum, et al.

D-Chiro-
inositol

2000). This suggests that the pregnancy specific P-IPG may

#Muscle
" Ovary
#Liver

be largely responsible for urinary P-IPG increase in pre-

#Fat

eclampsia. Of note, pre-eclampsia was not associated with

an increased amount of general serum P-IPGs as measured
by pyruvate dehydrogenase assay (Paine et al. 2006). Since
the antibody assay does not work well in plasma or serum,
Inositol transporters

" Placental SMIT-1

#Placental SMIT-1

it is difficult to confirm if circulating pregnancy-specific P-

IPG fraction is similarly increased.
Like in uncomplicated pregnancies, in pre-eclampsia
there is more P-IPG in amniotic fluid than in corresponding
maternal urine (Scioscia et al. 2011). However, in pre-
eclamptic pregnancies, but apparently not in uncomplicated
pregnancies, there are also higher amounts of P-IPG in the
umbilical arteries and vein relative to maternal uterine vein
Polycystic ovary syndrome

Uncomplicated pregnancy

and peripheral vein (Scioscia et al. 2011). This suggests that

Diabetes (type 1/ type 2)

Pregnancy with large or

small for gestational

the increased maternal urinary, placental and amniotic fluid

Condition or disorder

Gestational diabetes

Preexisting diabetes

P-IPG observed in pre-eclampsia is likely of fetal origin

in pregnancy

(Scioscia et al. 2011). Since P-IPG can act as an insulin-like

Pre-eclampsia
age infant

signal this could represent an example of fetal-maternal

communication, possibly as an adaptive response to the
increased maternal insulin resistance. Alternatively, P-IPG

produced by the fetus may play a role in the evolving patho-
physiology as subsequently discussed.
As mentioned earlier, placental IPGs may be cleaved and
released in response to insulin by placental GPI-PLD
(Scioscia et al. 2006; Scioscia et al. 2008; Deborde, Schofield,
and Rademacher 2003). However, although placental P-IPG
appears increased in pre-eclampsia (Kunjara, Greenbaum,
et al. 2000), insulin-induced release of P-IPG is decreased in
pre-eclamptic placental explants in-vitro (Scioscia et al. 2006;
Scioscia et al. 2008; Deborde, Schofield, and Rademacher
2003). The net effect of alterations in maternal, placental
and fetal inositol biology in pre-eclampsia is therefore
unclear (Scioscia et al. 2006; Scioscia et al. 2008).
Furthermore, GPI-PLD protein expression at delivery is
similar in placentas from both uncomplicated and pre-
eclamptic pregnancies (Deborde, Schofield, and Rademacher
2003). This suggests that increased placental P-IPG could be
due to increased synthesis or import, rather than to altera-
tions in GPI cleavage, or to the increased insulin-resistance
of pre-eclampsia placenta (Scioscia et al. 2006; Scioscia et al.
2008; Deborde, Schofield, and Rademacher 2003). However,
the degree to which the placenta may become insulin resist-
ant in pre-eclampsia is not well understood (Desoye and
Hauguel-de Mouzon 2007; Challier, Hauguel, and
Desmaizieres 1986).
It has been postulated that P-IPGs may play a role in the
generation of pre-eclampsia pathology (Kunjara et al. 1999;
Scioscia et al. 2011). Some P-IPGs have insulin-like effects,
so the increase in P-IPG could alter maternal physiology to
further compromise nutrient mobilization to the fetus result-
ing in fetal growth restriction (Kunjara et al. 1999; Scioscia
et al. 2011). P-IPGs also increase glycogen synthesis in rat
and bovine liver by activating pyruvate dehydrogenase phos-
phatase, glycogen synthase phosphatase, and glycerol-3-
phosphate acyltransferase (Varela-Nieto, Le on, and Caro
1996). It has therefore been suggested that increased placen-
tal P-IPGs could be responsible for the observed increase in
placental glycogen synthesis and glycogen synthase activity
in pre-eclampsia (Deborde, Schofield, and Rademacher
2003). However, IPGs have a range of bioactivities (Kunjara,
Greenbaum, et al. 2000), and the precise role of the preg-
nancy-specific P-IPG, and other IPGs in the dysregulation
of maternal-fetal physiology remains to be elucidated.
Insulin signaling though the PI3K signaling pathway was
decreased in pre-eclampsia in the placenta compared to con-
trols (Scioscia et al. 2006). These changes decreased PIP3
and PKB activation which in turn are thought to cause
endothelial dysfunction and insulin resistance (D’Oria et al.,
2017). Human endothelial cells (HUVECs), exposed in vitro
to myo-inositol or D-chiro-inositol, showed increased PKB
phosphorylation on Ser473, reflective of increased activation.
Furthermore, the magnitude of changes induced by inositol
treatment were greater than could be induced by insulin (
D’Oria et al. 2017). These findings suggest that inositol may
be able to combat the pre-eclampsia-related defects in PI3K
signaling, suggesting that increased inositol in pre-eclampsia
could be adaptive.
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 1659
Myo-inositol and D-chiro-inositol were also found to
increase mitogen-activated protein kinase (MAPK) phos-
phorylation (D’Oria et al. 2017; Brancho et al. 2003). MAPK
phosphorylation and activity are upregulated in both the
placenta and umbilical cord in pre-eclampsia (Afroze et al.
2016). MAPK regulates diverse cellular processes, including
placental development and trophoblast invasion and growth
(Adams et al. 2000; Li et al. 2003), but whether the conse-
quences of increased MAPK activation are protective or
pathological in pre-elcampsia is unclear (Adams et al. 2000;
Li et al. 2003; Peters et al. 2000).
Overall, it is not yet clear how systemic and local inositol
concentrations are altered in pre-eclampsia, nor how this
may alter maternal insulin resistance (D’Oria et al. 2017). It
is thus, too early to suggest if inositols or their derivatives
could be potential therapeutic targets in pre-eclampsia.
Conclusion
Inositols and their derivatives are highly bioactive molecules
that influence glycemia regulation, insulin signaling and
lipid metabolism. Optimal inositol intake, metabolism, trans-
port and excretion are necessary for health, and inositol dys-
regulation is associated with conditions involving insulin
resistance, dysglycemia and deranged lipidemia, including
those occurring during pregnancy such as gestational dia-
betes and pre-eclampsia (Table 8).
Inositols participate in maternal-placental-fetal cross talk
and play an important regulatory role in the adaptation of
maternal physiology to nurture a healthy pregnancy. Thus,
inositol supplements could be promising interventions for
the prevention and treatment of a range of metabolic disor-
ders and in adverse conditions in pregnancy such as GDM.
However, their effects need to be better understood in order
to ensure they are used safely and effectively, targeting rele-
vant populations.
Author contributions and Acknowledgements
Manuscript was written by Watkins O.C., and Chan S.Y.
with advice and editing provided by Yong H.E.J. and
Sharma N. We acknowledge Celes Maria Catherine Dado,
Samantha Grace Loon Magadia, Preben Selvam, Victoria K.
Cracknell and Reshma Appukuttan Pillai for their support
in preparing this manuscript.
Disclosure statement
This research is supported by a Clinician Scientist Award awarded to
Chan S.Y. from the Singapore National Medical Research Council
(NMRC/CSA-INV/0010/2016), by the National University of
Singapore, National University Health System Singapore and the
ASTAR Singapore Institute for Clinical Sciences. SYC is part of an
academic consortium that has received research funding from Nestec
and is a co-inventor on pending patents, which covers the use of inosi-
tol in human health applications. The other authors have no financial
or personal conflict of interest to declare.
1660 O. C. WATKINS ET AL.
ORCID
Oliver C. Watkins http://orcid.org/0000-0001-8202-6412
Hannah E. J. Yong http://orcid.org/0000-0002-8814-752X
Neha Sharma http://orcid.org/0000-0002-4287-5994
Shiao-Yng Chan http://orcid.org/0000-0002-3530-3023
References
Adams, R. H., A. Porras, G. Alonso, M. Jones, K. Vintersten, S. Panelli,
A. Valladares, L. Perez, R. Klein, and A. R. Nebreda. 2000. Essential
role of p38a MAP kinase in placental but not embryonic cardiovas-
cular development. Molecular Cell 6 (1):109–116. doi: 10.1016/
S1097-2765(05)00014-6.
Afroze, S. H., R. R. Kalagiri, M. Reyes, J. D. Zimmerman, M. R.
Beeram, N. Drever, D. C. Zawieja, T. J. Kuehl, and M. N. Uddin.
2016. Apoptotic and stress signaling markers are augmented in pree-
clamptic placenta and umbilical cord. BBA Clinical 6:25–30. doi: 10.
1016/j.bbacli.2016.05.003.
Alvarez, J., J. Sanchez-Arias, A. Guadano, F. Estevez, I. Varela, J. Feliu,
and J. Mato. 1991. Transport in isolated rat hepatocytes of the phos-
pho-oligosaccharide that mimics insulin action. Effects of adrenalec-
tomy and glucocorticoid treatment. Biochemical Journal 274 (2):
369–74. doi: 10.1042/bj2740369.
Amaefule, C. E., Z. Drymoussi, J. Dodds, L. Sweeney, E. Pizzo, J. Daru,
J. Robson, L. Poston, A. Khalil, J. Myers, et al. 2018. Effectiveness
and acceptability of myo-inositol nutritional supplement in the pre-
vention of gestational diabetes (EMmY): A protocol for a rando-
mised, placebo-controlled, double-blind pilot trial. BMJ Open 8 (9):
e022831., doi: 10.1136/bmjopen-2018-022831.
Andersen, D., and B. Holub. 1976. The influence of dietary inositol on
glyceride composition and synthesis in livers of rats fed different
fats. The Journal of Nutrition 106 (4):529–36. doi: 10.1093/jn/106.4.
529.
Andersen, D., and B. Holub. 1980. Myo-inositol-responsive liver lipid
accumulation in the rat. The Journal of Nutrition 110 (3):488–95.
doi: 10.1093/jn/110.3.488.
Andersen, D., and B. Holub. 1980. The relative response of hepatic lip-
ids in the rat to graded levels of dietary myo-inositol and other lipo-
tropes. The Journal of Nutrition 110 (3):496–504. doi: 10.1093/jn/
110.3.496.
Anderson, R. G., B. A. Kamen, K. G. Rothberg, and S. W. Lacey. 1992.
Potocytosis: Sequestration and transport of small molecules by cav-
eolae. Science255 (5043):410–412. doi: 10.1126/science.1310359.
Antonsson, B. E. 1994. Purification and characterization of phosphati-
dylinositol synthase from human placenta. Biochemical Journal 297
(3):517–522. doi: 10.1042/bj2970517.
Antony, P. J., G. R. Gandhi, A. Stalin, K. Balakrishna, E. Toppo, K.
Sivasankaran, S. Ignacimuthu, and N. A. Al-Dhabi. 2017.
Myoinositol ameliorates high-fat diet and streptozotocin-induced
diabetes in rats through promoting insulin receptor signaling.
Biomedicine & Pharmacotherapy ¼ Biomedecine & Pharmacotherapie
88:1098–113. doi: 10.1016/j.biopha.2017.01.170.
Aouameur, R., S. Da Cal, P. Bissonnette, M. J. Coady, and J.-Y.
Lapointe. 2007. SMIT2 mediates all myo-inositol uptake in apical
membranes of rat small intestine. American Journal of Physiology.
Gastrointestinal and Liver Physiology 293 (6):G1300–G1307. doi: 10.
1152/ajpgi.00422.2007.
Arner, R. J., K. S. Prabhu, J. T. Thompson, G. R. Hildenbrandt, A. D.
Liken, and C. C. Reddy. 2001. Myo-Inositol oxygenase: Molecular
cloning and expression of a unique enzyme that oxidizes myo-inosi-
tol and D-chiro-inositol. The Biochemical Journal 360 (Pt 2):
313–320. doi: 10.1042/bj3600313.
Arner, R. J., K. S. Prabhu, V. Krishnan, M. C. Johnson, and C. C.
Reddy. 2006. Expression of myo-inositol oxygenase in tissues sus-
ceptible to diabetic complications. Biochemical and Biophysical
Research Communications 339 (3):816–820. doi: 10.1016/j.bbrc.2005.
11.090.
Artini, P. G., O. Di Berardino, F. Papini, A. Genazzani, G. Simi, M.
Ruggiero, and V. Cela. 2013. Endocrine and clinical effects of myo-
inositol administration in polycystic ovary syndrome. A randomized
study. Gynecological Endocrinology 29 (4):375–379. doi: 10.3109/
09513590.2012.743020.
Ashcroft, F. M., M. Rohm, A. Clark, and M. F. Brereton. 2017. Is type
2 diabetes a glycogen storage disease of pancreatic b cells? Cell
Metabolism 26 (1):17–23. doi: 10.1016/j.cmet.2017.05.014.
Asplin, I., G. Galasko, and J. Larner. 1993. Chiro-inositol deficiency
and insulin resistance: A comparison of the chiro-inositol-and the
myo-inositol-containing insulin mediators isolated from urine,
hemodialysate, and muscle of control and type II diabetic subjects.
Proceedings of the National Academy of Sciences 90 (13):5924–8. doi:
10.1073/pnas.90.13.5924.
Baillargeon, J. P., E. Diamanti-Kandarakis, R. E. Ostlund, T.
Apridonidze, M. J. Iuorno, and J. E. Nestler. 2006. Altered D-chiro-
inositol urinary clearance in women with polycystic ovary syndrome.
Diabetes Care 29 (2):300–5. doi: 10.2337/diacare.29.02.06.dc05-1070.
Baillargeon, J.-P., J. E. Nestler, R. E. Ostlund, T. Apridonidze, and E.
Diamanti-Kandarakis. 2008. Greek hyperinsulinemic women, with
or without polycystic ovary syndrome, display altered inositols
metabolism. Human Reproduction 23 (6):1439–46. doi: 10.1093/
humrep/den097.
Baillargeon, J.-P., M. J. Iuorno, D. J. Jakubowicz, T. Apridonidze, N.
He, and J. E. Nestler. 2004. Metformin therapy increases insulin-
stimulated release of D-chiro-inositol-containing inositolphosphogly-
can mediator in women with polycystic ovary syndrome. The
Journal of Clinical Endocrinology and Metabolism 89 (1):242–9. doi:
10.1210/jc.2003-030437.
Baillargeon, J. P., M. J. Iuorno, T. Apridonidze, and J. E. Nestler. 2010.
Uncoupling between insulin and release of a D-chiro-inositol–con-
taining inositolphosphoglycan mediator of insulin action in obese
women with polycystic ovary syndrome. Metabolic Syndrome and
Related Disorders 8 (2):127–36. doi: 10.1089/met.2009.0052.
Baker, L., R. Piddington, A. Goldman, J. Egler, and J. Moehring. 1990.
Myo-inositol and prostaglandins reverse the glucose inhibition of
neural tube fusion in cultured mouse embryos. Diabetologia 33 (10):
593–596. doi: 10.1007/BF00400202.
Balla, T. 2013. Phosphoinositides: Tiny lipids with giant impact on cell
regulation. Physiological Reviews 93 (3):1019–137. doi: 10.1152/phys-
rev.00028.2012.
Barberini, L., A. Noto, C. Fattuoni, D. Grapov, A. Casanova, G. Fenu,
M. Gaviano, R. Carboni, G. Ottonello, M. Crisafulli, et al. 2014.
Urinary metabolomics (GC-MS) reveals that low and high birth
weight infants share elevated inositol concentrations at birth. The
Journal of Maternal-Fetal & Neonatal Medicine 27 (sup2):20–26.,
doi: 10.3109/14767058.2014.954786.
Barker, C. J., and P.-O. Berggren. 2013. New horizons in cellular regu-
lation by inositol polyphosphates: Insights from the pancreatic
b-cell. Pharmacological Reviews 65 (2):641–69. doi: 10.1124/pr.112.
006775.
Barker, D. 2004. The developmental origins of adult disease. Journal of
the American College of Nutrition 23 (sup6):588S–595S. doi: 10.
1080/07315724.2004.10719428.
Battaglia, F. C., G. Meschia, J. N. Blechner, and D. H. Barron. 1961.
The free myo-inositol concentration of adult and fetal tissues of sev-
eral species. Quarterly Journal of Experimental Physiology and
Cognate Medical Sciences 46:188–193. doi: 10.1113/expphysiol.1961.
sp001532.
Baumann, M. U., H. Schneider, A. Malek, V. Palta, D. V. Surbek, R.
Sager, S. Zamudio, and N. P. Illsley. 2014. Regulation of human
trophoblast GLUT1 glucose transporter by insulin-like growth factor
I (IGF-I). PLoS One 9 (8):e106037. doi: 10.1371/journal.pone.
0106037.
Bayon, Y., M. Croset, V. Chirouze, J. Tayot, and M. Lagarde. 1993.
Phospholipid molecular species from human placenta lipids. Lipids
28 (7):631–636. doi: 10.1007/BF02536058.
Beach, D. C., and P. K. Flick. 1982. Early effect of myo-inositol defi-
ciency on fatty acid synthetic enzymes of rat liver. Biochimica et

Biophysica Acta (BBA) - Lipids and Lipid Metabolism 711 (3):452–9.
doi: 10.1016/0005-2760(82)90059-5.
Behuria, B.,. S. Ghimere, S. Choudhary, M. Agrawal, R. P. Bodroth,
and T. V. G. Rao. 2018. Possible enhancement of phosphatidyl
inositol (PI) depends on its metabolic pathway components as
second messengers: Evidence from the growth and pi levels of nor-
mal, PI grown, and UV exposed Saccharomyces cerevisiae. Global
Journal of Biology. Agriculture & Health Sciences 7:26–31.
Bellamy, L., J. P. Casas, A. D. Hingorani, and D. Williams. 2009. Type
2 diabetes mellitus after gestational diabetes: A systematic review
and meta-analysis. The Lancet 373 (9677):1773–1779. doi: 10.1016/
S0140-6736(09)60731-5.
Berridge, M. J. 2009. Inositol trisphosphate and calcium signalling
mechanisms. Biochimica et Biophysica Acta (Bba) - Molecular Cell
Research 1793 (6):933–40. doi: 10.1016/j.bbamcr.2008.10.005.
Berridge, M. J., and R. F. Irvine. 1989. Inositol phosphates and cell sig-
nalling. Nature 341 (6239):197–205. doi: 10.1038/341197a0.
Berry, G. T., J. J. Mallee, H. M. Kwon, J. S. Rim, W. R. Mulla, M.
Muenke, and N. B. Spinner. 1995. The human osmoregulatory
Naþ/myo-inositol cotransporter gene (SLC5A3): molecular cloning
and localization to chromosome 21. Genomics 25 (2):507–513. doi:
10.1016/0888-7543(95)80052-N.
Berry, G. T., Z. J. Wang, S. F. Dreha, B. M. Finucane, and R. A.
Zimmerman. 1999. In vivo brain myo-inositol levels in children
with Down syndrome. The Journal of Pediatrics 135 (1):94–97. doi:
10.1016/S0022-3476(99)70334-3.
Bersudsky, Y., H. Einat, Z. Stahl, and R. H. Belmaker. 1999. Epi-inosi-
tol and inositol depletion: Two new treatment approaches in affect-
ive disorder. Current Psychiatry Reports 1 (2):141–147. doi: 10.1007/
s11920-999-0023-z.
Best, C., C. Lucas, J. M. Patterson, and J. H. Ridout. 1946. The influ-
ence of biotin upon the relative lipotropic effects of choline and
inositol. The Biochemical Journal 40 (3):368–73.
Bevilacqua, A., G. Carlomagno, S. Gerli, M. Montanino Oliva, P.
Devroey, A. Lanzone, C. Soulange, F. Facchinetti, G. Carlo Di
Renzo, M. Bizzarri, et al. 2015. Results from the International
Consensus Conference on myo-inositol and D-chiro-inositol in
Obstetrics and Gynecology–assisted reproduction technology.
Gynecological Endocrinology 31 (6):441–6. doi: 10.3109/09513590.
2015.1006616.
Bitsanis, D., M. A. Crawford, T. Moodley, H. Holmsen, K.
Ghebremeskel, and O. Djahanbakhch. 2005. Arachidonic acid pre-
dominates in the membrane phosphoglycerides of the early and
term human placenta. The Journal of Nutrition 135 (11):2566–71.
doi: 10.1093/jn/135.11.2566.
Bizzarri, M., and G. Carlomagno. 2014. Inositol: History of an effective
therapy for polycystic ovary syndrome. European Review for Medical
and Pharmacological Sciences 18 (13):1896–903.
Blazer-Yost, B. L., and C. Nofziger. 2005. Phosphoinositide lipid second
messengers: New paradigms for transepithelial signal transduction.
Pflugers Archiv: European Journal of Physiology 450 (2):75–82. doi:
10.1007/s00424-004-1371-5.
Boone, D. L., W. D. Currie, and P. C. K. Leung. 1993. Arachidonic
acid and cell signalling in the ovary and placenta. Prostaglandins,
Leukotrienes and Essential Fatty Acids 48 (1):79–87. doi: 10.1016/
0952-3278(93)90013-M.
Bourgeois, F., M. J. Coady, and J.-Y. Lapointe. 2005. Determination of
transport stoichiometry for two cation-coupled myo-inositol
cotransporters: SMIT2 and HMIT. The Journal of Physiology 563 (Pt
2):333–343. doi: 10.1113/jphysiol.2004.076679.
Brancho, D., N. Tanaka, A. Jaeschke, J.-J. Ventura, N. Kelkar, Y.
Tanaka, M. Kyuuma, T. Takeshita, R. A. Flavell, and R. J. Davis.
2003. Mechanism of p38 MAP kinase activation in vivo. Genes &
Development 17 (16):1969–1978. doi: 10.1101/gad.1107303.
Brautigan, D. L., M. Brown, S. Grindrod, G. Chinigo, A. Kruszewski,
S. M. Lukasik, J. H. Bushweller, M. Horal, S. Keller, S. Tamura,
et al. 2005. Allosteric activation of protein phosphatase 2C by d-
chiro-inositol
galactosamine, a putative mediator mimetic of insu-
lin action. Biochemistry 44 (33):11067–73. doi: 10.1021/bi0508845.
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 1661
Brown, J., J. Crawford Tineke, and J. Alsweiler. 2015. Myo-inositol for
preventing gestational diabetes – planning of reveiw. Cochrane
Database Syst Rev 4
Brusati, V., M. Jozwik, M. J
ozwik, C. Teng, C. Paolini, A. M. Marconi,
and F. C. Battaglia. 2005. Fetal and maternal non-glucose carbohy-
drates and polyols concentrations in normal human pregnancies at
term. Pediatric Research 58 (4):700–704. doi: 10.1203/01.PDR.
0000180549.86614.73.
Bry, K., and M. Hallman. 1991. Perinatal Development of inositol syn-
thesis and catabolism in rabbit kidney. Neonatology 60 (3-4):
249–257. doi: 10.1159/000243416.
Burgess, J. W., J. Boucher, T. A. Neville, P. Rouillard, C. Stamler, S.
Zachariah, and D. L. Sparks. 2003. Phosphatidylinositol promotes
cholesterol transport and excretion. Journal of Lipid Research 44 (7):
1355–63. doi: 10.1194/jlr.M300062-JLR200.
Burton, G. J., and E. Jauniaux. 2004. Placental oxidative stress: From
miscarriage to preeclampsia. Journal of the Society for Gynecologic
Investigation 11 (6):342–52. doi: 10.1016/j.jsgi.2004.03.003.
Burton, G. J., M. Scioscia, and T. W. Rademacher. 2011. Endometrial
secretions: Creating a stimulatory microenvironment within the
human early placenta and implications for the aetiopathogenesis of
preeclampsia. Journal of Reproductive Immunology 89 (2):118–25.
doi: 10.1016/j.jri.2011.02.005.
Burton, L. E., and W. W. Wells. 1976. Myo-inositol metabolism during
lactation and development in the rat. The prevention of lactation-
induced fatty liver by dietary myo-inositol. The Journal of Nutrition
106 (11):1617–28. doi: 10.1093/jn/106.11.1617.
Burton, L. E., and W. W. Wells. 1977. Characterization of the lacta-
tion-dependent fatty liver in myo-inositol deficient rats. The Journal
of Nutrition 107 (10):1871–83. doi: 10.1093/jn/107.10.1871.
Burton, L. E., and W. W. Wells. 1979. Myo-inositol deficiency: Studies
on the mechanism of lactation-dependent fatty liver formation in
the rat. The Journal of Nutrition 109 (8):1483–91. doi: 10.1093/jn/
109.8.1483.
Van Calker, D, and R. H. Belmaker. 2000. The high affinity inositol
transport system-implications for the pathophysiology and treatment
of bipolar disorder. Bipolar Disorders 2 (2):102–7. doi:10.1034/j.
1399-5618.2000.020203.x. PMC: 11252649
Calker, D., and R. H. Belmaker. 2000. The high affinity inositol trans-
port system–implications for the pathophysiology and treatment of
bipolar disorder. Bipolar Disorders 2 (2):102–7. doi: 10.1034/j.1399-
5618.2000.020203.x.
Calogero, A., G. Gullo, S. La Vignera, R. Condorelli, and A. Vaiarelli.
2015. Myoinositol improves sperm parameters and serum reproduct-
ive hormones in patients with idiopathic infertility: A prospective
double-blind randomized placebo-controlled study. Andrology 3 (3):
491–5. doi: 10.1111/andr.12025.
Campbell, W. W., M. D. Haub, J. D. Fluckey, R. E. Ostlund, Jr J. P.
Thyfault, H. Morse-Carrithers, M. W. Hulver, and Z. K. Birge. 2004.
Pinitol supplementation does not affect insulin-mediated glucose
metabolism and muscle insulin receptor content and phosphoryl-
ation in older humans. The Journal of Nutrition 134 (11):2998–3003.
doi: 10.1093/jn/134.11.2998.
Campling, J., and D. Nixon. 1954. The inositol content of foetal blood
and foetal fluids. The Journal of Physiology 126 (1):71–80. doi: 10.
1113/jphysiol.1954.sp005192.
Carlomagno, G., and V. Unfer. 2011. Inositol safety: Clinical evidences.
European Review for Medical and Pharmacological Sciences 15 (8):
931–6.
Carlomagno, G., V. Unfer, and S. Roseff. 2011. The D-chiro-inositol
paradox in the ovary. Fertility and Sterility 95 (8):2515–2516. doi:
10.1016/j.fertnstert.2011.05.027.
Caro, H. N., S. Kunjara, T. Rademacher, Y. Leon, D. Jones, M. Avila,
and I. Varela-Nieto. 1997. Isolation and partial characterisation of
insulin-mimetic inositol phosphoglycans from human liver.
Biochemical and Molecular Medicine 61 (2):214–28. doi: 10.1006/
bmme.1997.2607.
Catalano, P. M., J. P. Kirwan, S. Haugel-de Mouzon, and J. King. 2003.
Gestational diabetes and insulin resistance: Role in short-and long-
1662 O. C. WATKINS ET AL.
term implications for mother and fetus. The Journal of Nutrition
133 (5 Suppl 2):1674S–1683S. doi: 10.1093/jn/133.5.1674S.
Cavalli, P., G. Tonni, E. Grosso, and C. Poggiani. 2011. Effects of inosi-
tol supplementation in a cohort of mothers at risk of producing an
NTD pregnancy. Birth Defects Research Part A: Clinical and
Molecular Teratology 91 (11):962–965. doi: 10.1002/bdra.22853.
Celentano, C.,. B. Matarrelli, G. Pavone, E. Vitacolonna, P. A. Mattei,
V. Berghella, and M. Liberati. 2020. The influence of different inosi-
tol stereoisomers supplementation in pregnancy on maternal gesta-
tional diabetes mellitus and fetal outcomes in high-risk patients: A
randomized controlled trial. The Journal of Maternal-Fetal &
Neonatal Medicine 33 (5):743–751. doi: 10.1080/14767058.2018.
1500545.
Ceriello, A., D. Giugliano, A. Quatraro, and F. D’Onofrio. 1988. Does a
common mechanism induce diverse complications of diabetes?
Diabetes Care 11 (4):372–3. doi: 10.2337/diacare.11.4.372.
Challier, J., S. Hauguel, and V. Desmaizieres. 1986. Effect of insulin on
glucose uptake and metabolism in the human placenta. The Journal
of Clinical Endocrinology and Metabolism 62 (5):803–807. doi: 10.
1210/jcem-62-5-803.
Charalampous, F. C. 1959. Biochemical studies on inositol. Journal of
Biological Chemistry 234 (2):220–7.
Cheang, K. I., J. P. Baillargeon, P. A. Essah, R. E. Ostlund, T.
Apridonize, L. Islam, and J. E. Nestler. 2008. Insulin-stimulated
release of D-chiro-inositol-containing inositolphosphoglycan medi-
ator correlates with insulin sensitivity in women with polycystic
ovary syndrome . Metabolism: clinical and Experimental 57 (10):
1390–7. doi: 10.1016/j.metabol.2008.05.008.
Cheng, M.-H., and P.-H. Wang. 2009. Placentation abnormalities in
the pathophysiology of preeclampsia. Expert Review of Molecular
Diagnostics 9 (1):37–49. doi: 10.1586/14737159.9.1.37.
Chiu, T. T., M. S. Rogers, E. L. Law, C. M. Briton-Jones, L. Cheung,
and C. J. Haines. 2002. Follicular fluid and serum concentrations of
myo-inositol in patients undergoing IVF: Relationship with oocyte
quality. Human Reproduction 17 (6):1591–6. doi: 10.1093/humrep/
17.6.1591.
Chu, A. H., Tint, M. T. Chang, H. F. Wong, G. Yuan, W. L. Tull, D.
Nijagal, B. Narayana, V. K. Meikle, and P. J. Chang Kt. 2020. High
placental inositol content associated with suppressed pro-adipogenic
effects of maternal glycaemia in offspring: The GUSTO cohort.
International Journal of Obesity 1–11.
Chu, S. H. W., and D. Hegsted. 1980. Myo-inositol deficiency in ger-
bils: Comparative study of the intestinal lipodystrophy in Meriones
unguiculatus and Meriones libycus. The Journal of Nutrition 110 (6):
1209–16. doi: 10.1093/jn/110.6.1209.
Chukwuma, C. I., M. A. Ibrahim, and M. S. Islam. 2016. Myo-inositol
inhibits intestinal glucose absorption and promotes muscle glucose
uptake: A dual approach study. Journal of Physiology and
Biochemistry 72 (4):791–801. doi: 10.1007/s13105-016-0517-1.
Cianci, A., M. Panella, M. Fichera, C. Falduzzi, M. Bartolo, and S.
Caruso. 2015. D-chiro-Inositol and alpha lipoic acid treatment of
metabolic and menses disorders in women with PCOS.
Gynecological Endocrinology 31 (6):483–6. doi: 10.3109/09513590.
2015.1014784.
Clements Jr, R. 1979. The metabolism of myo-inositol by the human
kidney. Journal of Laboratory and Clinical Medicine 93:210–9.
Cline, G. W., K. F. Petersen, M. Krssak, J. Shen, R. S. Hundal, Z.
Trajanoski, S. Inzucchi, A. Dresner, D. L. Rothman, and G. I.
Shulman. 1999. Impaired glucose transport as a cause of decreased
insulin-stimulated muscle glycogen synthesis in type 2 diabetes. The
New England Journal of Medicine 341 (4):240–6. doi: 10.1056/
NEJM199907223410404.
Cogram, P., S. Tesh, J. Tesh, A. Wade, G. Allan, N. D. Greene, and
A. J. Copp. 2002. D-chiro-inositol is more effective than myo-inosi-
tol in preventing folate-resistant mouse neural tube defects. Human
Reproduction (Oxford, England) 17 (9):2451–2458. doi: 10.1093/
humrep/17.9.2451.
Colazingari, S., M. Treglia, R. Najjar, and A. Bevilacqua. 2013. The
combined therapy myo-inositol plus D-chiro-inositol, rather than D-
chiro-inositol, is able to improve IVF outcomes: Results from a
randomized controlled trial. Archives of Gynecology and Obstetrics
288 (6):1405–11. doi: 10.1007/s00404-013-2855-3.
Colone, M., G. Marelli, V. Unfer, G. Bozzuto, A. Molinari, and A.
Stringaro. 2010. Inositol activity in oligoasthenoteratospermia–an
in vitro study. European Review for Medical and Pharmacological
Sciences 14 (10):891–6.
Condorelli, R. A., S. La Vignera, L. M. Mongioı, S. G. Vitale, A. S.
Lagana, L. Cimino, and A. E. Calogero. 2017. A. Myo-inositol as a
male fertility molecule: Speed them up. European Review for Medical
and Pharmacological Sciences 21 (2 Suppl):30–35.
Copp, A. J., and N. D. Greene. 2010. Genetics and development of
neural tube defects. The Journal of Pathology 220 (2):217–230. doi:
10.1002/path.2643.
Coppey, L. J., J. S. Gellett, E. P. Davidson, J. A. Dunlap, and M. A.
Yorek. 2002. Effect of treating streptozotocin-induced diabetic rats
with sorbinil, myo-inositol or aminoguanidine on endoneurial blood
flow, motor nerve conduction velocity and vascular function of epi-
neurial arterioles of the sciatic nerve. International Journal of
Experimental Diabetes Research 3 (1):21–36. doi: 10.1080/
15604280212525.
Corrado, F., R. D’Anna, G. Di Vieste, D. Giordano, B. Pintaudi, A.
Santamaria, and A. Di Benedetto. 2011. The effect of myoinositol
supplementation on insulin resistance in patients with gestational
diabetes. Diabetic Medicine 28 (8):972–975. doi: 10.1111/j.1464-5491.
2011.03284.x.
Coupland, N. J., C. J. Ogilvie, K. M. Hegadoren, P. Seres, C. C.
Hanstock, and P. S. Allen. 2005. Decreased prefrontal Myo-inositol
in major depressive disorder. Biological Psychiatry 57 (12):1526–34.
doi: 10.1016/j.biopsych.2005.02.027.
Coustan, D. R. 2013. Can a dietary supplement prevent gestational dia-
betes mellitus? Diabetes Care 36 (4):777–9. doi: 10.2337/dc12-2505.
Crawford, M. 2000. Placental delivery of arachidonic and docosahexae-
noic acids: implications for the lipid nutrition of preterm infants.
The American Journal of Clinical Nutrition 71 (1 Suppl):275S–284S.
doi: 10.1093/ajcn/71.1.275S.
Crawford, T. J., C. A. Crowther, J. Alsweiler, and J. Brown. 2015.
Antenatal dietary supplementation with myo-inositol in women dur-
ing pregnancy for preventing gestational diabetes. Cochrane Database
of Systematic Reviews
Crowther, C. A., J. E. Hiller, J. R. Moss, A. J. McPhee, W. S. Jeffries,
and J. S. Robinson. 2005. Australian carbohydrate intolerance study
in pregnant women trial G. Effect of treatment of gestational dia-
betes mellitus on pregnancy outcomes. New England Journal of
Medicine 352 (24):2477–2486. doi: 10.1056/NEJMoa042973.
Croze, M. L., A. Gelo€en, and C. O. Soulage. 2015. Abnormalities in
myo-inositol metabolism associated with type 2 diabetes in mice fed
a high-fat diet: Benefits of a dietary myo-inositol supplementation.
British Journal of Nutrition 113 (12):1862–75. doi: 10.1017/
S000711451500121X.
Croze, M. L., and C. O. Soulage. 2013. Potential role and therapeutic
interests of myo-inositol in metabolic diseases. Biochimie 95 (10):
1811–27. doi: 10.1016/j.biochi.2013.05.011.
Czech, M. P. 2000. PIP2 and PIP3: Complex roles at the cell surface.
Cell 100 (6):603–6. doi: 10.1016/S0092-8674(00)80696-0.
D’Anna, R., and A. Santamaria. 2018. Myo-inositol supplementation in
gestational diabetes. Nutrition and diet in maternal diabetes,
229–35.Springer.
D’anna, R., V. Di Benedetto, P. Rizzo, E. Raffone, M. Interdonato, F.
Corrado, and A. Di Benedetto. 2012. Myo-inositol may prevent ges-
tational diabetes in PCOS women. Gynecological Endocrinology 28
(6):440–2. doi: 10.3109/09513590.2011.633665.
D’Oria, R., L. Laviola, M. Scioscia, F. Fascilla, S. Bettocchi, and F.
Giorgino. 2017. PKB/Akt phosphorylation in human umbilical vein
endothelial cells is highly induced by myo-inositol and D-chiro
inositol: Novel potential insights in the pathogenesis of preeclamp-
sia. Pregnancy Hypertension: An International Journal of Women’s
Cardiovascular Health 7:56. doi: 10.1016/j.preghy.2016.10.005.
Dʼ Anna, R., A. Di Benedetto, A. Scilipoti, A. Santamaria, M. L.
Interdonato, E. Petrella, I. Neri, B. Pintaudi, F. Corrado, and F.
Facchinetti. 2015. Myo-inositol supplementation for prevention of

gestational diabetes in obese pregnant women: A randomized con-
trolled trial. Obstetrics and Gynecology 126 (2):310–315. doi: 10.
1097/AOG.0000000000000958.
D’Anna, R., A. Scilipoti, D. Giordano, C. Caruso, M. L. Cannata, M. L.
Interdonato, F. Corrado, and A. Di Benedetto. 2013. Di Benedetto
A. myo-Inositol supplementation and onset of gestational diabetes
mellitus in pregnant women with a family history of type 2 diabetes:
A prospective, randomized, placebo-controlled study. Diabetes Care
36 (4):854–857. doi: 10.2337/dc12-1371.
Daughaday, W. H., and J. Larner. 1954. The renal excretion of inositol
in normal and diabetic human beings. The Journal of Clinical
Investigation 33 (3):326–32. doi: 10.1172/JCI102901.
Davanzo, P., K. Yue, M. A. Thomas, T. Belin, J. Mintz, T.
Venkatraman, E. Santoro, S. Barnett, and J. McCracken. 2003.
Proton magnetic resonance spectroscopy of bipolar disorder versus
intermittent explosive disorder in children and adolescents. The
American Journal of Psychiatry 160 (8):1442–52. doi: 10.1176/appi.
ajp.160.8.1442.
Davanzo, P., M. A. Thomas, K. Yue, T. Oshiro, T. Belin, M. Strober,
and J. McCracken. 2001. Decreased anterior cingulate myo-inositol/
creatine spectroscopy resonance with lithium treatment in children
with bipolar disorder. Neuropsychopharmacology: Official Publication
of the American College of Neuropsychopharmacology 24 (4):359–69.
doi: 10.1016/S0893-133X(00)00207-4.
Davis, A., M. Christiansen, J. F. Horowitz, S. Klein, M. K. Hellerstein,
and R. E. Ostlund. 2000. Effect of pinitol treatment on insulin action
in subjects with insulin resistance. Diabetes Care 23 (7):1000–5. doi:
10.2337/diacare.23.7.1000.
Dawonauth, L., L. Rademacher, A. D. L’Omelette, S. Jankee, M. Y. L.
K. Yan, R. B. Jeeawoody, and T. W. Rademacher. 2014. Urinary
inositol phosphoglycan-P type: Near patient test to detect pree-
clampsia prior to clinical onset of the disease. A study on 416 preg-
nant Mauritian women. Journal of Reproductive Immunology 101-
102:148–152. doi: 10.1016/j.jri.2013.06.001.
De, V. L., A. M. La, V. Cappelli, A. Stendardi, R. Focarelli, M.
Musacchio, and P. Piomboni. 2012. Evaluation of the treatment with
D-chiro-inositol on levels of oxidative stress in PCOS patients.
Minerva Ginecologica 64:531–8.
Debierre-Grockiego, F., and R. T. Schwarz. 2010. Immunological reac-
tions in response to apicomplexan glycosylphosphatidylinositolsF
Debierre-Grockiego and R T Schwarz. Glycobiology 20 (7):801–11.
doi: 10.1093/glycob/cwq038.
Deborde, S., J. Schofield, and T. Rademacher. 2003. Placental GPI-PLD
is of maternal origin and its GPI substrate is absent from placentae
of pregnancies associated with pre-eclampsia. Journal of
Reproductive Immunology 59 (2):277–294. doi: 10.1016/S0165-
0378(03)00054-8.
Del Monte, M. A., R. Rabbani, T. C. Diaz, S. A. Lattimer, J. Nakamura,
M. C. Brennan, and D. A. Greene. 1991. Sorbitol, myo-inositol, and
rod outer segment phagocytosis in cultured hRPE cells exposed to
glucose: In vitro model of myo-inositol depletion hypothesis of dia-
betic complications. Diabetes 40 (10):1335–45. doi: 10.2337/diabetes.
40.10.1335.
Delhaes, F., S. A. Giza, T. Koreman, G. Eastabrook, C. A. McKenzie, S.
Bedell, T. R. H. Regnault, and B. de Vrijer. 2018. Altered maternal
and placental lipid metabolism and fetal fat development in obesity:
Current knowledge and advances in non-invasive assessment.
Placenta 69:118–124. doi: 10.1016/j.placenta.2018.05.011.
Desoye, G., and S. Hauguel-de Mouzon. 2007. The human placenta in
gestational diabetes mellitus: The insulin and cytokine network.
Diabetes Care 30 (Supplement 2):S120–S126. doi: 10.2337/dc07-s203.
Dessı, A., and V. Fanos. 2013. Myoinositol: A new marker of intrauter-
ine growth restriction? Journal of Obstetrics and Gynaecology:
Gynaecology 33 (8):776–80. doi: 10.3109/01443615.2013.831046.
Di Cianni, G., R. Miccoli, L. Volpe, C. Lencioni, and S. Del Prato.
2003. Intermediate metabolism in normal pregnancy and in gesta-
tional diabetes. Diabetes/Metabolism Research and Reviews 19 (4):
259–270. doi: 10.1002/dmrr.390.
Di Daniel, E., M. H. Mok, E. Mead, C. Mutinelli, E. Zambello, L. L.
Caberlotto, T. J. Pell, C. J. Langmead, A. J. Shah, G. Duddy, et al.
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 1663
2009. Evaluation of expression and function of the Hþ/myo-inositol
transporter HMIT. BMC Cell Biology 10 (1):54. doi: 10.1186/1471-
2121-10-54.
Di Paolo, G., and P. De Camilli. 2006. Phosphoinositides in cell regula-
tion and membrane dynamics. Nature 443 (7112):651–7. doi: 10.
1038/nature05185.
Dona, G., C. Sabbadin, C. Fiore, M. Bragadin, F. L. Giorgino, E.
Ragazzi, C. G. Bordin, and L. Armanini. 2012. D. Inositol adminis-
tration reduces oxidative stress in erythrocytes of patients with poly-
cystic ovary syndrome. European Journal of Endocrinology 166:
703–10.
D’Oria, R., L. Laviola, F. Giorgino, V. Unfer, S. Bettocchi, and M.
Scioscia. 2017. PKB/Akt and MAPK/ERK phosphorylation is highly
induced by inositols: Novel potential insights in endothelial dysfunc-
tion in preeclampsia. Pregnancy Hypertension 10:107–112. doi: 10.
1016/j.preghy.2017.07.001.
D’Souza, K., and R. M. Epand. 2014. Enrichment of phosphatidylinosi-
tols with specific acyl chains. Biochimica et Biophysica Acta (BBA) -
Biomembranes 1838 (6):1501–8. doi: 10.1016/j.bbamem.2013.10.003.
Ehrmann, D. A. 2005. Polycystic ovary syndrome. The New England
Journal of Medicine 352 (12):1223–36. doi: 10.1056/NEJMra041536.
Ehrmann, D. A., R. B. Barnes, R. L. Rosenfield, M. K. Cavaghan, and J.
Imperial. 1999. Prevalence of impaired glucose tolerance and dia-
betes in women with polycystic ovary syndrome. Diabetes Care 22
(1):141–6. doi: 10.2337/diacare.22.1.141.
Einat, H., and R. Belmaker. 2001. The effects of inositol treatment in
animal models of psychiatric disorders. Journal of Affective Disorders
62 (1-2):113–121. doi: 10.1016/S0165-0327(00)00355-4.
Eisenberg, F., Jr, and A. H. Bolden. 1963. Biosynthesis of inositol in rat
testis homogenate. Biochemical and Biophysical Research
Communications 12 (1):72–77. doi: 10.1016/0006-291X(63)90416-9.
Elased, K. M., K. Gumaa, J. De Souza, H. Rahmoune, J. H. Playfair,
and T. Rademacher. 2001. Reversal of type 2 diabetes in mice by
products of malaria parasites: II. Role of inositol phosphoglycans
(IPGs). Molecular Genetics and Metabolism 73 (3):248–58. doi: 10.
1006/mgme.2001.3186.
Eriksson, U. J., and L. H. Borg. 1993. Diabetes and embryonic malfor-
mations: Role of substrate-induced free-oxygen radical production
for dysmorphogenesis in cultured rat embryos. Diabetes 42 (3):
411–9. doi: 10.2337/diab.42.3.411.
Eriksson, U., and L. Borg. 1991. Protection by free oxygen radical scav-
enging enzymes against glucose-induced embryonic malformations
in vitro. Diabetologia 34 (5):325–31. doi: 10.1007/BF00405004.
Facchinetti, F., M. Bizzarri, S. Benvenga, R. D’Anna, A. Lanzone, C.
Soulage, D. G. C. Renzo, M. Hod, P. Cavalli, and T. T. Chiu. 2015.
Results from the International Consensus Conference on Myo-inosi-
tol and d-chiro-inositol in Obstetrics and Gynecology: The link
between metabolic syndrome and PCOS. European Journal of
Obstetrics & Gynecology and Reproductive Biology 195:72–6.
Fagerberg, L., B. M. Hallstr€ om, P. Oksvold, C. Kampf, D. Djureinovic,
J. Odeberg, M. Habuka, S. Tahmasebpoor, A. Danielsson, K.
Edlund, et al. 2014. Analysis of the human tissue-specific expression
by genome-wide integration of transcriptomics and antibody-based
proteomics. Molecular & Cellular Proteomics: Proteomics 13 (2):
397–406. doi: 10.1074/mcp.M113.035600.
Falavigna, M., M. I. Schmidt, J. Trujillo, L. F. Alves, E. R. Wendland,
M. R. Torloni, S. Colagiuri, and B. B. Duncan. 2012. Effectiveness of
gestational diabetes treatment: A systematic review with quality of
evidence assessment. Diabetes Research and Clinical Practice 98 (3):
396–405. doi: 10.1016/j.diabres.2012.09.002.
Farese, R. V. 1983. The phosphatidate-phosphoinositide cycle: An
intracellular messenger system in the action of hormones and neu-
rotransmitters. Metabolism 32 (6):628–41. doi: 10.1016/0026-
0495(83)90035-5.
Farese, R. V., M. Standaert, K. Yamada, L. Huang, C. Zhang, D.
Cooper, Z. Wang, Y. Yang, S. Suzuki, and T. Toyota. 1994. Insulin-
induced activation of glycerol-3-phosphate acyltransferase by a
chiro-inositol-containing insulin mediator is defective in adipocytes
of insulin-resistant, type II diabetic, Goto-Kakizaki rats. Proceedings
1664 O. C. WATKINS ET AL.
of the National Academy of Sciences 91 (23):11040–4. doi: 10.1073/
pnas.91.23.11040.
Farren, M., N. Daly, A. McKeating, B. Kinsley, M. J. Turner, and S.
Daly. 2017. The prevention of gestational diabetes mellitus with
antenatal oral inositol supplementation: A randomized controlled
trial. Diabetes Care 40 (6):759–763. doi: 10.2337/dc16-2449.
Fenili, D. 2010. Characterization of inositol transporters as a method
for drug delivery to the central nervous system.
Fenili, D., M. Brown, R. Rappaport, and J. McLaurin. 2007. Properties
of scyllo–inositol as a therapeutic treatment of AD-like pathology.
Journal of Molecular Medicine (Berlin, Germany) 85 (6):603–11. doi:
10.1007/s00109-007-0156-7.
Fisher, S. K., J. E. Novak, and B. W. Agranoff. 2002. Inositol and
higher inositol phosphates in neural tissues: Homeostasis, metabol-
ism and functional significance. Journal of Neurochemistry 82 (4):
736–754. doi: 10.1046/j.1471-4159.2002.01041.x.
Formuso, C., M. Stracquadanio, and L. Ciotta. 2015. Myo-inositol vs.
D-chiro inositol in PCOS treatment. Minerva Ginecologica 67 (4):
321–325.
Fraser, D., S. Weitzman, J. Leiberman, and E. Eschwege. 1990. Factors
influencing birth weight in newborns of diabetic and non-diabetic
women a population based study. European Journal of Epidemiology
6 (4):427–431. doi: 10.1007/BF00151720.
Fraticelli, F.,. C. Celentano, I. A. Zecca, G. Di Vieste, B. Pintaudi, M.
Liberati, M. Franzago, M. Di Nicola, and E. Vitacolonna. 2018.
Effect of inositol stereoisomers at different dosages in gestational
diabetes: An open-label, parallel, randomized controlled trial. Acta
Diabetologica 55 (8):805–812. doi: 10.1007/s00592-018-1157-4.
Freedman, N. D., R. Sinha, S. C. Moore, A. J. Cross, J. N. Sampson, S.
Boca, N. E. Caporaso, and W.-Y. Huang. 2014. Metabolites of
tobacco smoking and colorectal cancer risk. Carcinogenesis 35 (7):
1516–22. doi: 10.1093/carcin/bgu071.
Frej, A. D., G. P. Otto, and R. S. Williams. 2017. Tipping the scales:
Lessons from simple model systems on inositol imbalance in neuro-
logical disorders. European Journal of Cell Biology 96 (2):154–163.
doi: 10.1016/j.ejcb.2017.01.007.
Frey, R., D. Metzler, P. Fischer, A. Heiden, J. Scharfetter, E. Moser,
and S. Kasper. 1998. Myo-inositol in depressive and healthy subjects
determined by frontal 1H-magnetic resonance spectroscopy at 1.5
tesla. Journal of Psychiatric Research 32 (6):411–20. doi: 10.1016/
S0022-3956(98)00033-8.
Fruen, B., and B. Lester. 1991. High-affinity [3 H] inositol uptake by
dissociated brain cells and cultured fibroblasts from fetal mice.
Neurochemical Research 16 (8):913–918. doi: 10.1007/BF00965541.
Fukami, K., and T. Takenawa. 1989. Quantitative changes in polyphos-
phoinositides 1, 2-diacylglycerol and inositol 1, 4, 5-trisphosphate by
platelet-derived growth factor and prostaglandin F2 alpha. The
Journal of Biological Chemistry 264 (25):14985–9.
Gaggini, M., C. Saponaro, and A. Gastaldelli. 2015. Not all fats are cre-
ated equal: Adipose vs. ectopic fat, implication in cardiometabolic
diseases. Hormone Molecular Biology and Clinical Investigation 22
(1):7–18. doi: 10.1515/hmbci-2015-0006.
Galasko, G.,. S. Abe, K. Lilley, C. Zhang, and J. Larner. 1996.
Circulating factors and insulin resistance. II. The action of the novel
myo-inositol cyclic 1,2-inositol phosphate phosphoglycan insulin
antagonist from human plasma in regulating pyruvate dehydrogen-
ase phosphatase. The Journal of Clinical Endocrinology and
Metabolism 81 (3):1051–7. doi: 10.1210/jcem.81.3.8772575.
Gallo, L. A., H. L. Barrett, and M. D. Nitert. 2017. Review: Placental
transport and metabolism of energy substrates in maternal obesity
and diabetes. Placenta 54:59–67. doi: 10.1016/j.placenta.2016.12.006.
Ganapathy, V., P. D. Prasad, M. E. Ganapathy, and F. H. Leibach.
2000. Placental transporters relevant to drug distribution across the
maternal-fetal interface. The Journal of Pharmacology and
Experimental Therapeutics 294 (2):413–420.
Gao J, Nalls MA, Shi M, Joubert BR, Hernandez DG, Huang X,
Hollenbeck A, Singleton AB, Chen H. 2012. An exploratory analysis
on gene-environment interactions for Parkinson disease.
Neurobiology of Aging, 33:2528.e1.e2521–2528.e2526 doi: 10.1016/j.
neurobiolaging.2012.06.007.
Garcia-Perez, A., and M. B. Burg. 1990. Importance of organic osmo-
lytes for osmoregulation by renal medullary cells. Hypertension16
(6):595–602. doi: 10.1161/01.HYP.16.6.595.
Gateva, A., V. Unfer, and Z. Kamenov. 2018. The use of inositol (s)
isomers in the management of polycystic ovary syndrome: A com-
prehensive review. Gynecological Endocrinology 34 (7):545–6. doi: 10.
1080/09513590.2017.1421632.
Gavin, G., and E. McHenry. 1941. Inositol: A lipotropic factor. Journal
of Biological Chemistry 139
Genazzani, A. D., A. Prati, S. Santagni, F. Ricchieri, E. Chierchia, E.
Rattighieri, A. Campedelli, T. Simoncini, and P. G. Artini. 2012.
Differential insulin response to myo-inositol administration in obese
polycystic ovary syndrome patients. Gynecological Endocrinology 28
(12):969–973. doi: 10.3109/09513590.2012.685205.
Gerli, S., E. Papaleo, A. Ferrari, D. Renzo, and G. Randomized. 2007.
Double blind placebo-controlled trial: Effects of myo-inositol on
ovarian function and metabolic factors in women with PCOS.
European Review for Medical and Pharmacological Sciences 11:
347–54.
Ghulmiyyah, L., and B. Sibai. 2012. Maternal mortality from pree-
clampsia/eclampsia. Seminars in Perinatology 36 (1):56–59. doi: 10.
1053/j.semperi.2011.09.011.
Giordano, D., F. Corrado, A. Santamaria, S. Quattrone, B. Pintaudi, A.
Di Benedetto, and R. D’Anna. 2011. Effects of myo-inositol supple-
mentation in postmenopausal women with metabolic syndrome: A
perspective, randomized, placebo-controlled study. Menopause18 (1):
102–104. doi: 10.1097/gme.0b013e3181e8e1b1.
Godfrey, K. M., W. Cutfield, S. Y. Chan, P. N. Baker, and Y. S. Chong.
2017. Nutritional intervention preconception and during pregnancy
to maintain healthy glucose metabolism and offspring health
(“NiPPeR”): Study protocol for a randomised controlled trial. Trials
18 (1):131. doi: 10.1186/s13063-017-1875-x.
Goel, M., and V. N. Azev. 2009. The biological activity of structurally
defined inositol glycans.
Goodarzi, M. O., D. A. Dumesic, G. Chazenbalk, and R. Azziz. 2011.
Polycystic ovary syndrome: Etiology, pathogenesis and diagnosis.
Nature Reviews. Endocrinology 7 (4):219–31. doi: 10.1038/nrendo.
2010.217.
Grases, F., Simonet, B. M. Vucenik, I. Prieto, R. M. Costa,-Bauza, A.
March, J. G. Shamsuddin. and A. M. 2001. Absorption and excre-
tion of orally administered inositol hexaphosphate (IP6 or phytate)
in humans. BioFactors 15 (1):53–61. doi: 10.1002/biof.5520150105.
Greene, D. A., P. V. De Jesus, Jr., and A. I. Winegrad. 1975. Effects of
insulin and dietary myoinositol on impaired peripheral motor nerve
conduction velocity in acute streptozotocin diabetes. The Journal of
Clinical Investigation 55 (6):1326–36. doi: 10.1172/JCI108052.
Greene, D., and A. Mackway. 1986. Decreased myo-inositol content
and Naþ-Kþ-ATPase activity in superior cervical ganglion of STZ-
diabetic rat and prevention by aldose reductase inhibition. Diabetes
35 (10):1106–8. doi: 10.2337/diab.35.10.1106.
Greene, D., S. Chakrabarti, S. Lattimer, and A. Sima. 1987. Role of
sorbitol accumulation and myo-inositol depletion in paranodal swel-
ling of large myelinated nerve fibers in the insulin-deficient spon-
taneously diabetic bio-breeding rat. Reversal by insulin replacement,
an aldose reductase inhibitor, and myo-inositol. The Journal of
Clinical Investigation 79 (5):1479–85. doi: 10.1172/JCI112977.
Groenen, P. M., H. M. Merkus, F. C. Sweep, R. A. Wevers, F. S.
Janssen, and R. P. Steegers-Theunissen. 2003. Kinetics of myo-inosi-
tol loading in women of reproductive age. Annals of Clinical
Biochemistry: International Journal of Laboratory Medicine 40 (1):
79–85. doi: 10.1258/000456303321016213.
Groenen, P. M., P. G. Peer, R. A. Wevers, D. W. Swinkels, B. Franke,
E. C. Mariman, and R. P. Steegers-Theunissen. 2003. myo-inositol,
glucose, and zinc status is associated with the risk of offspring with
spina bifida. American Journal of Obstetrics and Gynecology 189 (6):
1713–1719. doi: 10.1016/S0002-9378(03)00807-X.
Groenen, P. M., R. A. Wevers, F. S. Janssen, J. H. Tuerlings, J. M.
Merkus, and R. P. Steegers-Theunissen. 2003. Are myo-inositol, glu-
cose and zinc concentrations in amniotic fluid of fetuses with spina

bifida different from controls? Early Human Development 71 (1):
1–8. doi: 10.1016/S0378-3782(02)00040-3.
Guan, G.,. P. Dai, and I. Shechter. 2003. cDNA cloning and gene
expression analysis of human myo-inositol 1-phosphate synthase.
Archives of Biochemistry and Biophysics 417 (2):251–259. doi: 10.
1016/S0003-9861(03)00388-6.
Guo, W., S. Shimada, H. Tajiri, A. Yamauchi, T. Yamashita, S. Okada,
and M. Tohyama. 1997. Developmental regulation of Naþ/myo-
inositol cotransporter gene expression. Molecular Brain Research 51
(1-2):91–96. doi: 10.1016/S0169-328X(97)00220-9.
Handwerger, S., and M. Freemark. 2000. The roles of placental growth
hormone and placental lactogen in the regulation of human fetal
growth and development. Journal of Pediatric Endocrinology &
Metabolism: JPEM 13 (4):343–356. doi: 10.1515/JPEM.2000.13.4.343.
Hansen, B., and N. Bodkin. 1986. Heterogeneity of insulin responses:
Phases leading to type 2 (non-insulin-dependent) diabetes mellitus
in the rhesus monkey. Diabetologia 29 (10):713–9. doi: 10.1007/
BF00870281.
Hansen, S. B. 2015. Lipid agonism: The PIP 2 paradigm of ligand-gated
ion channels. Biochimica et Biophysica Acta (BBA)-Molecular and
Cell Biology of Lipids 1851:620–8.
Harwood, A. J. 2005. Lithium and bipolar mood disorder: The inositol-
depletion hypothesis revisited. Molecular Psychiatry 10 (1):117–26.
doi: 10.1038/sj.mp.4001618.
Hashimoto, M., S. Akazawa, M. Akazawa, M. Akashi, H. Yamamoto,
Y. Maeda, Y. Yamaguchi, H. Yamasaki, D. Tahara, and T.
Nakanishi. 1990. Effects of hyperglycaemia on sorbitol and myo-
inositol contents of cultured embryos: Treatment with aldose reduc-
tase inhibitor and myo-inositol supplementation. Diabetologia 33
(10):597–602. doi: 10.1007/BF00400203.
Hauguel-de Mouzon, S., J. Lepercq, and P. Catalano. 2006. The known
and unknown of leptin in pregnancy. American Journal of Obstetrics
and Gynecology 194 (6):1537–1545. doi: 10.1016/j.ajog.2005.06.064.
Hauser, G., and V. N. Finelli. 1963. The biosynthesis of free and phos-
phatide myo-inositol from glucose by mammalian tissue slices.
Journal of Biological Chemistry 238:64.
H€aussinger, D. 1998. Osmoregulation of liver cell function: signalling,
osmolytes and cell heterogeneity. Cell Volume Regulation. Vol 123, ;
185–204 Karger Publishers.
Hayashi, E., R. Hasegawa, and T. Tomita. 1976. Accumulation of neu-
tral lipids in Saccharomyces carlsbergensis by myo-inositol defi-
ciency and its mechanism. Reciprocal regulation of yeast acetyl-CoA
carboxylase by fructose bisphosphate and citrate. The Journal of
Biological Chemistry 251 (18):5759–69.
Hayashi, E., T. Maeda, R. Hasegawa, and T. Tomita. 1978. The effect
of myo-inositol deficiency on lipid metabolism in rats: III. The
mechanism of an enhancement in lipolysis due to myo-inositol defi-
ciency in rats. Biochimica et Biophysica Acta 531 (2):197–205. doi:
10.1016/0005-2760(78)90143-1.
Hegsted, D., K. Hayes, A. Gallagher, and H. Hanford. 1973. Inositol
deficiency: An intestinal lipodystrophy in the gerbil. The Journal of
Nutrition 103 (2):302–7. doi: 10.1093/jn/103.2.302.
Heimark, D., J. McAllister, and J. Larner. 2014. Decreased myo-inositol
to chiro-inositol (M/C) ratios and increased M/C epimerase activity
in PCOS theca cells demonstrate increased insulin sensitivity com-
pared to controls. Endocrine Journal 61 (2):111–7. doi: 10.1507/
endocrj.EJ13-0423.
Hernandez-Mijares, A., C. Ba~ nuls, J. E. Peris, N. Monz
o, A. Jover, L.
Bellod, V. M. Victor, and M. Rocha. 2013. A single acute dose of
pinitol from a naturally-occurring food ingredient decreases hyper-
glycaemia and circulating insulin levels in healthy subjects. Food
Chemistry 141 (2):1267–72. doi: 10.1016/j.foodchem.2013.04.042.
Herrera, E., and H. Ortega-Senovilla. 2010. Disturbances in lipid
metabolism in diabetic pregnancy–are these the cause of the prob-
lem? Best Practice & Research Clinical Endocrinology & Metabolism
24 (4):515–525. doi: 10.1016/j.beem.2010.05.006.
Herrera, E., and H. Ortega-Senovilla. 2018. Implications of lipids in
neonatal body weight and fat mass in gestational diabetic mothers
and non-diabetic controls. Current Diabetes Reports 18 (2):7. doi:
10.1007/s11892-018-0978-4.
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 1665
Hipps, P. P., K. E. Ackermann, and W. R. Sherman. 1982. Inositol epi-
merase - Inosose reductase from bovine brain. Methods in enzym-
ology. Vol 89, 593–8. Academic Press.
Hipps, P. P., W. H. Holland, and W. R. Sherman. 1977.
Interconversion of myo- and scyllo-inositol with simultaneous for-
mation of neo-inositol by an NADP þ dependent epimerase from
bovine brain. Biochemical and Biophysical Research Communications
77 (1):340–346. doi: 10.1016/S0006-291X(77)80202-7.
Holub, B. J. 1986. Metabolism and function of myo-inositol and inosi-
tol phospholipids. Annual Review of Nutrition 6:563–97. doi: 10.
1146/annurev.nu.06.070186.003023.
Holub, B. J. The nutritional significance, metabolism, and function of
myo-inositol and phosphatidylinositol in health and disease. Advances
in nutritional research, 1982, 107–41. Springer.
Hong, J. H., H. W. Jang, Y. E. Kang, J. H. Lee, K. S. Kim, H. J. Kim,
K. R. Park, and B. J. Ku. 2012. Urinary chiro-and myo-inositol levels
as a biological marker for type 2 diabetes mellitus. Disease Markers
33 (4):193–199. doi: 10.1155/2012/734718.
Hori, H.,. T. Sasaoka, H. Ishihara, T. Wada, S. Murakami, M. Ishiki,
and M. Kobayashi. 2002. Association of SH2-containing inositol
phosphatase 2 with the insulin resistance of diabetic db/db mice.
Diabetes 51 (8):2387–94. doi: 10.2337/diabetes.51.8.2387.
Hu, M. L., Y. K. Chen, and Y. F. Lin. 1995. The antioxidant and
prooxidant activity of some B vitamins and vitamin-like compounds.
Chemico-Biological Interactions 97 (1):63–73. doi: 10.1016/0009-
2797(95)03608-8.
Huang, L., M. Fonteles, D. Houston, C. Zhang, and J. Larner. 1993.
Chiroinositol deficiency and insulin resistance. III. Acute glycogenic
and hypoglycemic effects of two inositol phosphoglycan insulin
mediators in normal and streptozotocin-diabetic rats in vivo.
Endocrinology 132 (2):652–7. doi: 10.1210/endo.132.2.8425485.
I, E., H. d. Valk, B. Moll, E. t. Braak, and V. G. 2002. Macrosomia
despite good glycaemic control in Type I diabetic pregnancy; results
of a nationwide study in The Netherlands. Diabetologia 45 (11):
1484–9. doi:10.1007/s00125-002-0958-7.
Isaacks, R. E., A. S. Bender, C. Y. Kim, Y. F. Shi, and M. D.
Norenberg. 1999. Effect of osmolality and anion channel inhibitors
on myo-inositol efflux in cultured astrocytes. Journal of Neuroscience
Research 57 (6):866–871. doi: 10.1002/(SICI)1097-
4547(19990915)57:6<866::AID-JNR12>3.0.CO;2-K.
Ishida, S., A. Funakoshi, K. Miyasaka, H. Shimokata, F. Ando, and S.
Takiguchi. 2006. Association of SH-2 containing inositol 50 -phos-
phatase 2 gene polymorphisms and hyperglycemia. Pancreas 33:
63–7. doi: 10.1097/01.mpa.0000222317.82231.16.
Islam, M. O., P. Selvam, R. Appukuttan Pillai, O. C. Watkins, and S. Y.
Chan. 2019. An enzymatic assay for quantification of inositol in
human term placental tissue. Analytical Biochemistry 586:113409.
doi: 10.1016/j.ab.2019.113409.
Iuorno, M., Maria, J. Jakubowicz, M. Daniela, J. Baillargeon, M. Jean-
Patrice, D. B. Pamela, Gunn, M. Ronald, D. Allan, P. Nestler, G,
et al. 2002. Effects of D-chiro-inositol in lean women with the poly-
cystic ovary syndrome. Endocrine Practice: Official Journal of the
American College of Endocrinology and the American Association of
Clinical Endocrinologists 8 (6):417–23. doi: 10.4158/EP.8.6.417.
Jackson, P. S., and K. Strange. 1993. Volume-sensitive anion channels
mediate swelling-activated inositol and taurine efflux. American
Journal of Physiology-Cell Physiology 265 (6):C1489–C1500. doi: 10.
1152/ajpcell.1993.265.6.C1489.
Jansson, N., F. J. Rosario, F. Gaccioli, S. Lager, H. N. Jones, S. Roos, T.
Jansson, and T. L. Powell. 2013. Activation of placental mTOR sig-
naling and amino acid transporters in obese women giving birth to
large babies. The Journal of Clinical Endocrinology & Metabolism 98
(1):105–113. doi: 10.1210/jc.2012-2667.
Jayabalan, N., S. Nair, Z. Nuzhat, G. E. Rice, F. A. Zu~ niga, L. Sobrevia,
A. Leiva, C. Sanhueza, J. A. Gutierrez, M. Lappas, et al. 2017. Cross
talk between adipose tissue and placenta in obese and gestational
diabetes mellitus pregnancies via exosomes. Frontiers in
Endocrinology 8:239. doi: 10.3389/fendo.2017.00239.
Jenkins, C., R. Wilson, J. Roberts, H. Miller, J. H. McKillop, and J. J.
Walker. 2000. Antioxidants: Their role in pregnancy and
1666 O. C. WATKINS ET AL.
miscarriage. Antioxidants & Redox Signaling 2 (3):623–8. doi: 10.
1089/15230860050192369.
Jiang, W. D., L. Feng, Y. Liu, J. Jiang, and X. Q. Zhou. 2009. Myo-
inositol prevents oxidative damage, inhibits oxygen radical gener-
ation and increases antioxidant enzyme activities of juvenile Jian
carp (Cyprinus carpio var. Jian. Aquaculture Research 40 (15):
1770–6. doi: 10.1111/j.1365-2109.2009.02283.x.
Johansson, M., T. Jansson, and T. Powell. 2000. Naþ-Kþ-ATPase is
distributed to microvillous and basal membrane of the syncytiotro-
phoblast in human placenta. American Journal of Physiology-
Regulatory, Integrative and Comparative Physiology 279 (1):
R287–R294. doi: 10.1152/ajpregu.2000.279.1.R287.
Jung, T.-S., J.-R. Hahm, J.-J. Kim, J.-H. Jung, M.-Y. Kang, S.-W. Moon,
K.-W. Lee, H.-C. Kim, J.-D. Lee, J.-H. Kim, et al. 2005.
Determination of urinary myo-/chiro-inositol ratios from Korean
diabetes patients. Yonsei Medical Journal 46 (4):532–8. doi: 10.3349/
ymj.2005.46.4.532.
Kaaja, R., H. Laivuori, M. Laakso, M. J. Tikkanen, and O. Ylikorkala.
1999. Evidence of a state of increased insulin resistance in pree-
clampsia. Metabolism 48 (7):892–896. doi: 10.1016/S0026-
0495(99)90225-1.
Kagawa, S., T. Sasaoka, S. Yaguchi, H. Ishihara, H. Tsuneki, S.
Murakami, K. Fukui, T. Wada, S. Kobayashi, I. Kimura, et al. 2005.
Impact of SRC homology 2-containing inositol 50 -phosphatase 2
gene polymorphisms detected in a Japanese population on insulin
signaling. The Journal of Clinical Endocrinology & Metabolism 90
(5):2911–9., doi: 10.1210/jc.2004-1724.
Kalra, B., S. Kalra, and J. Sharma. 2016. The inositols and polycystic
ovary syndrome. Indian Journal of Endocrinology and Metabolism 20
(5):720–724. doi: 10.4103/2230-8210.189231.
Kang, M.J., J.I. Kim, S.Y. Yoon, J. C. Kim, and I.J. Cha. 2006. Pinitol
from soybeans reduces postprandial blood glucose in patients with
type 2 diabetes mellitus. Journal of Medicinal Food 9 (2):182–6. doi:
10.1089/jmf.2006.9.182.
Kawa, J. M., R. Przybylski, and C. G. Taylor. 2003. Urinary chiro-inosi-
tol and myo-inositol excretion is elevated in the diabetic db/db
mouse and streptozotocin diabetic rat. Experimental Biology and
Medicine (Maywood, N.J.) 228 (8):907–14. doi: 10.1177/
153537020322800806.
Kennington, A. S., C. R. Hill, J. Craig, C. Bogardus, I. Raz, H. K.
Ortmeyer, B. C. Hansen, G. Romero, and J. Larner. 1990. Low urin-
ary chiro-inositol excretion in non-insulin-dependent diabetes melli-
tus. New England Journal of Medicine 323 (6):373–8. doi: 10.1056/
NEJM199008093230603.
Kennington, O. A. 1992. Insulin mediators and their inositol
components.
Kim, H. J., K. S. Park, S. K. Lee, K. W. Min, K. A. Han, Y. K. Kim,
and B. J. Ku. 2012. Effects of pinitol on glycemic control, insulin
resistance and adipocytokine levels in patients with type 2 diabetes
mellitus. Annals of Nutrition and Metabolism 60 (1):1–5. doi: 10.
1159/000334834.
Kim, J. N., S. N. Han, and H. K. Kim. 2014. Phytic acid and myo-
inositol support adipocyte differentiation and improve insulin sensi-
tivity in 3T3-L1 cells. Nutrition Research 34 (8):723–31. doi: 10.
1016/j.nutres.2014.07.015.
Kim, J., E. Dare, S. S. Rajasekaran, S. H. Ryu, P.-O. Berggren, and C. J.
Barker. 2019. Inositol pyrophosphates and Akt/PKB: Is the pancre-
atic b-cell the exception to the rule? Cellular Signalling 58:131–6.
doi: 10.1016/j.cellsig.2019.02.003.
Kim, J.-I., J. Kim, M.-J. Kang, M.-S. Lee, J.-J. Kim, and I.-J. Cha. 2005.
Effects of pinitol isolated from soybeans on glycaemic control and
cardiovascular risk factors in Korean patients with type II diabetes
mellitus: A randomized controlled study. European Journal of
Clinical Nutrition 59 (3):456–458. doi: 10.1038/sj.ejcn.1602081.
Kim, M. J., K. H. Yoo, J. H. Kim, Y. T. Seo, B. W. Ha, J. H. Kho,
Y. G. Shin, and C. H. Chung. 2007. Effect of pinitol on glucose
metabolism and adipocytokines in uncontrolled type 2 diabetes.
Diabetes Research and Clinical Practice 77 (3):S247–S251. doi: 10.
1016/j.diabres.2007.01.066.
Kondoh, G., H. Tojo, Y. Nakatani, N. Komazawa, C. Murata, K.
Yamagata, Y. Maeda, T. Kinoshita, M. Okabe, R. Taguchi, et al.
2005. Angiotensin-converting enzyme is a GPI-anchored protein
releasing factor crucial for fertilization. Nature Medicine 11 (2):
160–6. doi: 10.1038/nm1179.
Krystal, G. 2000. Lipid phosphatases in the immune system. Seminars
in Immunology 12 (4):397–403. doi: 10.1006/smim.2000.0222.
Kunjara, S., A. L. Greenbaum, D.-Y. Wang, H. N. Caro, P. McLean,
C. W. Redman, and T. W. Rademacher. 2000. Inositol phosphogly-
cans and signal transduction systems in pregnancy in preeclampsia
and diabetes: Evidence for a significant regulatory role in pree-
clampsia at placental and systemic levels. Molecular Genetics and
Metabolism 69 (2):144–58. doi: 10.1006/mgme.2000.2964.
Kunjara, S., D. Y. Wang, A. L. Greenbaum, P. McLean, A. Kurtz, and
T. W. Rademacher. 1999. Inositol phosphoglycans in diabetes and
obesity: Urinary levels of IPG A-type and IPG P-type, and relation-
ship to pathophysiological changes. Molecular Genetics and
Metabolism 68 (4):488–502. doi: 10.1006/mgme.1999.2936.
Kunjara, S., D. Y. Wang, P. McLean, A. L. Greenbaum, and T. W.
Rademacher. 2000. Inositol phosphoglycans and the regulation of
the secretion of leptin: In vitro effects on leptin release from adipo-
cytes and the relationship to obesity. Molecular Genetics and
Metabolism 70 (1):61–68. doi: 10.1006/mgme.2000.2988.
Lagana, A. S., L. Barbaro, and A. Pizzo. 2015. Evaluation of ovarian
function and metabolic factors in women affected by polycystic
ovary syndrome after treatment with D-Chiro-Inositol. Archives of
Gynecology and Obstetrics 291 (5):1181–6. doi: 10.1007/s00404-014-
3552-6.
Lager, S., and T. L. Powell. 2012. Regulation of nutrient transport
across the placenta. Journal of Pregnancy 2012:1–14. doi: 10.1155/
2012/179827.
Lamar, M., C. M. L. Foy, F. Beacher, E. Daly, M. Poppe, N. Archer, V.
Prasher, K. C. Murphy, R. G. Morris, A. Simmons, et al. 2011.
Down syndrome with and without dementia: An in vivo proton
magnetic resonance spectroscopy study with implications for
Alzheimer’s disease. Neuroimage 57 (1):63–8. doi: 10.1016/j.neuro-
image.2011.03.073.
Lampe, D., and B. V. L. Potter. 1993. Synthesis of 2-fluoro-2-deoxy-
myo-inositol 1,4,5-trisphosphate and scyllo-inositol 1,2,4-trisphos-
phate, novel analogues of the second messenger myo-inositol 1,4,5-
trisphosphate. Tetrahedron Letters 34 (14):2365–8. doi: 10.1016/
S0040-4039(00)77615-5.
Larner, J. 2002. D-chiro-inositol–its functional role in insulin action
and its deficit in insulin resistance. Journal of Diabetes Research 3:
47–60.
Larner, J., D. L. Brautigan, and M. O. Thorner. 2010. D-chiro-inositol
glycans in insulin signaling and insulin resistance. Molecular
Medicine 16 (11-12):543–52. doi: 10.2119/molmed.2010.00107.
Larner, J., J. D. Price, D. Heimark, L. Smith, G. Rule, T. Piccariello,
M. C. Fonteles, C. Pontes, D. Vale, and L. Huang. 2003. Isolation,
structure, synthesis, and bioactivity of a novel putative insulin medi-
ator. A galactosamine chiro-inositol pseudo-disaccharide Mn2þ che-
late with insulin-like activity. Journal of Medicinal Chemistry 46
(15):3283–91. doi: 10.1021/jm030071j.
Larque, E., A. Pagan, M. T. Prieto, J. E. Blanco, A. Gil-Sanchez, M.
Zornoza-Moreno, M. Ruiz-Palacios, A. Gazquez, H. Demmelmair,
J. J. Parrilla, et al. 2014. Placental fatty acid transfer: A key factor in
fetal growth. Annals of Nutrition & Metabolism 64 (3-4):247–253.,
doi: 10.1159/000365028.
Lawrence, J., J. Guinovart, and J. Larner. 1977. Activation of rat adipo-
cyte glycogen synthase by insulins. The Journal of Biological
Chemistry 252 (2):444–50.
Lazar, D. F., J. J. Knez, M. E. Medof, P. Cuatrecasas, and A. R. Saltiel.
1994. Stimulation of glycogen synthesis by insulin in human
erythroleukemia cells requires the synthesis of glycosyl-phosphatidy-
linositol. Proceedings of the National Academy of Sciences 91 (21):
9665–9. doi: 10.1073/pnas.91.21.9665.
Lee, G., M. Price, C. Mejia, H. Galan, and J. Arroyo. 2014. Increased
trophoblast expression of NFAT5/TonEBP in pre-eclamptic placen-
tas and hyperosmolar-treated BeWo cells. European Journal of

Obstetrics & Gynecology and Reproductive Biology 183:37–43. doi:
10.1016/j.ejogrb.2014.10.002.
Letcher, A. J., M. J. Schell, and R. F. Irvine. 2008. Do mammals make
all their own inositol hexakisphosphate? Biochemical Journal 416 (2):
263–70. doi: 10.1042/BJ20081417.
Lewin, L. M., Y. Yannai, S. Melmed, and M. Weiss. 1982. myo-inositol
in the reproductive tract of the female rat. The International Journal
of Biochemistry 14 (2):147–150. doi: 10.1016/0020-711X(82)90154-9.
Lewis, R. M., C. Wadsack, and G. Desoye. 2018. Placental fatty acid
transfer. Current Opinion in Clinical Nutrition and Metabolic Care
21 (2):78–82. doi: 10.1097/MCO.0000000000000443.
Li, H.-Y., S.-P. Chang, C.-C. Yuan, H.-T. Chao, H.-T. Ng, and Y.-J.
Sung. 2003. Induction of p38 mitogen-activated protein kinase-
mediated apoptosis is involved in outgrowth of trophoblast cells on
endometrial epithelial cells in a model of human trophoblast-endo-
metrial interactions. Biology of Reproduction 69 (5):1515–1524. doi:
10.1095/biolreprod.103.015669.
Lin, X., L. Ma, C. Gopalan, and R. E. Ostlund. 2009. D-chiro-Inositol
is absorbed but not synthesised in rodents. British Journal of
Nutrition 102 (10):1426–1434. doi: 10.1017/S0007114509990456.
Lin, X., L. Ma, R. L. Fitzgerald, and R. E. Ostlund. 2009. Human
sodium/inositol cotransporter 2 (SMIT2) transports inositols but not
glucose in L6 cells. Archives of Biochemistry and Biophysics 481 (2):
197–201. doi: 10.1016/j.abb.2008.11.008.
Liscovitch, M., M. Czarny, G. Fiucci, and T. Xiaoqing. 2000.
Phospholipase D: Molecular and cell biology of a novel gene family.
Biochemical Journal 345 (3):401–415. doi: 10.1042/bj3450401.
Lizcano, J. M., and D. R. Alessi. 2002. The insulin signalling pathway.
Current Biology: CB 12 (7):R236–R238. doi: 10.1016/S0960-
9822(02)00777-7.
Low, M. G. 2000. Structure and function of GPI-specific phospholi-
pases. In PNH and the GPI-Linked Proteins, eds. N. S. Young and J.
Moss, 239–68. San Diego: Academic Press.
Loy, A., K. G. Lurie, A. Ghosh, J. M. Wilson, L. C. MacGregor, and
F. M. Matschinsky. 1990. Diabetes and the myo-inositol paradox.
Diabetes 39 (10):1305–12. doi: 10.2337/diab.39.10.1305.
Lubin, V., R. Shojai, P. Darmon, and E. Cosson. 2016. A pilot study of
gestational diabetes mellitus not controlled by diet alone: First-line
medical treatment with myoinositol may limit the need for insulin.
Diabetes & Metabolism 42 (3):192–195. doi: 10.1016/j.diabet.2016.01.
005.
Lubrich, B., and D. van Calker. 1999. Inhibition of the high affinity
Myo-inositol transport system: A common mechanism of action of
antibipolar drugs? Neuropsychopharmacology: Official Publication of
the American College of Neuropsychopharmacology 21 (4):519–29.
doi: 10.1016/S0893-133X(99)00037-8.
Ma, K., L. A. M. Thomason, and J. McLaurin. 2012. scyllo-Inositol,
Preclinical, and Clinical Data for Alzheimer’s Disease. In: Michaelis
EK, Michaelis ML, eds. Advances in Pharmacology. Vol 64:
Academic Press; 177–212.
Ma, K., L. A. Thomason, and J. McLaurin. 2012. Scyllo-inositol, preclin-
ical, and clinical data for Alzheimer’s disease. Advances in pharma-
cology. Vol 64, 177–212. Elsevier.
Ma, R. C., G. E. Tutino, K. A. Lillycrop, M. A. Hanson, and W. H.
Tam. 2015. Maternal diabetes, gestational diabetes and the role of
epigenetics in their long term effects on offspring. Progress in
Biophysics and Molecular Biology 118 (1-2):55–68. doi: 10.1016/j.
pbiomolbio.2015.02.010.
Mackenzie, R. W., and B. T. Elliott. 2014. Akt/PKB activation and insu-
lin signaling: A novel insulin signaling pathway in the treatment of
type 2 diabetes. Diabetes, metabolic syndrome and obesity. Targets
and Therapy 7:55.
Magnusson-Olsson, A. L., B. Hamark, A. Ericsson, M. Wennergren, T.
Jansson, and T. L. Powell. 2006. Gestational and hormonal regula-
tion of human placental lipoprotein lipase. Journal of Lipid Research
47 (11):2551–2561. doi: 10.1194/jlr.M600098-JLR200.
Malik, A., F. Steinbeis, M. A. Carillo, P. H. Seeberger, B. Lepenies, and
D. Varon Silva. 2020. Immunological evaluation of synthetic glyco-
sylphosphatidylinositol glycoconjugates as vaccine candidates against
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 1667
malaria. ACS Chemical Biology 15 (1):171–8. doi: 10.1021/acschem-
bio.9b00739.
Malvasi, A., F. Casciaro, M. Minervini, I. Kosmas, O. Mynbaev, E.
Pacella, V. M. Condesnitt, A. Creanza, D. Renzo, and G. Tinelli.
2014. A. Myo-inositol, D-chiro-inositol, folic acid and manganese in
second trimester of pregnancy: A preliminary investigation.
European Review for Medical and Pharmacological Sciences. 18:
270–274.
Manna, P., and S. K. Jain. 2013. PIP3 but not PIP2 increases GLUT4
surface expression and glucose metabolism mediated by AKT/PKCf/
k phosphorylation in 3T3L1 adipocytes. Molecular and Cellular
Biochemistry 381 (1-2):291–9. doi: 10.1007/s11010-013-1714-7.
Mariggio, S., C. Iurisci, J. Sebastia, J. Patton-Vogt, and D. Corda. 2006.
Molecular characterization of a glycerophosphoinositol transporter
in mammalian cells. FEBS Letters 580 (30):6789–96. doi: 10.1016/j.
febslet.2006.11.039.
Marincola, F. C., A. Dessi, M. G. Pattumelli, S. Corbu, C. Ossicini, S.
Ciccarelli, R. Agostino, M. Mussap, and V. Fanos. 2015. 1H NMR-
based urine metabolic profile of IUGR, LGA, and AGA newborns in
the first week of life. Clinica Chimica Acta; International Journal of
Clinical Chemistry 451:28–34. doi: 10.1016/j.cca.2015.08.008.
Marion, E., P. J. Kaisaki, V. Pouillon, C. Gueydan, J. C. Levy, A.
Bodson, G. Krzentowski, J.-C. Daubresse, J. Mockel, J. Behrends,
et al. 2002. The gene INPPL1, encoding the lipid phosphatase
SHIP2, is a candidate for type 2 diabetes in rat and man. Diabetes
51 (7):2012–7., doi: 10.2337/diabetes.51.7.2012.
Matarrelli, B., E. Vitacolonna, M. D’angelo, G. Pavone, P. A. Mattei,
M. Liberati, and C. Celentano. 2013. Effect of dietary myo-inositol
supplementation in pregnancy on the incidence of maternal gesta-
tional diabetes mellitus and fetal outcomes: A randomized controlled
trial. The Journal of Maternal-Fetal & Neonatal Medicine26 (10):
967–972. doi: 10.3109/14767058.2013.766691.
Maurizi, A. R., M. Menduni, R. Del Toro, S. Kyanvash, D. Maggi, C.
Guglielmi, A. L. Pantano, G. Defeudis, E. Fioriti, S. Manfrini, et al.
2017. A pilot study of d-chiro-inositol plus folic acid in overweight
patients with type 1 diabetes. Acta Diabetologica 54 (4):361–5. doi:
10.1007/s00592-016-0954-x.
Mayer, J., and D. Tomlinson. 1983. Prevention of defects of axonal
transport and nerve conduction velocity by oral administration of
myo-inositol or an aldose reductase inhibitor in streptozotocin-dia-
betic rats. Diabetologia 25 (5):433–8. doi: 10.1007/BF00282524.
McLean, P., S. Kunjara, A. L. Greenbaum, K. Gumaa, J. L opez-Prados,
M. Martin-Lomas, and T. W. Rademacher. 2008. Reciprocal control
of pyruvate dehydrogenase kinase and phosphatase by inositol phos-
phoglycans dynamic state set by “push-pull” system. The Journal of
Biological Chemistry 283 (48):33428–36. doi: 10.1074/jbc.
M801781200.
McPhee, F., C. Downes, and G. Lowe. 1991. Studies of inositol ana-
logues as inhibitors of the phosphoinositide pathway, and incorpor-
ation of 2-deoxy-2-fluoro-myo-inositol to give analogues of
phosphatidylinositol intermediates. Biochemical Journal 277 (2):
407–12. doi: 10.1042/bj2770407.
Mejia, C. A., P. R. Reynolds, and J. A. Arroyo. 2016. Placental expres-
sion of NFAT5, SLC5A3, and aldose reductase in gestational dia-
betes mellitus. The FASEB Journal 30 (851):855–851.
Metzger, B. E., L. P. Lowe, A. R. Dyer, E. R. Trimble, U. Chaovarindr,
D. R. Coustan, D. R. Hadden, D. R. McCance, M. Hod, H. D.
McIntyre, et al. 2008. Hyperglycemia and adverse pregnancy out-
comes. The New England Journal of Medicine 358 (19):1991–2002.
doi: 10.1056/NEJMoa0707943.
Michaelis, T., G. Helms, K. D. Merboldt, W. H€anicke, H. Bruhn, and J.
Frahm. 1993. Identification of scyllo-inositol in proton NMR spectra
of human brain in vivo. NMR in Biomedicine 6 (1):105–109. doi: 10.
1002/nbm.1940060116.
Michaelis, T., G. Helms, K.-D. Merboldt, W. H€anicke, H. Bruhn, and J.
Frahm. 1993. Identification of scyllo-inositol in proton NMR spectra
of human brain in vivo. NMR in Biomedicine 6 (1):105–109. doi: 10.
1002/nbm.1940060116.
1668 O. C. WATKINS ET AL.
Middleton, A., and B. Setchell. 1972. The origin of inositol in the rete
testis fluid of the ram. Reproduction 30 (3):473–475. doi: 10.1530/jrf.
0.0300473.
Miller, A. T., P. P. Chamberlain, and M. P. Cooke. 2008. Beyond IP3:
Roles for higher order inositol phosphates in immune cell signaling.
Cell Cycle (Georgetown, Tex.) 7 (4):463–7. doi: 10.4161/cc.7.4.5518.
Mi~
nambres, I., G. Cuixart, A. Gonçalves, and R. Corcoy. 2019. Effects
of inositol on glucose homeostasis: Systematic review and meta-ana-
lysis of randomized controlled trials. Clinical Nutrition38 (3):
1146–52. doi: 10.1016/j.clnu.2018.06.957.
Mitanchez, D., C. Yzydorczyk, B. Siddeek, F. Boubred, M. Benahmed,
and U. Simeoni. 2015. The offspring of the diabetic mother - Short-
and long-term implications. Best Practice & Research Clinical
Obstetrics & Gynaecology 29 (2):256–269. doi: 10.1016/j.bpobgyn.
2014.08.004.
Moore, C. M., J. L. Breeze, S. A. Gruber, S. M. Babb, B. B. Frederick,
R. A. Villafuerte, A. L. Stoll, J. Hennen, D. A. Yurgelun-Todd, B. M.
Cohen, et al. 2000. Choline, myo-inositol and mood in bipolar dis-
order: A proton magnetic resonance spectroscopic imaging study of
the anterior cingulate cortex. Bipolar Disorders 2 (3 Pt 2):207–16.
doi: 10.1034/j.1399-5618.2000.20302.x.
Moore, G. J., J. M. Bebchuk, J. K. Parrish, M. W. Faulk, C. L. Arfken,
J. Strahl-Bevacqua, and H. K. Manji. 1999. Temporal dissociation
between lithium-induced changes in frontal lobe myo-inositol and
clinical response in manic-depressive illness. The American Journal
of Psychiatry 156 (12):1902–8. doi: 10.1176/ajp.156.12.1902.
Mueckler, M., and B. Thorens. 2013. The SLC2 (GLUT) family of
membrane transporters. Molecular Aspects of Medicine 34 (2-3):
121–138. doi: 10.1016/j.mam.2012.07.001.
M€
uller, G., S. Wied, C. Piossek, A. Bauer, J. Bauer, and W. Frick. 1998.
Convergence and divergence of the signaling pathways for insulin
and phosphoinositolglycans. Molecular Medicine 4 (5):299–323. doi:
10.1007/BF03401738.
Murphy, A., A. Shamshirsaz, D. Markovic, R. Ostlund, and B. Koos.
2016. Urinary excretion of myo-inositol and d-chiro-inositol in early
pregnancy is enhanced in gravidas with gestational diabetes mellitus.
Reproductive Sciences (Thousand Oaks, Calif.) 23 (3):365–371. doi:
10.1177/1933719115602767.
Muscogiuri, G., S. Palomba, A. S. Lagana, and F. Orio. 2016. Inositols
in the treatment of insulin-mediated diseases. International Journal
of Endocrinology 2016:1. doi: 10.1155/2016/6189820.
Nagamatsu, S., and M. Ohara-Imaizumi. 2007. IP7 debut in insulin
release. Science318 (5854):1249–50. doi: 10.1126/science.1151361.
Nakamura, J., M. A. Del Monte, D. Shewach, S. A. Lattimer, and D. A.
Greene. 1992. Inhibition of phosphatidylinositol synthase by glucose
in human retinal pigment epithelial cells. American Journal of
Physiology-Endocrinology and Metabolism 262 (4):E417–E426. doi:
10.1152/ajpendo.1992.262.4.E417.
Napso, T., H. E. J. Yong, J. Lopez-Tello, and A. N. Sferruzzi-Perri.
2018. The role of placental hormones in mediating maternal adapta-
tions to support pregnancy and lactation. Frontiers in Physiology 9:
1091 doi: 10.3389/fphys.2018.01091.
Nascimento, N. R., L. M. Lessa, M. R. Kerntopf, C. M. Sousa, R. S.
Alves, M. G. Queiroz, J. Price, D. B. Heimark, J. Larner, X. Du,
et al. 2006. Inositols prevent and reverse endothelial dysfunction in
diabetic rat and rabbit vasculature metabolically and by scavenging
superoxide. Proceedings of the National Academy of Sciences of the
United States of America 103 (1):218–23. doi: 10.1073/pnas.
0509779103.
Navarro-Gonzalez, J. F., A. Jarque, M. Muros, C. Mora, and J. Garcıa.
2009. Tumor necrosis factor-a as a therapeutic target for diabetic
nephropathy. Cytokine & Growth Factor Reviews 20 (2):165–73. doi:
10.1016/j.cytogfr.2009.02.005.
Nestler, J. E., and V. Unfer. 2015. Reflections on inositol(s) for PCOS
therapy: Steps toward success. Gynecological Endocrinology31 (7):
501–5. doi: 10.3109/09513590.2015.1054802.
Nestler, J. E., D. J. Jakubowicz, A. F. de Vargas, C. Brik, N. Quintero,
and F. Medina. 1998. Insulin stimulates testosterone biosynthesis by
human thecal cells from women with polycystic ovary syndrome by
activating its own receptor and using inositolglycan mediators as the
signal transduction system. The Journal of Clinical Endocrinology
and Metabolism 83 (6):2001–5. doi: 10.1210/jcem.83.6.4886.
Nestler, J. E., D. J. Jakubowicz, P. Reamer, R. D. Gunn, and G. Allan.
1999. Ovulatory and metabolic effects of D-chiro-inositol in the
polycystic ovary syndrome. New England Journal of Medicine 340
(17):1314–20. doi: 10.1056/NEJM199904293401703.
Newsholme, P., E. Haber, S. Hirabara, E. Rebelato, J. Procopio, D.
Morgan, H. Oliveira-Emilio, A. R. Carpinelli, and R. Curi. 2007.
Diabetes associated cell stress and dysfunction: Role of mitochon-
drial and non-mitochondrial ROS production and activity. The
Journal of Physiology 583 (Pt 1):9–24. doi: 10.1113/jphysiol.2007.
135871.
Nielson, J. R., and J. P. Rutter. 2018. Lipid-mediated signals that regu-
late mitochondrial biology. Journal of Biological Chemistry 001655
Nissen, P. M., C. Nebel, N. Oksbjerg, and H. C. Bertram. 2011.
Metabolomics reveals relationship between plasma inositols and
birth weight: Possible markers for fetal programming of type 2 dia-
betes. Journal of Biomedicine and Biotechnology 2011:1–8. doi: 10.
1155/2011/378268.
Noble, K., J. Zhang, and S. Wray. 2006. Lipid rafts, the sarcoplasmic
reticulum and uterine calcium signalling: An integrated approach.
The Journal of Physiology 570 (Pt 1):29–35. doi: 10.1113/jphysiol.
2005.098475.
Nordio, M., and E. Proietti. 2012. The combined therapy with myo-
inositol and D-chiro-inositol reduces the risk of metabolic disease in
PCOS overweight patients compared to myo-inositol supplementa-
tion alone. European Review for Medical and Pharmacological
Sciences 16 (5):575–81.
Noventa, M., A. Vitagliano, M. Quaranta, S. Borgato, B. Abdulrahim,
and S. Gizzo. 2016. Preventive and therapeutic role of dietary inosi-
tol supplementation in periconceptional period and during preg-
nancy: A summary of evidences and future applications.
Reproductive Sciences (Thousand Oaks, Calif.) 23 (3):278–88. doi: 10.
1177/1933719115594018.
Nozadze, M., E. Mikautadze, E. Lepsveridze, E. Mikeladze, N.
Kuchiashvili, T. Kiguradze, M. Kikvidze, and R. Solomonia. 2011.
Anticonvulsant activities of myo-inositol and scyllo-inositol on pen-
tylenetetrazol induced seizures. Seizure20 (2):173–176. doi: 10.1016/j.
seizure.2010.10.008.
Oben, J. A., A. Mouralidarane, A.-M. Samuelsson, P. J. Matthews,
M. L. Morgan, C. McKee, J. Soeda, D. S. Fernandez-Twinn, M. S.
Martin-Gronert, S. E. Ozanne, et al. 2010. Maternal obesity during
pregnancy and lactation programs the development of offspring
non-alcoholic fatty liver disease in mice. Journal of Hepatology 52
(6):913–20. doi: 10.1016/j.jhep.2009.12.042.
Ortmeyer, H. K. 1996. Dietary myoinositol results in lower urine glu-
cose and in lower postprandial plasma glucose in obese insulin
resistant rhesus monkeys. Obesity Research 4 (6):569–75. doi: 10.
1002/j.1550-8528.1996.tb00271.x.
Ortmeyer, H. K., L. C. Huang, L. Zhang, B. C. Hansen, and J. Larner.
1993. Chiroinositol deficiency and insulin resistance. II. Acute
effects of D-chiroinositol administration in streptozotocin-diabetic
rats, normal rats given a glucose load, and spontaneously insulin-
resistant rhesus monkeys. Endocrinology 132 (2):646–51. doi: 10.
1210/endo.132.2.8425484.
Ortmeyer, H. K., N. Bodkin, K. Lilley, J. Larner, and B. C. Hansen.
1993. Chiroinositol deficiency and insulin resistance. I. Urinary
excretion rate of chiroinositol is directly associated with insulin
resistance in spontaneously diabetic rhesus monkeys. Endocrinology
132 (2):640–5. doi: 10.1210/endo.132.2.8425483.
Ostlund, R. E., J. B. McGill, I. Herskowitz, D. M. Kipnis, J. V.
Santiago, and W. R. Sherman. 1993. D-chiro-inositol metabolism in
diabetes mellitus. Proceedings of the National Academy of Sciences 90
(21):9988–92. doi: 10.1073/pnas.90.21.9988.
Owczarczyk-Saczonek, A., L. B. Lahuta, M. Ligor, W. Placek, R. J.
Gorecki, and B. Buszewski. 2018. The healing-promoting properties
of selected cyclitols—A review. Nutrients 10 (12):1891. doi: 10.3390/
nu10121891.
Paine, M. A., M. Scioscia, P. J. Williams, K. Gumaa, C. H. Rodeck, and
T. W. Rademacher. 2010. Urinary inositol phosphoglycan P-type as

a marker for prediction of preeclampsia and novel implications for
the pathophysiology of this disorder. Hypertension in Pregnancy 29
(4):375–384. doi: 10.3109/10641950903242667.
Paine, M., C. Rodeck, P. Williams, and T. Rademacher. 2003. Possible
involvement of inositol phosphoglycan-P in human parturition.
Journal of Reproductive Immunology 59 (2):267–75. doi: 10.1016/
S0165-0378(03)00053-6.
Paine, M., M. Scioscia, K. A. Gumaa, C. Rodeck, and T. Rademacher.
2006. P-type inositol phosphoglycans in serum and amniotic fluid in
active pre-eclampsia. Journal of Reproductive Immunology 69 (2):
165–79. doi: 10.1016/j.jri.2005.09.008.
Pak, Y., and J. Larner. 1992. Identification and characterization of chi-
roinositol-containing phospholipids from bovine liver. Biochemical
and Biophysical Research Communications 184 (2):1042–7. doi: 10.
1016/0006-291X(92)90696-I.
Pak, Y., C. R. Paule, Y.-D. Bao, L. C. Huang, and J. Larner. 1993.
Insulin stimulates the biosynthesis of chiro-inositol-containing phos-
pholipids in a rat fibroblast line expressing the human insulin recep-
tor. Proceedings of the National Academy of Sciences 90 (16):
7759–7763. doi: 10.1073/pnas.90.16.7759.
Pak, Y., L. C. Huang, K. J. Lilley, and J. Larner. 1992. In vivo conver-
sion of [3H]myoinositol to [3H]chiroinositol in rat tissues. Journal
of Biological Chemistry 267:16904–16910.
Pak, Y., Y. Hong, S. Kim, T. Piccariello, R. V. Farese, and J. Larner.
1998. Vivo chiro-Inositol Metabolism in the Rat: A Defect in
chiroInositol Synthesis from myo-Inositol and an Increased
Incorporation of chiro-[3H] lnositol into Phospholipid in the Goto-
Kakizaki (GK) Rat. Molecules & Cells, 8. Springer Science &
Business Media BV.
Palmano, K., P. H. Whiting, and J. N. Hawthorne. 1977. Free and lipid
myo-inositol in tissues from rats with acute and less severe strepto-
zotocin-induced diabetes. The Biochemical Journal 167 (1):229–35.
doi: 10.1042/bj1670229.
Papaleo, E., V. Unfer, J. Baillargeon, and T. Chiu. 2009. Contribution
of myo-inositol to reproduction. European Journal of Obstetrics &
Gynecology and Reproductive Biology 147 (2):120–123. doi: 10.1016/j.
ejogrb.2009.09.008.
Papaleo, E., V. Unfer, J.-P. Baillargeon, L. De Santis, F. Fusi, C.
Brigante, G. Marelli, I. Cino, A. Redaelli, and A. Ferrari. 2007. Myo-
inositol in patients with polycystic ovary syndrome: A novel method
for ovulation induction. Gynecological Endocrinology 23 (12):700–3.
doi: 10.1080/09513590701672405.
Parpal, S., J. Gustavsson, and P. Strålfors. 1995. Isolation of phosphoo-
ligosaccharide/phosphoinositol glycan from caveolae and cytosol of
insulin-stimulated cells. The Journal of Cell Biology 131 (1):125–135.
doi: 10.1083/jcb.131.1.125.
Parthasarathy, R., L. Parthasarathy, and R. Vadnal. 1997. Brain inositol
monophosphatase identified as a galactose 1-phosphatase. Brain
Research 778 (1):99–106. doi: 10.1016/S0006-8993(97)01042-1.
Pascente, R., F. Frigerio, M. Rizzi, L. Porcu, M. Boido, J. Davids, M.
Zaben, D. Tolomeo, M. Filibian, W. P. Gray, et al. 2016. Cognitive
deficits and brain myo-Inositol are early biomarkers of epileptogene-
sis in a rat model of epilepsy. Neurobiology of Disease 93:146–155.
doi: 10.1016/j.nbd.2016.05.001.
Patrussi, L., S. Mariggio, D. Corda, and C. Baldari. 2013. The glycero-
phosphoinositols: From lipid metabolites to modulators of T-cell
signaling. Frontiers in Immunology 4 doi: 10.3389/fimmu.2013.
00213.
Paul, C., and D. M. Brady. 2015. Inositol modulation of essential meta-
bolic pathways of insulin resistance in metabolic syndrome, polycys-
tic ovarian syndrome, and type 2 diabetes. Enzyme (GS) 7:16.
Paulick, M. G., and C. R. Bertozzi. 2008. The
Glycosylphosphatidylinositol Anchor: A Complex Membrane-
Anchoring Structure for Proteins. Biochemistry 47 (27):6991–7000.
doi: 10.1021/bi8006324.
Pedersen, J. 1952. Diabetes and pregnancy; blood sugar of newborn
infants during fasting and glucose administration. Nordisk Medicin
47 (30):1049.
Pereira, G. R., L. Baker, J. Egler, L. Corcoran, and R. Chiavacci. 1990.
Serum myoinositol concentrations in premature infants fed human
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 1669
milk, formula for infants, and parenteral nutrition. The American
Journal of Clinical Nutrition 51 (4):589–593. doi: 10.1093/ajcn/51.4.
589.
Perez-Perez, A., P. Guadix, J. Maymo, J. L. Due~ nas, C. Varone, M.
Fernandez-Sanchez, and V. Sanchez-Margalet. 2016. Insulin and lep-
tin signaling in placenta from gestational diabetic subjects. Hormone
and Metabolic Research ¼ Hormon- Und
Stoffwechselforschung ¼ Hormones et Metabolisme 48 (1):62–69. doi:
10.1055/s-0035-1559722.
Peters, T., B. Chapman, M. Wolfe, and M. Soares. 2000. Placental lac-
togen-I gene activation in differentiating trophoblast cells: Extrinsic
and intrinsic regulation involving mitogen-activated protein kinase
signaling pathways. The Journal of Endocrinology 165 (2):443–456.
doi: 10.1677/joe.0.1650443.
Petit, A., G. Guillon, M. Tence, S. Jard, N. Gallo-Payet, D. Bellabarba,
J. G. Lehoux, and S. Belisle. 1989. Angiotensin II stimulates both
inositol phosphate production and human placental lactogen release
from human trophoblastic cells. The Journal of Clinical
Endocrinology and Metabolism 69 (2):280–286. doi: 10.1210/jcem-69-
2-280.
Pettitt, T. R., S. K. Dove, A. Lubben, S. D. Calaminus, and M. J.
Wakelam. 2006. Analysis of intact phosphoinositides in biological
samples. Journal of Lipid Research 47 (7):1588–96. doi: 10.1194/jlr.
D600004-JLR200.
Philipps, L., S. Santhakumaran, C. Gale, E. Prior, K. Logan, M. Hyde,
and N. Modi. 2011. The diabetic pregnancy and offspring BMI in
childhood: A systematic review and meta-analysis. Diabetologia 54
(8):1957–1966. doi: 10.1007/s00125-011-2180-y.
Pillai, R. A., Islam M. O., P. Selvam, N. Sharma, A. H. Chu, O. C.
Watkins, K. M. Godfrey, R. M. Lewis, and S. Y. Chan 2020.
Placental inositol reduced in gestational diabetes as glucose alters
inositol transporters and IMPA1 enzyme expression. JCEM. In press
Pintaudi, B., G. Di Vieste, and M. Bonomo. 2016. The effectiveness of
myo-inositol and D-chiro inositol treatment in type 2 diabetes.
International Journal of Endocrinology 2016:1–5. doi: 10.1155/2016/
9132052.
Plows, J. F., F. Budin, R. A. Andersson, V. J. Mills, K. Mace, S. T.
Davidge, M. H. Vickers, P. N. Baker, I. Silva-Zolezzi, and J. L.
Stanley. 2017. The effects of myo-inositol and B and D vitamin sup-
plementation in the db/þ mouse model of gestational diabetes mel-
litus. Nutrients 9 (2):141. doi: 10.3390/nu9020141.
Plows, J., J. R. Nieves, F. Budin, K. Mace, C. Reynolds, M. Vickers, I.
Silva-Zolezzi, P. Baker, and J. Stanley. 2020. The effects of myo-
inositol and probiotic supplementation in a high fat fed preclinical
model of glucose intolerance in pregnancy. British Journal of
Nutrition 123 (5):516–39. doi: 10.1017/S0007114519003039.
Poston, L., R. Bell, H. Croker, A. C. Flynn, K. M. Godfrey, L. Goff, L.
Hayes, N. Khazaezadeh, S. M. Nelson, E. Oteng-Ntim, et al. 2015.
Effect of a behavioural intervention in obese pregnant women (the
UPBEAT study): A multicentre, randomised controlled trial. The
Lancet. Diabetes & Endocrinology 3 (10):767–777. doi: 10.1016/
S2213-8587(15)00227-2.
Prynne, C. J., A. McCarron, M. E. Wadsworth, and A. M. Stephen.
2010. Dietary fibre and phytate–a balancing act: Results from three
time points in a British Birth Cohort. British Journal of Nutrition
103 (2):274–80. doi: 10.1017/S0007114509991644.
Pugliese, G., R. G. Tilton, A. Speedy, E. Santarelli, D. M. Eades, M. A.
Province, C. Kilo, W. R. Sherman, and J. R. Williamson. 1990.
Modulation of hemodynamic and vascular filtration changes in dia-
betic rats by dietary myo-inositol. Diabetes 39 (3):312–22. doi: 10.
2337/diab.39.3.312.
Pundir, J., D. Psaroudakis, P. Savnur, P. Bhide, L. Sabatini, H. Teede,
A. Coomarasamy, and S. Thangaratinam. 2018. Inositol treatment of
anovulation in women with polycystic ovary syndrome: A meta-ana-
lysis of randomised trials. BJOG: An International Journal of
Obstetrics & Gynaecology 125 (3):299–308. doi: 10.1111/1471-0528.
14754.
Quirk, J. G., Jr., and J. E. Bleasdale. 1983. myo-Inositol homeostasis in
the human fetus. Obstetrics and Gynecology 62 (1):41–44.
1670 O. C. WATKINS ET AL.
Rajasekaran, S. S., J. Kim, G.-C. Gaboardi, J. Gromada, S. B. Shears,
K. T. dos Santos, E. L. Nolasco, S. d S. Ferreira, C. Illies, M. K€
ohler,
et al. 2018. Inositol hexakisphosphate kinase 1 is a metabolic sensor
in pancreatic b-cells. Cellular Signalling 46:120–8. doi: 10.1016/j.cell-
sig.2018.03.001.
Reeves, V. L., C. M. Thomas, and E. J. Smart. 2012. Lipid rafts, caveo-
lae and GPI-linked proteins, 3–13. Caveolins and Caveolae: Springer.
Regidor, P.-A., A. E. Schindler, B. Lesoine, and R. Druckman. 2018.
Management of women with PCOS using myo-inositol and folic
acid. New clinical data and review of the literature. Hormone
Molecular Biology and Clinical Investigation 0 (0) doi: 10.1515/
hmbci-2017-0067.
Roach, J. C., K. Deutsch, S. Li, A. F. Siegel, L. M. Bekris, D. C.
Einhaus, C. M. Sheridan, G. Glusman, L. Hood, A. Lernmark, et al.
2006. Genetic mapping at 3-kilobase resolution reveals inositol
1,4,5-triphosphate receptor 3 as a risk factor for type 1 diabetes in
Sweden. American Journal of Human Genetics 79 (4):614–27., doi:
10.1086/507876.
Roll, P., A. Massacrier, S. Pereira, A. Robaglia-Schlupp, P. Cau, and P.
Szepetowski. 2002. New human sodium/glucose cotransporter gene
(KST1): Identification, characterization, and mutation analysis in
ICCA (infantile convulsions and choreoathetosis) and BFIC (benign
familial infantile convulsions) families. Gene 285 (1-2):141–148. doi:
10.1016/S0378-1119(02)00416-X.
Romero, G., and J. Larner. 1993. Insulin mediators and the mechanism
of insulin action. Advances in pharmacology. Vol 24, 21–50. Elsevier.
Rubin, L. J., and C. C. Hale. 1993. Characterization of a Mg-dependent,
Na-inositol Co-transport process in cardiac sarcolemmal vesicles.
Journal of Molecular and Cellular Cardiology 25 (6):721–731. doi:
10.1006/jmcc.1993.1084.
Ruchat, S. M., M. F. Hivert, and L. Bouchard. 2013. Epigenetic pro-
gramming of obesity and diabetes by in utero exposure to gesta-
tional diabetes mellitus. Nutrition Reviews 71 (Suppl 1):S88–S94. doi:
10.1111/nure.12057.
Sacks, D. A., D. R. Hadden, M. Maresh, C. Deerochanawong, A. R.
Dyer, B. E. Metzger, L. P. Lowe, D. R. Coustan, M. Hod, J. J. Oats,
et al. 2012. Frequency of gestational diabetes mellitus at collaborat-
ing centers based on IADPSG consensus panel-recommended crite-
ria: The Hyperglycemia and Adverse Pregnancy Outcome (HAPO)
Study. Diabetes Care 35 (3):526–528. doi: 10.2337/dc11-1641.
Salman, M., J. T. Lonsdale, G. S. Besra, and P. J. Brennan. 1999.
Phosphatidylinositol synthesis in mycobacteria. Biochimica et
Biophysica Acta 1436 (3):437–450. doi: 10.1016/S0005-
2760(98)00151-9.
Saltiel, A. R. 1990. Second messengers of insulin action. Diabetes Care
13 (3):244–56. doi: 10.2337/diacare.13.3.244.
Sampson, M., M. Wolf, R. Thadhani, J. L. Ecker, E. W. Seely, C. Lam,
S. A. Karumanchi, V. P. Sukhatme, A. S. M. Shakir, A. Daftary,
et al. 2004. Preeclampsia and future cardiovascular disease: Potential
role of altered angiogenesis and insulin resistance. The Journal of
Clinical Endocrinology & Metabolism 89 (12):6239–6243. doi: 10.
1210/jc.2004-0548.
Santamaria, A., A. Alibrandi, A. Di Benedetto, B. Pintaudi, F. Corrado,
F. Facchinetti, and R. D’Anna. 2018. Clinical and metabolic out-
comes in pregnant women at risk for gestational diabetes mellitus
supplemented with myo-inositol: A secondary analysis from 3 RCTs.
American Journal of Obstetrics and Gynecology 219 (3):
300.e1–300.e6. doi: 10.1016/j.ajog.2018.05.018.
Santamaria, A., A. Di Benedetto, E. Petrella, B. Pintaudi, F. Corrado, R.
D’Anna, I. Neri, and F. Facchinetti. 2016. Myo-inositol may prevent
gestational diabetes onset in overweight women: A randomized, con-
trolled trial. The Journal of Maternal-Fetal & Neonatal Medicine 29
(19):3234–3237. doi: 10.3109/14767058.2015.1121478.
Santamaria, A., D. Giordano, F. Corrado, B. Pintaudi, M. Interdonato,
G. D. Vieste, A. D. Benedetto, and R. D’Anna. 2012. One-year
effects of myo-inositol supplementation in postmenopausal women
with metabolic syndrome. Climacteric15 (5):490–495. doi: 10.3109/
13697137.2011.631063.
Santamaria, A., F. Corrado, G. Baviera, G. Carlomagno, V. Unfer, and
R. D’anna. 2016. Second trimester amniotic fluid myo-inositol
concentrations in women later developing gestational diabetes melli-
tus or pregnancy-induced hypertension. The Journal of Maternal-
Fetal & Neonatal Medicine 29 (14):2245–2247. doi: 10.3109/
14767058.2015.1081886.
Santamaria, A., F. Corrado, M. L. Interdonato, G. Baviera, G.
Carlomagno, P. Cavalli, V. Unfer, and R. D’Anna. 2014. Myo-inosi-
tol in Down syndrome amniotic fluid. A case-control study.
Prenatal Diagnosis 34 (9):917–8. doi: 10.1002/pd.4398.
Satake, W., Y. Nakabayashi, I. Mizuta, Y. Hirota, C. Ito, M. Kubo, T.
Kawaguchi, T. Tsunoda, M. Watanabe, A. Takeda, et al. 2009.
Genome-wide association study identifies common variants at four
loci as genetic risk factors for Parkinsons disease. Nature Genetics
41 (12):1303–1307. doi: 10.1038/ng.485.
Sayers, N., and A. C. Hanyaloglu. 2018. Intracellular follicle-stimulating
hormone receptor trafficking and signaling. Frontiers in
Endocrinology 9:653. doi: 10.3389/fendo.2018.00653.
Schaefer, -Graf, U., Meitzner, K. Ortega,-Senovilla, H. Graf, K. Vetter,
K. Abou-Dakn, M. Herrera. and E. 2011. Differences in the implica-
tions of maternal lipids on fetal metabolism and growth between
gestational diabetes mellitus and control pregnancies. Diabetic
Medicine 28 (9):1053–1059. doi: 10.1111/j.1464-5491.2011.03346.x.
Schaefer-Graf, U. M., K. Graf, I. Kulbacka, S. L. Kjos, J. Dudenhausen,
K. Vetter, and E. Herrera. 2008. Maternal lipids as strong determi-
nants of fetal environment and growth in pregnancies with gesta-
tional diabetes mellitus. Diabetes Care 31 (9):1858–1863. doi: 10.
2337/dc08-0039.
Schlemmer, U., W. Frølich, R. M. Prieto, and F. Grases. 2009. Phytate
in foods and significance for humans: Food sources, intake, process-
ing, bioavailability, protective role and analysis. Molecular Nutrition
& Food Research 53 (S2):S330–S375. doi: 10.1002/mnfr.200900099.
Schneider, S. 2015. Inositol transport proteins. FEBS Letters 589 (10):
1049–1058. doi: 10.1016/j.febslet.2015.03.012.
Schrey, M. P., A. M. Read, and P. J. Steer. 1987. Stimulation of
phospholipid hydrolysis and arachidonic acid mobilization in
human uterine decidua cells by phorbol ester. The Biochemical
Journal 246 (3):705–713. doi: 10.1042/bj2460705.
Schrey, M. P., J. R. Holt, P. A. Cornford, H. Monaghan, and F. Al-
Ubaidi. 1992. Human decidua is a target tissue for bradykinin and
kallikrein: Phosphoinositide hydrolysis accompanies arachidonic
acid release in uterine decidua cells in vitro. The Journal of clinical
Endocrinology and Metabolism 74 (2):426–435. doi: 10.1210/jcem.74.
2.1309839.
Schwartz, R., P. A. Gruppuso, K. Petzold, D. Brambilla, V. Hiilesmaa,
and K. A. Teramo. 1994. Hyperinsulinemia and macrosomia in the
fetus of the diabetic mother. Diabetes Care 17 (7):640–648. doi: 10.
2337/diacare.17.7.640.
Scioscia, M. 2017. D-chiro inositol phosphoglycans in preeclampsia:
Where are we, where are we going? Journal of Reproductive
Immunology 124:1–7. doi: 10.1016/j.jri.2017.09.010.
Scioscia, M., A. Pesci, G. Zamboni, B. Huppertz, and L. Resta. 2013.
D-chiro-inositol phosphoglycan expression in human placenta at
term in diabetes. Archives of Gynecology and Obstetrics 288 (2):
459–60. doi: 10.1007/s00404-013-2729-8.
Scioscia, M., K. Gumaa, and T. W. Rademacher. 2009. The link
between insulin resistance and preeclampsia: New perspectives.
Journal of Reproductive Immunology 82 (2):100–5. doi: 10.1016/j.jri.
2009.04.009.
Scioscia, M., K. Gumaa, L. E. Selvaggi, C. H. Rodeck, and T. W.
Rademacher. 2009. Increased inositol phosphoglycan P-type in the
second trimester in pregnant women with type 2 and gestational
diabetes mellitus. Journal of Perinatal Medicine 37 (5):469–471. doi:
10.1515/JPM.2009.082.
Scioscia, M., K. Gumaa, M. Whitten, L. E. Selvaggi, C. H. Rodeck, and
T. W. Rademacher. 2007. Inositol phosphoglycan P-type in healthy
and preeclamptic pregnancies. Journal of Reproductive Immunology
76 (1-2):85–90. doi: 10.1016/j.jri.2007.03.016.
Scioscia, M., K. Gumaa, S. Kunjara, M. A. Paine, L. E. Selvaggi, C. H.
Rodeck, and T. W. Rademacher. 2006. Insulin resistance in human
preeclamptic placenta is mediated by serine phosphorylation of

insulin receptor substrate-1 and-2. The Journal of Clinical
Endocrinology & Metabolism 91 (2):709–17. doi: 10.1210/jc.2005-
1965.
Scioscia, M., M. A. Paine, K. Gumaa, C. H. Rodeck, and T. W.
Rademacher. 2008. Release of inositol phosphoglycan P-type by the
human placenta following insulin stimulus: A multiple comparison
between preeclampsia, intrauterine growth restriction, and gesta-
tional hypertension. The Journal of Maternal-Fetal & Neonatal
Medicine 21 (8):581–5. doi: 10.1080/14767050802199934.
Scioscia, M., P. J. Williams, K. Gumaa, N. Fratelli, C. Zorzi, and T. W.
Rademacher. 2011. Inositol phosphoglycans and preeclampsia: From
bench to bedside. Journal of Reproductive Immunology 89 (2):
173–177. doi: 10.1016/j.jri.2011.03.001.
Scioscia, M., S. Kunjara, K. Gumaa, A. M. Gomez Galan, P. McLean,
C. H. Rodeck, and T. W. Rademacher. 2007. Altered urinary release
of inositol phosphoglycan A-type in women with gestational dia-
betes mellitus. Gynecologic and Obstetric Investigation 64 (4):217–23.
doi: 10.1159/000106494.
Scioscia, M., S. Kunjara, K. Gumaa, P. McLean, C. Rodeck, and T.
Rademacher. 2007. Urinary excretion of inositol phosphoglycan P-
type in gestational diabetes mellitus. Diabetic Medicine 24 (11):
1300–1304. doi: 10.1111/j.1464-5491.2007.02267.x.
Seaquist, E. R., and R. Gruetter. 1998. Identification of a high concen-
tration of scyllo-inositol in the brain of a healthy human subject
using 1H- and 13C-NMR . Magnetic Resonance in Medicine 39 (2):
313–316. doi: 10.1002/mrm.1910390220.
Seely, E. W., and C. G. Solomon. 2003. Insulin resistance and its
potential role in pregnancy-induced hypertension. The Journal of
Clinical Endocrinology and Metabolism 88 (6):2393–2398. doi: 10.
1210/jc.2003-030241.
Shaldubina, A., R. Buccafusca, R. Johanson, G. Agam, R. Belmaker, G.
Berry, and Y. Bersudsky. 2007. Behavioural phenotyping of sodium-
myo-inositol cotransporter heterozygous knockout mice with
reduced brain inositol. Genes, Brain and Behavior 6 (3):253–259.
doi: 10.1111/j.1601-183X.2006.00253.x.
Sharma, K., L. Wang, Y. Zhu, A. DeGuzman, G.-Y. Cao, R. B. Lynn,
and S. K. Joseph. 1999. Renal type I inositol 1, 4, 5-trisphosphate
receptor is reduced in streptozotocin-induced diabetic rats and mice.
American Journal of Physiology-Renal Physiology 276 (1):F54–F61.
doi: 10.1152/ajprenal.1999.276.1.F54.
Shears, S. B. 2015. Inositol pyrophosphates: Why so many phosphates?
Advances in Biological Regulation 57:203–16. doi: 10.1016/j.jbior.
2014.09.015.
Sherman, W. R., M. A. Stewart, M. M. Kurien, and S. L. Goodwin.
1968. The measurement of myo-inositol, myo-inosose-2 and scyllo-
inositol in mammalian tissues. Biochimica et Biophysica Acta
(Bba) - General Subjects 158 (2):197–205. doi: 10.1016/0304-
4165(68)90131-1.
Sherman, W. R., M. A. Stewart, P. C. Simpson, and S. L. Goodwin.
1968. The identification of myo-inosose-2 and scyllo-inositol in
mammalian tissues. Biochemistry 7 (2):819–824. doi: 10.1021/
bi00842a040.
Sherman, W. R., S. L. Goodwin, and K. D. Gunnell. 1971. neo-Inositol
in mammalian tissues. Identification, measurement, and enzymic
synthesis from mannose 6-phosphate. Biochemistry 10 (19):
3491–3499. doi: 10.1021/bi00795a002.
Shewan, A., D. J. Eastburn, and K. Mostov. 2011. Phosphoinositides in
cell architecture. Cold Spring Harbor Perspectives in Biology 3 (8):
a004796. doi: 10.1101/cshperspect.a004796.
Shimon, H., Y. Sobolev, M. Davidson, V. Haroutunian, R. H.
Belmaker, and G. Agam. 1998. Inositol levels are decreased in post-
mortem brain of schizophrenic patients. Biological Psychiatry 44 (6):
428–432. doi: 10.1016/S0006-3223(98)00071-7.
Shin, J.-A., H.-M. Kwon, K.-H. Han, and H.-Y. Lee. 2012. TonEBP and
SMIT expression in human placenta. Anatomy & Cell Biology 45
(3):155–159. doi: 10.5115/acb.2012.45.3.155.
Siddle, K. 2011. Signalling by insulin and IGF receptors: Supporting
acts and new players. Journal of Molecular Endocrinology 47 (1):
R1–R10. doi: 10.1530/JME-11-0022.
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 1671
Silverstone, P. H., B. M. McGrath, and H. Kim. 2005. Bipolar disorder
and myo-inositol: A review of the magnetic resonance spectroscopy
findings. Bipolar Disorders 7 (1):1–10. doi: 10.1111/j.1399-5618.2004.
00174.x.
Simons, K., and R. Ehehalt. 2002. Cholesterol, lipid rafts, and disease.
The Journal of Clinical Investigation 110 (5):597–603. doi: 10.1172/
JCI16390.
Soeda, Y., H. Tsuneki, H. Muranaka, N. Mori, S. Hosoh, Y. Ichihara, S.
Kagawa, X. Wang, N. Toyooka, Y. Takamura, et al. 2010. The inosi-
tol phosphatase SHIP2 negatively regulates insulin/IGF-I actions
implicated in neuroprotection and memory function in mouse brain.
Molecular Endocrinology (Baltimore, Md.) 24 (10):1965–77. doi: 10.
1210/me.2010-0163.
Solomonia, R., E. Mikautadze, M. Nozadze, N. Kuchiashvili, E.
Lepsveridze, and T. Kiguradze. 2010. Myo-inositol treatment pre-
vents biochemical changes triggered by kainate-induced status epi-
lepticus. Neuroscience Letters 468 (3):277–81. doi: 10.1016/j.neulet.
2009.11.012.
Staat, B. C., H. L. Galan, J. E. Harwood, G. Lee, A. M. Marconi, C. L.
Paolini, A. Cheung, and F. C. Battaglia. 2012. Transplacental supply
of mannose and inositol in uncomplicated pregnancies using stable
isotopes. The Journal of Clinical Endocrinology and Metabolism 97
(7):2497–2502. doi: 10.1210/jc.2011-1800.
Stamler, C. J., D. Breznan, T. A. Neville, F. J. Viau, E. Camlioglu, and
D. L. Sparks. 2000. Phosphatidylinositol promotes cholesterol trans-
port in vivo. Journal of Lipid Research 41 (8):1214–21.
Stanirowski, P. J., D. Szukiewicz, M. Pyzlak, N. Abdalla, W. Sawicki,
and K. Cendrowski. 2017. Impact of pre-gestational and gestational
diabetes mellitus on the expression of glucose transporters GLUT-1,
GLUT-4 and GLUT-9 in human term placenta. Endocrine 55 (3):
799–808. doi: 10.1007/s12020-016-1202-4.
Steegers-Theunissen, R., P. Groenen, and P. Beemster. 2002.
Involvement of Inositol in Reproduction. Nutrition Reviews 60 (3):
80–87. doi: 10.1301/00296640260042748.
Steer, T. E., and G. R. Gibson. 2002. The microbiology of phytic acid
metabolism by gut bacteria and relevance for bowel cancer.
International Journal of Food Science and Technology 37 (7):783–90.
doi: 10.1046/j.1365-2621.2002.00616.x.
Stewart, M. A., W. R. Sherman, and J. T. Harris. 1970. Effects of gal-
actose on levels of free myo-inositol in rat tissues. Annals of the
New York Academy of Sciences 165:609–614.
Stokes, C. E., and J. N. Hawthorne. 1987. Reduced phosphoinositide
concentrations in anterior temporal cortex of Alzheimer-diseased
brains. Journal of Neurochemistry 48 (4):1018–1021. doi: 10.1111/j.
1471-4159.1987.tb05619.x.
Stokes, C. E., K. R. W. Gillon, and J. N. Hawthorne. 1983. Free and
total lipid myo-inositol concentrations decrease with age in human
brain. Biochimica et Biophysica Acta (BBA) - Lipids and Lipid
Metabolism 753 (1):136–138. doi: 10.1016/0005-2760(83)90108-X.
Strange, K., F. Emma, A. Paredes, and R. Morrison. 1994.
Osmoregulatory changes in Myo-inositol content and Naþ/Myo-
inositol contransport in rat cortical astrocytes. Glia 12 (1):35–43.
doi: 10.1002/glia.440120105.
Strieleman, P. J., M. A. Connors, and B. E. Metzger. 1992.
Phosphoinositide metabolism in the developing conceptus. Effects of
hyperglycemia and scyllo-inositol in rat embryo culture. Diabetes 41
(8):989–997. doi: 10.2337/diab.41.8.989.
Strieleman, P., and B. E. Metzger. 1993. Glucose and scyllo-inositol
impair phosphoinositide hydrolysis in the 10.5-day cultured rat con-
ceptus: a role in dysmorphogenesis? Teratology 48 (3):267–278. doi:
10.1002/tera.1420480310.
Strieleman, P., M. Connors, and B. E. Metzger. 1992. Phosphoinositide
metabolism in the developing conceptus: Effects of hyperglycemia
and scyllo-inositol in rat embryo culture. Diabetes 41 (8):989–997.
doi: 10.2337/diab.41.8.989.
Stull, A. J., J. P. Thyfault, M. D. Haub, R. E. Ostlund, Jr, and W. W.
Campbell. 2008. Relationships between urinary inositol excretions
and whole-body glucose tolerance and skeletal muscle insulin recep-
tor phosphorylation. Metabolism 57 (11):1545–1551. doi: 10.1016/j.
metabol.2008.06.009.
1672 O. C. WATKINS ET AL.
Sun, T-H, D. B. Heimark, T. Nguygen, J. L. Nadler, and J. Larner.
2002. Both myo-inositol to chiro-inositol epimerase activities and
chiro-inositol to myo-inositol ratios are decreased in tissues of GK
type 2 diabetic rats compared to Wistar controls. Biochemical and
Biophysical Research Communications 293 (3):1092–8. doi: 10.1016/
S0006-291X(02)00313-3.
Sussman, I., and F. M. Matschinsky. 1988. Diabetes affects sorbitol and
myo-inositol levels of neuroectodermal tissue during embryogenesis
in rat. Diabetes 37 (7):974–981. doi: 10.2337/diab.37.7.974.
Suzuki, S.,. C. Suzuki, Y. Hinokio, Y. Ishigaki, H. Katagiri, M. Kanzaki,
V. N. Azev, N. Chakraborty, and M. d’Alarcao. 2014. Insulin-mim-
icking bioactivities of acylated inositol glycans in several mouse
models of diabetes with or without obesity. PloS One 9 (6):e100466.
doi: 10.1371/journal.pone.0100466.
Suzuki, S.,. H. Kawasaki, Y. Satoh, M. Ohtomo, M. Hirai, A. Hirai, S.
Hirai, M. Onoda, M. Matsumoto, Y. Hinokio, et al. 1994. Urinary
chiro-inositol excretion is an index marker of insulin sensitivity in
Japanese type II diabetes. Diabetes Care 17 (12):1465–8., doi: 10.
2337/diacare.17.12.1465.
Suzuki, S.,. Y. Taneda, S. Hirai, S. Abe, A. Sasaki, K-I Suzuki, and T.
Toyota. 1991. Molecular mechanism of insulin resistance in spontan-
eous diabetic GK (Goto-Kakizaki) rats. New Directions in Research
and Clinical Works for. Obesity and Diabetes Mellitus :197–203.
Sweeting, A. N., G. P. Ross, J. Hyett, L. Molyneaux, M. Constantino,
A. J. Harding, and J. Wong. 2016. Gestational diabetes mellitus in
early pregnancy: Evidence for poor pregnancy outcomes despite
treatment. Diabetes Care 39 (1):75–81. doi: 10.2337/dc15-0433.
Tabrizi, R., V. Ostadmohammadi, K. B. Lankarani, P. Peymani, M.
Akbari, F. Kolahdooz, and Z. Asemi. 2018. The effects of inositol
supplementation on lipid profiles among patients with metabolic
diseases: A systematic review and meta-analysis of randomized con-
trolled trials. Lipids in Health and Disease 17 (1):123. doi: 10.1186/
s12944-018-0779-4.
Taguchi, R., J. Yamazaki, Y. Tsutsui, and H. Ikezawa. 1997.
Identification of chiro-inositol and its formation by isomerization of
myo-inositol during hydrolysis of glycosylphosphatidylinositol-anch-
ored proteins. Archives of Biochemistry and Biophysics 342 (1):
161–168. doi: 10.1006/abbi.1997.9991.
Tessier, D., Z. Ferraro, and A. Gruslin. 2013. Role of leptin in preg-
nancy: Consequences of maternal obesity. Placenta 34 (3):205–211.
doi: 10.1016/j.placenta.2012.11.035.
Thomas, M. P., S. J. Mills, and B. V. L. Potter. 2016. The “Other”
Inositols and Their Phosphates: Synthesis, Biology, and Medicine
(with Recent Advances in myo-Inositol Chemistry). Angewandte
Chemie (International ed. In English) 55 (5):1614–1650. doi: 10.
1002/anie.201502227.
Thomas, T. P., E. L. Feldman, J. Nakamura, K. Kato, M. Lien, M. J.
Stevens, and D. A. Greene. 1993. Ambient glucose and aldose reduc-
tase-induced myo-inositol depletion modulate basal and carbachol-
stimulated inositol phospholipid metabolism and diacylglycerol
accumulation in human retinal pigment epithelial cells in culture.
Proceedings of the National Academy of Sciences 90 (20):9712–6. doi:
10.1073/pnas.90.20.9712.
Thomas, T. P., F. Porcellati, K. Kato, M. J. Stevens, W. R. Sherman,
and D. A. Greene. 1994. Effects of glucose on sorbitol pathway acti-
vation, cellular redox, and metabolism of myo-inositol, phosphoino-
sitide, and diacylglycerol in cultured human retinal pigment
epithelial cells. The Journal of Clinical Investigation 93 (6):2718–24.
doi: 10.1172/JCI117286.
Thurston, J. H., W. R. Sherman, R. E. Hauhart, and R. F. Kloepper.
1989. myo-Inositol: A Newly Identified Nonnitrogenous
Osmoregulatory Molecule in Mammalian Brain. Pediatric Research
26 (5):482–485. doi: 10.1203/00006450-198911000-00024.
Toh, N., T. Inoue, H. Tanaka, and E. Kimoto. 1987. Polyol accumula-
tion in human placenta and umbilical cord. Biological Research in
Pregnancy and Perinatology 8 (1 1ST Half):13–15.
Tominaga, T.,. R. K. Dutta, D. Joladarashi, T. Doi, J. K. Reddy, and
Y. S. Kanwar. 2016. Transcriptional and translational modulation of
myo-inositol oxygenase (Miox) by fatty acids Implications in renal
tubular injury induced in obesity and diabetes. The Journal of
Biological Chemistry 291 (3):1348–67. doi: 10.1074/jbc.M115.698191.
Trama, J., Q. Lu, R. G. Hawley, and S. N. Ho. 2000. The NFAT-related
protein NFATL1 (TonEBP/NFAT5) is induced upon T cell activa-
tion in a calcineurin-dependent manner. The Journal of Immunology
165 (9):4884–4894. doi: 10.4049/jimmunol.165.9.4884.
Traynor-Kaplan, A., M. Kruse, E. J. Dickson, G. Dai, O. Vivas, H. Yu,
D. Whittington, and B. Hille. 2017. Fatty-acyl chain profiles of cellu-
lar phosphoinositides. Biochimica et Biophysica Acta (Bba) -
Molecular and Cell Biology of Lipids 1862 (5):513–22. doi: 10.1016/j.
bbalip.2017.02.002.
Trocino, R. A., S. Akazawa, M. Ishibashi, K. Matsumoto, H. Matsuo,
H. Yamamoto, S. Goto, Y. Urata, T. Kondo, and S. Nagataki. 1995.
Significance of glutathione depletion and oxidative stress in early
embryogenesis in glucose-induced rat embryo culture. Diabetes 44
(8):992–8. doi: 10.2337/diab.44.8.992.
Troyer, D., D. Schwertz, J. Kreisberg, and M. A. Venkatachalam. 1986.
Inositol phospholipid metabolism in the kidney. Annual Review of
Physiology 48:51–71. doi: 10.1146/annurev.ph.48.030186.000411.
Tsai, Y.-H., X. Liu, and P. H. Seeberger. 2012. Chemical biology of glyco-
sylphosphatidylinositol anchors. Angewandte Chemie (International ed.
In English) 51 (46):11438–56. doi: 10.1002/anie.201203912.
Turner, D. I., N. Chakraborty, and M. d’Alarcao. 2005. A fluorescent
inositol phosphate glycan stimulates lipogenesis in rat adipocytes by
extracellular activation alone. Bioorganic & Medicinal Chemistry
Letters 15 (8):2023–5. doi: 10.1016/j.bmcl.2005.02.061.
Uhl, O., H. Demmelmair, M. T. Segura, J. Florido, R. Rueda, C.
Campoy, and B. Koletzko. 2015. Effects of obesity and gestational
diabetes mellitus on placental phospholipids. Diabetes Research and
Clinical Practice 109 (2):364–371. doi: 10.1016/j.diabres.2015.05.032.
Unfer, V., and G. Porcaro. 2014. Updates on the myo-inositol plus D-
chiro-inositol combined therapy in polycystic ovary syndrome.
Expert Review of Clinical Pharmacology 7 (5):623–31. doi: 10.1586/
17512433.2014.925795.
Unfer, V., F. Facchinetti, B. Orr u, B. Giordani, and J. Nestler. 2017.
Myo-inositol effects in women with PCOS: A meta-analysis of
randomized controlled trials. Endocrine Connections 6 (8):647–658.
doi: 10.1530/EC-17-0243.
Unfer, V., G. Carlomagno, G. Dante, and F. Facchinetti. 2012. Effects
of myo-inositol in women with PCOS: A systematic review of
randomized controlled trials. Gynecological Endocrinology: The
Official Journal of the International Society of Gynecological
Endocrinology 28 (7):509–15. doi: 10.3109/09513590.2011.650660.
Valluru, R., and W. Van den Ende. 2011. Myo-inositol and beyond-
emerging networks under stress. Plant Science: An International
Journal of Experimental Plant Biology 181 (4):387–400. doi: 10.1016/
j.plantsci.2011.07.009.
Van Sande, J., D. Dequanter, P. Lothaire, C. Massart, J. E. Dumont,
and C. Erneux. 2006. Thyrotropin stimulates the generation of inosi-
tol 1, 4, 5-trisphosphate in human thyroid cells. The Journal of
Clinical Endocrinology and Metabolism 91 (3):1099–107. doi: 10.
1210/jc.2005-1324.
Varela-Nieto, I., Y. Le on, and H. N. Caro. 1996. Cell signalling by
inositol phosphoglycans from different species. Comparative
Biochemistry and Physiology Part B: Biochemistry and Molecular
Biology 115 (2):223–41. doi: 10.1016/0305-0491(96)00087-9.
Vernon, D. M., and H. J. Bohnert. 1992. A novel methyl transferase
induced by osmotic stress in the facultative halophyte
Mesembryanthemum crystallinum. The EMBO Journal 11 (6):
2077–85. doi: 10.1002/j.1460-2075.1992.tb05266.x.
Vernon, R. G. 2005. Lipid metabolism during lactation: A review of adipose
tissue-liver interactions and the development of fatty liver. The Journal of
Dairy Research 72 (4):460–9. doi: 10.1017/S0022029905001299.
Villalba, M., K. L. Kelly, and J. M. Mato. 1988. Inhibition of cyclic AMP-
dependent protein kinase by the polar head group of an insulin-sensi-
tive glycophospholipid. Biochimica et Biophysica Acta (Bba) - Molecular
Cell Research 968 (1):69–76. doi: 10.1016/0167-4889(88)90045-6.
Vinggaard, A. M., and H. S. Hansen. 1995. Characterization and partial
purification of phospholipase D from human placenta. Biochimica et
Biophysica Acta 1258 (2):169–176. doi: 10.1016/0005-2760(95)00121-R.

Vitagliano, A., G. Saccone, E. Cosmi, S. Visentin, F. Dessole, G.
Ambrosini, and V. Berghella. 2019. Inositol for the prevention of
gestational diabetes: A systematic review and meta-analysis of
randomized controlled trials. Archives of Gynecology and Obstetrics
299 (1):55–68. doi: 10.1007/s00404-018-5005-0.
Vivien, D., E. Petitfrere, L. Martiny, H. Sartelet, P. Galera, B. Haye,
and J.-P. Pujol. 1993. IPG (inositolphosphate glycan) as a cellular
signal for TGF-b1 modulation of chondrocyte cell cycle. Journal of
Cellular Physiology 155 (3):437–44. doi: 10.1002/jcp.1041550302.
Voglmayr, J., and I. White. 1971. Synthesis and metabolism of myoino-
sitol in testicular and ejaculated spermatozoa of the ram. Journal of
Reproduction and Fertility 24 (1):29–37. doi: 10.1530/jrf.0.0240029.
Walsh, S. W., and V. M. Parisi. 1986. The role of arachidonic acid metabo-
lites in preeclampsia. Paper presented at: Seminars in perinatology.
Wang, X., S. P. Devaiah, W. Zhang, and R. Welti. 2006. Signaling func-
tions of phosphatidic acid. Progress in Lipid Research 45 (3):
250–278. doi: 10.1016/j.plipres.2006.01.005.
Watkins, O. C., M. O. Islam, P. Selvam, R. A. Pillai, A. Cazenave-
Gassiot, A. K. Bendt, N. Karnani, K. M. Godfrey, R. M. Lewis,
M. R. Wenk, et al. 2019. Inositol alters 13C-labeled fatty acid metab-
olism in human placental explants. Journal of Endocrinology 243 (1):
73–84., doi: 10.1530/JOE-19-0267.
Wells, I. C., and J. Hogan. 1968. Effects of dietary deficiencies of lipotropic
factors on plasma cholesterol esterification and tissue cholesterol in rats.
The Journal of Nutrition 95 (1):55–62. doi: 10.1093/jn/95.1.55.
Wells, W. W., T. A. Pittman, and H. J. Wells. 1965. Quantitative analysis
of myoinositol in rat tissue by gas-liquid chromatography. Analytical
Biochemistry 10 (3):450–458. doi: 10.1016/0003-2697(65)90314-3.
Wenk, M. R., L. Lucast, G. Di Paolo, A. J. Romanelli, S. F. Suchy, R. L.
Nussbaum, G. W. Cline, G. I. Shulman, W. McMurray, and P. De
Camilli. 2003. Phosphoinositide profiling in complex lipid mixtures
using electrospray ionization mass spectrometry. Nature
Biotechnology 21 (7):813–7. doi: 10.1038/nbt837.
Wentzel, P., and U. J. Eriksson. 2020. Embryopathy and Diabetes.
Gestational Diabetes. Vol 28: Karger Publishers; 132–44.
Wentzel, P., C. R. Wentzel, M. B. G€areskog, and U. J. Eriksson. 2001.
Induction of embryonic dysmorphogenesis by high glucose concen-
tration, disturbed inositol metabolism, and inhibited protein kinase
C activity. Teratology 63 (5):193–201. doi: 10.1002/tera.1034.
Wentzel, P., N. Welsh, and U. J. Eriksson. 1999. Developmental dam-
age, increased lipid peroxidation, diminished cyclooxygenase-2 gene
expression, and lowered prostaglandin E2 levels in rat embryos
exposed to a diabetic environment. Diabetes 48 (4):813–20. doi: 10.
2337/diabetes.48.4.813.
Werner, E. F., P. Has, G. Tarabulsi, J. Lee, and A. Satin. 2016. Early
postpartum glucose testing in women with gestational diabetes mel-
litus. Obstetrical & Gynecological Survey 71:697–699. doi: 10.1097/01.
ogx.0000510809.66411.87.
White, D. 1973. The phospholipid composition of mammalian tissues.
Form and Function of Phospholipids 441–82.
Wilcox, R. A., W. U. Primrose, S. R. Nahorski, and R. A. J. Challiss.
1998. New developments in the molecular pharmacology of the
myo-inositol 1,4,5-trisphosphate receptor. Trends in Pharmacological
Sciences 19 (11):467–75. doi: 10.1016/S0165-6147(98)01260-7.
Williams, P. J., K. Gumaa, M. Scioscia, C. W. Redman, and T. W.
Rademacher. 2007. Inositol phosphoglycan P-type in preeclampsia: a
novel marker. Hypertension 49 (1):84–89. ? doi: 10.1161/01.HYP.
0000251301.12357.ba.
Willmroth, F., T. Drieling, U. Lamla, M. Marcushen, H.-J. Wark, and
D. Van Calker. 2007. Sodium-myo-inositol co-transporter (SMIT-1)
mRNA is increased in neutrophils of patients with bipolar I disorder
and down-regulated under treatment with mood stabilizers. The
International Journal of Neuropsychopharmacology 10 (1):63–71. doi:
10.1017/S1461145705006371.
Witters, L., and B. Kemp. 1992. Insulin activation of acetyl-CoA carb-
oxylase accompanied by inhibition of the 5’-AMP-activated protein
kinase. The Journal of Biological Chemistry 267 (5):2864–7.
Wolfson, M., Y. Bersudsky, E. Zinger, M. Simkin, R. Belmaker, and L.
Hertz. 2000. Chronic treatment of human astrocytoma cells with
CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 1673
lithium, carbamazepine or valproic acid decreases inositol uptake at
high inositol concentrations but increases it at low inositol concentra-
tions. Brain Research 855 (1):158–61. doi: 10.1016/S0006-
8993(99)02371-9.
Xie, P., L. Sun, P. J. Oates, S. K. Srivastava, and Y. S. Kanwar. 2010.
Pathobiology of renal specific oxidoreductase/myo-inositol oxygenase
in diabetic nephropathy: Its implications in tubulo-interstitial fibrosis.
American Journal of Physiology-Heart and Circulatory Physiology
Yamashita, T., M. Tamatani, M. Taniguchi, T. Takagi, T. Yoshimine,
and M. Tohyama. 1998. Regulation of Naþ/myo-inositol cotrans-
porter gene expression in hyperglycemic rat hippocampus. Brain
Research. Molecular Brain Research 57 (1):167–72. doi: 10.1016/
S0169-328X(98)00078-3.
Yamazaki, H., K. C. Zawalich, and W. S. Zawalich. 2010. Physiologic
implications of phosphoinositides and phospholipase C in the regu-
lation of insulin secretion. Journal of Nutritional Science and
Vitaminology 56 (1):1–8. doi: 10.3177/jnsv.56.1.
Yorek, M. A., J. A. Dunlap, and W. L. Lowe. 1998. Opposing effects of
tumour necrosis factor a and hyperosmolarity on Naþ/myo-inositol co-
transporter mRNA levels and myo-inositol accumulation by 3T3-L1
adipocytes. Biochemical Journal 336 (2):317–25. doi: 10.1042/bj3360317.
Yue, D. K., S. McLennan, E. Fisher, S. Heffernan, C. Capogreco, G. R.
Ross, and J. R. Turtle. 1989. Ascorbic acid metabolism and polyol path-
way in diabetes. Diabetes 38 (2):257–61. doi: 10.2337/diab.38.2.257.
Zeitler, P., and S. Handwerger. 1985. Arachidonic acid stimulates phos-
phoinositide hydrolysis and human placental lactogen release in an
enriched fraction of placental cells. Molecular Pharmacology 28:549–554.
Zeitler, P., E. Markoff, and S. Handwerger. 1983. Characterization of
the synthesis and release of human placental lactogen and human
chorionic gonadotropin by an enriched population of dispersed pla-
cental cells. The Journal of Clinical Endocrinology and Metabolism
57 (4):812–818. doi: 10.1210/jcem-57-4-812.
Zeitler, P., Y. Q. Wu, and S. Handwerger. 1991. Melittin stimulates
phosphoinositide hydrolysis and placental lactogen release:
Arachidonic acid as a link between phospholipase A2 and phospho-
lipase C signal-transduction pathways. Life Sciences 48 (21):
2089–2095. doi: 10.1016/0024-3205(91)90166-9.
Zerbino, D. R., P. Achuthan, W. Akanni, M. R. Amode, D. Barrell, J.
Bhai, K. Billis, C. Cummins, A. Gall, C. G. Gir on, et al. 2018.
Ensembl 2018. Nucleic Acids Research 46 (D1):D754–D761. doi: 10.
1093/nar/gkx1098.
Zhan, M., I. M. Usman, L. Sun, and Y. S. Kanwar. 2015. Disruption of
renal tubular mitochondrial quality control by Myo-inositol oxygen-
ase in diabetic kidney disease. Journal of the American Society of
Nephrology : JASN 26 (6):1304–21. doi: 10.1681/ASN.2014050457.
Zhang, H., and C. Zhang. 2010. Adipose “talks” to distant organs to
regulate insulin sensitivity and vascular function. Obesity (Silver
Spring. Md) 18:2071.
Zhang, H., Y. Lv, Z. Li, L. Sun, and W. Guo. 2019. The efficacy of
myo-inositol supplementation to prevent gestational diabetes onset:
A meta-analysis of randomized controlled trials. The Journal of
Maternal-Fetal & Neonatal Medicine32 (13):2249–2255. doi: 10.
1080/14767058.2018.1428303.
Zheng, X., Z. Liu, Y. Zhang, Y. Lin, J. Song, L. Zheng, and S. Lin.
2015. Relationship between myo-inositol supplementary and gesta-
tional diabetes mellitus: A meta-analysis. Medicine 94 (42):e1604.
doi: 10.1097/MD.0000000000001604.
Zhu, X., and J. Eichberg. 1990. A myo-inositol pool utilized for phos-
phatidylinositol synthesis is depleted in sciatic nerve from rats with
streptozotocin-induced diabetes. Proceedings of the National
Academy of Sciences 87 (24):9818–22. doi: 10.1073/pnas.87.24.9818.
Zhuo, Z.,. A. Wang, and H. Yu. 2014. Effect of metformin intervention
during pregnancy on the gestational diabetes mellitus in women
with polycystic ovary syndrome: a systematic review and meta-ana-
lysis. Journal of Diabetes Research 2014:381231. doi: 10.1155/2014/
381231.
Ziyadeh, F. N. 2004. Mediators of diabetic renal disease: The case for TGF-
b as the major mediator. Journal of the American Society of Nephrology 15
(90010):55S–S57. doi: 10.1097/01.ASN.0000093460.24823.5B.