Acta Diabetologica (2018) 55:805–812

https://doi.org/10.1007/s00592-018-1157-4

ORIGINAL ARTICLE

Effect of inositol stereoisomers at different dosages in gestational

diabetes: an open-label, parallel, randomized controlled trial
Federica Fraticelli1 · Claudio Celentano1 · Isaia AL Zecca2 · Giacoma Di Vieste3 · Basilio Pintaudi4 · Marco Liberati1 ·
Marica Franzago1 · Marta Di Nicola5 · Ester Vitacolonna1

Received: 1 February 2018 / Accepted: 6 May 2018 / Published online: 17 May 2018
© Springer-Verlag Italia S.r.l., part of Springer Nature 2018

Abstract
Aims  Gestational diabetes mellitus (GDM) is the most common metabolic disorder of pregnancy. The aim of the study is
to compare the effect of different dosages of inositol stereoisomers supplementation on insulin resistance levels and several
maternal-fetal outcomes in GDM women.
Methods  Participants were randomly allocated to receive daily: 400 mcg folic acid (control treatment), 4000 mg myo-inositol
plus 400 mcg folic acid (MI treatment), 500 mg d-chiro-inositol plus 400 mcg folic acid (DCI treatment) or 1100/27.6 mg
myo/d-chiro-inositol plus 400 mcg folic acid (MI plus DCI treatment). The homeostasis model assessment of insulin resist-
ance (HOMA-IR) was measured at the diagnosis of GDM and after 8 weeks of treatment. Secondary outcomes, obstetric
outcomes and any maternal or fetal complication at delivery were also collected.
Results  Eighty GDM women were assigned to one of the four arms of study (20 per arm). A significant delta decrease in
HOMA-IR index was found in subjects of MI group without insulin therapy compared to control group (p < 0.001). A lower
variation in average weight gain (at delivery vs pre-pregnancy and OGTT period) was detected in MI group vs control group
(p = 0.001 and p = 0.019, respectively). Moreover, women exposed to MI and MI plus DCI required a significantly lower
necessity of an intensified insulin treatment. Women of the control group had newborns with higher birth weight compared
with women treated with inositol (p = 0.032).
Conclusions  Our study provides interesting but preliminary results about the potential role of inositol stereoisomers sup-
plementation in the treatment of GDM on insulin resistance levels and several maternal-fetal outcomes. Further studies are
required to examine the optimal and effective dosages of different inositol supplements.
Clinical trial reg. no.  NCT02097069, ClinicalTrial.gov.

Keywords  Gestational diabetes mellitus · Myo-inositol · d-Chiro-inositol · Nutraceutics · Insulin resistance · Pregnancy
outcome

Abbreviations
Managed By Massimo Federici. GDM Gestational diabetes mellitus
MI Myo-inositol
* Ester Vitacolonna
e.vitacolonna@unich.it DCI  d-Chiro-inositol
HOMA-IR Homeostatic model assessment of insulin
1
Department of Medicine and Aging, School of Medicine resistance
and Health Sciences, “G. d’Annunzio” University Chieti-
Pescara, Via dei Vestini, 66100 Chieti, Italy
2
Department of Medicine and Science of Ageing, School Introduction
of Hygiene and Preventive Medicine, “G. D’Annunzio”
University Chieti-Pescara, Chieti, Italy
3 Gestational diabetes mellitus (GDM) is the most common
Diabetes Unit, Cantù Hospital, Abbiategrasso, Italy
metabolic disorder of pregnancy, and it is defined as “diabe-
4
Diabetes Unit, Niguarda Cà Granda Hospital, Milan, Italy tes diagnosed in the second or third trimester of pregnancy
5
Laboratory of Biostatistics, Department of Medical, Oral that was not clearly overt diabetes prior to gestation” [1].
and Biotechnological Sciences, “G. D’Annunzio” University
Chieti-Pescara, Chieti, Italy

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Pregnancy is characterized by significant hormonal and
metabolic maternal changes for ensuring adequate fetal
nutrition: anabolic changes, at first, to increase maternal
adipose tissue; these are followed by catabolic changes that
increase lipolysis, glycaemia, insulinemia, post-prandial
fatty acid levels, and decrease maternal fat deposits [2, 3].
Insulin resistance represents, with the advance of pregnancy,
a physiological status that promotes glucose supply to the
fetus. However, if this condition is not adequately counter-
balanced by the insulin secretion due to increase in β-cell
mass and response, it could contribute to a higher risk for
developing GDM [2]. In fact, GDM is characterized by an
increase of physiological insulin resistance and it is associ-
ated with an increased risk of perinatal and maternal mor-
bidity and long-term complications [3–5].
In a recent review, Chiefari et al., have highlighted the
importance of determining shared effective strategies for
the prevention, diagnosis and treatment of GDM, given the
growing worldwide incidence of this complication and the
increase in its health care costs [3].
Inositol is a six-carbon polyol, which has been catego-
rized as an insulin-sensitizing agent. It occurs as nine differ-
ent stereo-isomeric forms also comprising myo-inositol (MI)
and d-chiro-inositol (DCI), which are the most represented
in human body, with proven insulin-mimetic properties and
efficiency in lowering post-prandial glycaemia [6]. The
administration of MI and DCI glycans has been described to
have beneficial effects on metabolic, hormonal and ovarian
aspects [6, 7]. MI is normally available in a variety of foods
such as fresh fruit and vegetables, seeds, oats and bran [6].
A study conducted by Murphy and colleagues has
detected a greater MI and DCI urinary excretion, during
the first trimester, in pregnant women high-risk GDM preg-
nant women, thus demonstrating an early-altered synthesis,
metabolism and renal excretion of inositol in this group [8].
In the last few years, given the observed effects of inosi-
tol on insulin sensitivity, some studies have focused on its
supplementation during pregnancy. Specifically, four Italian
studies have demonstrated the effect of MI supplementation
vs placebo, during pregnancy, in reducing the incidence of
GDM in women at risk of this disorder [9–12]. However, a
randomized controlled trial that used the combination of MI/
DCI in pregnancy, has found that inositol did not reduce the
incidence of GDM in women with a family history of dia-
betes [13]. Another recent trial [14] has not reported differ-
ences among different arms of treatment (none of the women
in the study developed GDM even in the placebo arms).
Corrado et al. have conducted a study on women affected by
GDM to evaluate if the MI supplementation could increase
the insulin sensitivity [15]. This work has demonstrated that
MI supplementation improves insulin resistance in GDM
patients.
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Acta Diabetologica (2018) 55:805–812
Recently, another Italian study has been conducted to
assess the role of DCI supplementation in the metabolic
control of GDM women as well as to evaluate its impact
on pregnancy and fetal outcomes. Results indicated that
DCI (in the dosage of 500 mg twice a day) ameliorates glu-
cose metabolism during pregnancy and promotes control of
maternal weight gain and fetal growth [16]. An improvement
of metabolic control, a significant reduction in HbA1c lev-
els, was previously found by Maurizi et al. in overweight and
obese insulin-treated T1D patients randomized to receive 1 g
DCI plus 400 mcg folic acid once daily vs 400 mcg folic acid
only once daily [17].
There are just preliminary data about the use of MI plus
DCI in women during pregnancy [13, 14].
The aim of the present study was to compare the effects
of different dosages of inositol stereoisomers supplementa-
tion on insulin resistance levels after 8 weeks of treatment
in pregnant women with GDM and on several maternal-fetal
outcomes in GDM women.
Materials and methods
Study design and participants
The study design was an open-label, parallel, randomized
controlled trial. It was registered at ClinicalTrial.gov
(NCT02097069). The study was in accordance with the
ethical standards of the institutional and/or national research
committee and with the 1964 Helsinki declaration and its
later amendments. Informed consent was obtained from
the patients included in the study. The institutional review
board (Department of Medicine and Ageing Science of the
University G. d’Annunzio of Chieti-Pescara, Chieti, Italy)
approved the project.
From July 2013 to October 2015, 80 pregnant women,
attending the Diabetes and Metabolism Unit at the Hospital
of University “Gabriele d’Annunzio” in Chieti, were ran-
domized as reported in the participant flow chart (Fig. 1).
The diagnosis of GDM was based on an abnormal 75 g oral
glucose tolerance test (OGTT) where either one or more
blood glucose values were above the values of 5.1 mmol/L
(92 mg/dL) at fasting, 10.0 mmol/L (180 mg/dL) at 1-h-after
load, and 8.5 mmol/L (153 mg/dL) at 2-h-after load [18].
Women received information about the study protocol and,
if they accept to participate, they were randomized to receive
400 mcg/day folic acid (control treatment), 2000 mg twice
a day Myo-inositol (MI treatment), 250 mg twice a day
d-chiro-inositol (DCI treatment) or 550/13.8 mg twice a day
Myo-inositol plus d-chiro-inositol (MI plus DCI treatment).
All the available inositol formulations also contained folic
acid (200 mcg).
Acta Diabetologica (2018) 55:805–812 807
Fig. 1  Participant flow chart
The allocation sequence was generated at the Diabetes
and Metabolism Unit at the Hospital of University “Gabriele
d’Annunzio” in Chieti. In addition, the data were collected
by the same Unit.
Inclusion and exclusion criteria
The inclusion criteria were: pregnant women aged
18–45 years, Caucasian ethnicity, with Gestational Diabe-
tes diagnosed within 24–28 weeks gestation. The exclusion
criteria were: women with pre-gestational diabetes and non-
singleton pregnancy, therapy with hypoglycaemic or insulin-
sensitizing drugs during pregnancy.
Randomization and masking
All women were informed of their hyperglycaemic status;
they received dietary advice.
According to scientific evidences [19, 20], since all
women no presented contraindications, they were encour-
aged to perform regular and no structured daily physical
activity, such as walking. All women were engaged in light
physical activity.
Procedures for a careful self-monitoring blood glucose
control (SMBG) were also been explained. The generation
of the allocation sequence to receive folic acid or inositol
stereoisomers treatment at different dosages, was performed
by a random number table.
Each woman was advised about the therapy and instructed
on how to take the supplement and on the possible adverse
reactions. All pregnancies were periodically monitored,
about every 2 weeks, to examine treatment compliance and
to verify data concerning the SMBG, the maternal clinical
and anthropometric measurements and the perinatal obstet-
ric parameters. Moreover, during the visits, women received
a physical examination and were asked if they were taking
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808
other supplements, vitamins and/or drugs, thus avoiding fac-
tors that could alter the study results.
Methods
The primary outcome was the insulin resistance level evalu-
ated by the homeostasis model assessment of insulin resist-
ance index (HOMA-IR) [21]. The HOMA-IR was calculated
at the diagnosis of GDM and after 8 weeks of treatment. The
secondary outcomes were the maternal lipid profile, mater-
nal weight variations, insulin therapy need, gestational age
at insulin therapy start, hypertensive disorders, gestational
age at birth, fetal macrosomia (either birth weight > 4500 g,
and expressed as percentile), caesarean section, neonatal
hypoglycaemia, jaundice requiring phototherapy, shoulder
dystocia.
At the first visit conducted at the Diabetes and Metabo-
lism Unit, data on sociodemographic characteristics, anthro-
pometric and clinical parameters of pregnant women were
collected. At the end of pregnancy, obstetric outcomes and
any maternal or fetal complication were recorded. Fur-
thermore, the maternal lipid profile, the maternal weight
increase, the rate of women needing insulin therapy and the
insulin dosage were registered.
Statistical analysis
The sample size was based on the primary endpoint of
the study, the degree of insulin resistance measured by
the Homeostatic Model Assessment of Insulin Resistance
(HOMA-IR). The only data available in the literature [15]
shows a 2.1-point reduction in HOMA-IR (calculated as
the difference between HOMA-IR values at baseline and
HOMA-IR values at the end of treatment) in the women’s
Placebo arm, while a 3.4-point reduction in HOMA-IR was
observed in the group of women receiving myo-inositol.
Assuming a minimum difference between the treatment
groups of at least 1.0 point of ΔHOMA-IR, a sample size of
20 patients per arm was required to highlight this difference
with a statistical power of 80% (α = 0.05), assuming a stand-
ard deviation of 1.5. Continuous variables were reported
as either mean and standard deviation (SD) or median and
interquartile range (IQR) according to their distribution, as
assessed by the Shapiro–Wilk test. Categorical variables
were reported as frequency and percentage.
One-way ANOVA or Kruskal–Wallis test and Pearson’s
Chi-squared test were performed to evaluate differences
among arms.
Post-hoc analyses to evaluate pairwise comparison among
arms were performed with Dunnett’s test or Kruskal–Wallis
post-hoc test, when appropriate.
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Acta Diabetologica (2018) 55:805–812
In addition, a linear mixed model, with interaction term,
was conducted to assess the effect on HOMA-IR relative
variation adjusted for insulin therapy use.
Subsequently subgroup analysis “a priori” specified was
after conduct on women not in insulin therapy.
In all statistical tests the threshold of statistical signifi-
cance was assumed equal to p = 0.05.
Statistical analysis was performed using the Statistical
Package for Social Science (SPSS) program, version 14.0
software for Windows ­(SPSS®, Chicago, IL, USA).
Results
From July 2013 to October 2015, 93 pregnant women with
diagnosis of GDM have been recruited into the study. Five
patients did not meet all inclusion criteria and eight declined
to participate. 80 subjects were randomly assigned to one of
the four arms of study: 20 to the control group, 20 to the MI
group, 20 to the DCI group and 20 to the MI plus DCI group.
All participants completed the study, and no one showed any
adverse effects due to the treatment received. The trial was
stopped when the study covered the total sample size.
Table 1 summarizes the baseline maternal characteristics.
The insulin resistance, our primary outcome, did not show
any significant differences among groups after treatment.
However, considering the differences between the base-
line HOMA-IR and the final values, the subjects allocated
to receive MI without insulin therapy showed a significant
reduction in insulin resistance vs control group (p < 0.001)
(Table 2).
As for our secondary outcomes, a reduced increase in
weight gain at delivery compared to the weight measured in
pre-gestational (p = 0.001) and OGTT (p = 0.019) periods
were observed in all groups treated with stereoisomers ino-
sitol supplementation and at different dosages.
Specifically, MI group when compared to the control
group showed a significantly lower increase in average
weight gain at delivery vs the weight recorded before preg-
nancy and at the OGTT period (p < 0.005 post-hoc test)
(Table 2).
The incidence of women requiring insulin therapy was
not significantly different between the four groups. However,
women exposed to MI and MI plus DCI required a lower
necessity of an intensified insulin treatment (rapid-acting
and long-acting insulin). Furthermore, in all groups treated
with inositol the timing of introduction of insulin therapy,
expressed as median of days, was later than in the control
group (Table 2).
After treatment, no significant difference was detected
between the four groups as far as it concerns maternal lipid
profile, shoulder dystocia and jaundice requiring photother-
apy (Tables 1, 3). Interestingly, the caesarean sections in
Acta Diabetologica (2018) 55:805–812 809

Table 1  Baseline characteristics of the 80 women with gestational diabetes randomized to receive control treatment (folic acid), myo-inositol
treatment, d-chiro-inositol treatment or myo-inositol and d-chiro-inositol treatment
Characteristic Control (n = 20) Myo-inositol (n = 20) d-Chiro-inositol (n = 20) MI plus DCI (n = 20) ANOVA
p value
(ANOVA)

Maternal age (year), mean ± SD 33.4 ± 5.4 34.8 ± 4.12 35.0 ± 4.4 35.3 ± 4.4 0.574

Pre-gestational BMI (kg/m2), 25.2 ± 6.2 25.0 ± 5.2 25.4 ± 4.6 26.2 ± 6.2 0.924
mean ± SD
 Normal, n (%) 11 (55.0) 12 (60.0) 10 (50.0) 10 (50.0) 0.960a
 Overweight, n (%) 5 (25.0) 3 (15.0) 6 (30.0) 5 (25.0)
 Obese, n (%) 4 (20.0) 5 (25.0) 4 (20.0) 5 (25.0)
Number of pregnancies, n (%)
 Nulliparous 6 (30.0) 7 (35.0) 9 (45.0) 4 (20.0) 0.535a
 1 10 (50.0) 7 (35.0) 5 (25.0) 8 (40.0)
 ≥ 2 4 (20.0) 6 (30.0) 6 (30.0) 8 (40.0)
Previous gestational diabetes, n (%) 2 (10.0) 2 (10.0) 1 (5.0) 2 (10.0) 0.925a
Fasting glucose (mg/dL), mean ± SD 91.4 ± 8.0 90.8 ± 11.0 90.7 ± 10.4 88.5 ± 7.3 0.637
Positive family history of diabetes, n 11 (55.0) 13 (65.0) 16 (80.0) 17 (85.0) 0.135a
(%)
HOMA-IR, mean ± SD 2.35 ± 1.63 2.27 ± 1.42 2.12 ± 1.16 2.11 ± 1.35 0.895
Total cholesterol (mg/dL), mean ± SD 255.3 ± 51.3 251.4 ± 43.1 243.0 ± 47.0 253.4 ± 51.1 0.869
LDL (mg/dL), mean ± SD 139.2 ± 49.8 135.7 ± 35.8 130.8 ± 34.4 142.5 ± 47.6 0.852
HDL (mg/dL), mean ± SD 75.0 ± 17.0 76.4 ± 20.3 73.7 ± 17.5 70.0 ± 14.2 0.719
TG (mg/dL), mean ± SD 205.3 ± 75.6 199.4 ± 56.5 185.2 ± 51.4 204.0 ± 59.6 0.708
a
 p value relative to Chi-squared test

Table 2  Outcomes in women with gestational diabetes randomized to receive control treatment (folic acid), myo-inositol treatment, d-chiro-
inositol treatment or myo-inositol and d-chiro-inositol treatment
Outcome Control (n = 20) Myo-inositol (n = 20) d-Chiro-inositol (n = 20) MI plus DCI (n = 20) ANOVA p value

Insulin therapy, n (%) 9 (45) 10 (50.0) 12 (60) 9 (45) 0.753a

Intensified insulin therapy, 5 (25.0) 1 (5.0) 10 (50.0) 1 (5.0) 0.001
n (%)
Insulin free time (days 205 (182–233) 213 (202–232) 211 (201–223) 230 (224–240) 0.147b
of pregnancy), median
(IQR)
Weight variation, mean ± SD
 Delivery vs pre-preg- 13.06 ± 7.96 6.35 ± 3.21* 8.29 ± 4.38 9.34 ± 2.17 0.001
nancy (kg)
 Delivery vs OGTT​ 4.09 ± 3.55 2.13 ± 0.85* 2.32 ± 1.47 3.52 ± 2.17 0.019
HOMA-IR, mean ± SD 2.24 ± 1.16 2.35 ± 2.06 1.95 ± 0.74 2.13 ± 1.02 0.808
HOMA-IR relative variation
 Overall, mean ± SD 0.22 ± 0.90 − 0.04 ± 0.53 0.08 ± 0.42 0.13 ± 0.50 0.604
 Women not in insulin − 0.17 (− 0.32; 0.03) − 0.37 (− 0.57; − 0.25)° 0.45 (− 0.18; 0.73) 0.17 (− 0.07; 0.45) < 0.001b
therapy, median (IQR)

Statistically significant values are in bold

*p < 0.05 Dunnett test vs control group
°p < 0.05 Kruskal–Wallis post-hoc test
a
 Chi square test
b
 Non-parametric Kruskal–Wallis test

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Table 3  Neonatal outcomes relative to women with gestational diabetes randomized to receive control treatment (folic acid), myo-inositol treat-
ment, d-chiro-inositol treatment or myo-inositol and d-chiro-inositol treatment
Outcome Control (n = 20) Myo-inositol (n = 20)
Neonatal Jaundice, n (%) 1 (5.0)
Caesarean section, n (%) 7 (35.0)
Shoulder dystocia, n (%) 1 (5.0)
Birth weight (percentiles), mean ± SD 60.6 ± 17.1
Ponderal index (g/cm3 × 100), mean ± SD 28.51 (9.39)
Statistically significant values are in bold
a
 One-way ANOVA test
women treated with MI were double than in women treated
with only DCI, but no significant difference was detected
among the four groups about the percentage of caesarean
sections.
No women presented high blood pressure at the beginning
of pregnancy and no one developed hypertensive disorders
during pregnancy; moreover, no cases of neonatal hypo-
glycaemia or macrosomia occurred. Neonatal birth weight
expressed as percentiles was significantly different among
groups (p = 0.032), with higher values in the control group
(60.6 ± 17.1) (Table 3).
Conclusions
Hyperinsulinemia and insulin resistance occur physiologi-
cally during pregnancy [12]. Pregnancy is characterized by
a progressive reduction in insulin sensitivity with a resultant
increase in β-cells mass and activity to produce insulin to
maintain glucose homeostasis. A β-cells defection seems
to contribute to GDM development [2]. Physiologically,
insulin resistance provides glucose to the fetus although a
more severe degree predisposes to development of GDM.
This common condition in pregnancy is comparable to that
detected in type 2 diabetes, in which post-receptor alterations
concerning glucose transport and intracellular metabolism
in insulin-sensitive tissues cause a reduced insulin action
[2]. Moreover, insulin resistance is frequently observed in
overweight and obese subjects, due to endocrine action of
adipokines produced by visceral adipose tissue [12]. Indeed,
in obese women (BMI > 30 or weight > 150% of ideal body
weight) has been observed a higher incidence of GDM, from
1.4- to 20-fold, in comparison with normal weight individu-
als [22].
In our placebo-controlled randomized study conducted
in women affected by GDM, we studied the effects of dif-
ferent dosages of inositol stereoisomers supplementation
on insulin resistance levels and several maternal-fetal out-
comes. Recently, inositol stereoisomers have been proposed
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Acta Diabetologica (2018) 55:805–812
d-Chiro-inositol (n = 20) MI plus DCI (n = 20) Chi-
squared p
value
1 (5.0) 2 (10.0) 1 (5.0) 0.887
10 (50.0) 5 (25.0) 11 (55.0) 0.196
1 (5.0) – – 0.562
47.8 ± 23.5 41.9 ± 19.9 43.0 ± 25.8 0.032a
27.06 (2.88) 26.72 (2.30) 26.72 (2.30) 0.653a
in different studies for GDM prevention and treatment [23].
Many studies regarded myo-inositol and only recently evi-
dence on d-chiro inositol has been added.
In our study, it is interesting to note that the amount of the
d-chiro used in MI plus DCI group was actually low, because
the effect of different dosages was not known, although it
was in line with other studies [13]. Only recently, Di Biase
et  al. [16] have evidenced results with higher effective
dosages.
The proposed dosages for stereoisomers are various;
therefore, more studies would be necessary to verify which
dosages, which stereoisomers and which “combinations”
may be efficient.
Our results showed a lower insulin resistance during
pregnancy and a greater control of maternal weight gain at
delivery in subjects treated with MI.
Our results are consistent with the previous literature
according to which MI supplementation plus folic acid pro-
duces a greater delta change in HOMA-IR vs folic acid only,
and this is associated with improved insulin resistance in
GDM patients [15].
However, it is important to highlight that these results
must be interpreted considering the different dosages of the
various stereoisomers. Presumably, different dosages in the
DCI treatment group or MI plus DCI treatment group could
have given different outcomes. In the light of our prelimi-
nary data, we can say that probably the “phenotyping” of
women that could take advantage of the posology, stereoi-
somers and their combination would be useful. The need
for this reflection is also due to GDM heterogeneity and its
physiopathological aspects [24]. Additional studies should/
could examine in depth these aspects for a tailored therapy
with inositols too.
Recently, Benelli and coll [25] have shown a significant
reduction of several endocrine and metabolic parameters,
including HOMA index in young obese women affected by
polycystic ovary syndrome (PCOS) with a combined therapy
of MI plus DCI. In addition, previous studies have found an
improvement of insulin sensitivity in lean and obese women
Acta Diabetologica (2018) 55:805–812 811
with PCOS after DCI supplementation (600 mg once daily
and 1200 mg once daily, respectively) [7, 26]. In our study,
the supplementation with lower dosages of DCI and MI plus
DCI did not produce a similar effect on insulin sensitivity.
We know, also, that physical activity has an insulin sen-
sitivity effects. As reported by scientific evidences [19, 20,
27, 28], regular physical activity, mainly aerobic, of moder-
ate intensity and duration, can be recommended for every
pregnant woman in absence of contraindications.
All women performed daily fasting and post-prandial
self-monitoring of blood glucose (SMBG). According to the
current guidelines [29, 30], insulin therapy was introduced
when a good glycemic control had not been achieved despite
the diet and/or inositol supplementation. In particular, the
preprandial insulin was titrated based on post-prandial gly-
cemia results (fast-acting insulin anologue) and the bed-time
insulin dosage (long-acting insulin analogue) was based on
fasting glycemia data.
A significant result of our study is that the percentage
of women allocated to receive MI (5%) and MI plus DCI
(5%) have had less need for a double types of insulin treat-
ment (rapid-acting and long-acting insulin) in comparison
with DCI (50%) and control groups (25%). Kopec et al. [31]
in a study conducted in GDM patients evidenced that the
requirement of insulin therapy is one of the factors associ-
ated with distress, especially for women who required more
than one injection daily in comparison with those untreated
with insulin.
Furthermore, in all groups treated with inositol the tim-
ing of introduction of insulin therapy, expressed as median
of days, was later than in the control group (MI = 213 days;
DCI = 211  days and MI plus DCI = 230  days vs pla-
cebo = 205 days). These data may be interesting in terms of
cost–benefits and cost-effectiveness analysis.  In fact, some
Authors recently suggested that further research is needed
to identify more cost-effective measures to detect and treat
GDM [32, 33] and to explore the optimal dose, frequency
and timing of supplementation [33].
Inositol supplementation seems to reduce increase in
weight gain at delivery compared to the weight measured
in pre-gestational and OGTT periods; especially in the MI
group, used at the best dosage, it was observed a significant
lower increase in average weight gain at delivery vs that
recorded before pregnancy and at the OGTT period when
compared to the control group.
Another result of our research is the significantly differ-
ent neonatal birth weight (expressed in percentiles) found
among groups with control group consistently higher value.
Previously, D’Anna et al. [10] and Matarrelli et al. [9] have
demonstrated that birth weight expressed as grams or per-
centiles, respectively, was significantly lower in the offspring
of women treated with myo-inositol compared to control
group related to a good metabolic control.
Similar findings were found in the DCI trial [16], in
which the neonatal ponderal index resulted significantly
lower in DCI group vs control.
As regards the caesarean sections, we found that women
treated with MI are double than women treated with DCI.
However, no significant difference was detected between the
four groups as far as it concerns the percentage of caesarean
sections and anyway, they were not due to macrosomia.
Moreover, we have no information about the previous
caesarean sections. 65% of women receiving MI were rep-
resented, in fact, by pluriparous women, with a possible
previous caesarean section, maybe in recent times (in turn
indication for caesarean section).
The main limits of the study are the small sample size and
the fact that all subjects were Caucasian women. An increase
in the number of subjects enrolled and the representation of
different ethnic groups could increase the consistency of the
results. Another weakness is given by the unmasked treat-
ment administered.
However, a strength of this study is that, to our knowl-
edge, this is the first attempt to evaluate the effects of dif-
ferent dosages of inositol stereoisomers supplementation on
insulin resistance levels and several maternal-fetal outcomes
in GDM women.
Our study provides preliminary results and interesting
insights about the potential role of inositol stereoisomers
supplementation in treatment of GDM. Further studies are
required to examine the optimal and effective dosages of
different inositol supplements.
Acknowledgements  The authors wish to thank Lucrezia Gasparini for
the contribution and all women who participated in this study.
Author contributions  The study was designed by EV, CC, BP, and
GDV. CC and ML contributed to clinical evaluation and support to the
recruitment of patients. FF contributed to data acquisition, analysis, and
interpretation. The manuscript was drafted by FF, MF, and EV. MDN
and IZ were the statisticians that performed and supervised the statisti-
cal analyses; they also helped in the drafting and editing of the manu-
script. CC, FF, BP, GDV, MDN, and MF contributed to the reviewed
of the manuscript. All authors were involved in critical revision and
approved the final version of the manuscript before submission. EV
and MDN are the guarantor of this work and, as such, had full access
to all the data in the study and take responsibility for the integrity of
the data and the accuracy of the data analysis.
Funding  This research did not receive any specific grant from funding
agencies in the public, commercial or not-for-profit sectors.
Compliance with ethical standards 
Conflict of interest  The authors declare that they have no conflict of
interest.
Ethical standard statement  The study was in accordance with the ethi-
cal standards of the institutional and/or national research committee
and with the 1964 Helsinki declaration and its later amendments.
13

812 Acta Diabetologica (2018) 55:805–812

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