Pathophysiology of Type 2 Diabetes and The Impact of Altered Metabolic Interorgan Crosstalk

STATE-OF-THE-ART REVIEW
Pathophysiology of type 2 diabetes and the impact of

altered metabolic interorgan crosstalk
Jose Marcos Sanches1, Li Na Zhao1 , Albert Salehi1 , Claes B. Wollheim1,2 and
Philipp Kaldis1
€, Sweden
1 Department of Clinical Sciences, Lund University, Malmo
2 Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland
Keywords Diabetes is a complex and multifactorial disease that affects millions of

diabetes; free fatty acids; inflammation; people worldwide, reducing the quality of life significantly, and results in
interorgan crosstalk; liver; metabolites;
grave consequences for our health care system. In type 2 diabetes (T2D),
metabolomics; organokines; type 2 diabetes
the lack of b-cell compensatory mechanisms overcoming peripherally devel-
Correspondence oped insulin resistance is a paramount factor leading to disturbed blood
P. Kaldis, Department of Clinical Sciences, glucose levels and lipid metabolism. Impaired b-cell functions and insulin
Lund University, Box 50332, Malmo € SE-202 resistance have been studied extensively resulting in a good understanding
13, Sweden of these pathways but much less is known about interorgan crosstalk,
Tel: +4673 776 8101 which we define as signaling between tissues by secreted factors. Besides
E-mail: philipp.kaldis@med.lu.se
hormones and organokines, dysregulated blood glucose and long-lasting
hyperglycemia in T2D is associated with changes in metabolism with
(Received 21 May 2021, revised 14 October
2021, accepted 29 November 2021) metabolites from different tissues contributing to the development of this
disease. Recent data suggest that metabolites, such as lipids including free
doi:10.1111/febs.16306 fatty acids and amino acids, play important roles in the interorgan cross-
talk during the development of T2D. In general, metabolic remodeling
affects physiological homeostasis and impacts the development of T2D.
Hence, we highlight the importance of metabolic interorgan crosstalk in
this review to gain enhanced knowledge of the pathophysiology of T2D,
which may lead to new therapeutic approaches to treat this disease.
Abbreviations
AAT, alanine aminotransferase; ACC, acetyl-CoA carboxylase; ACL, ATP citrate lyase; AKT, also known as protein kinase B (PKB); ASC,
adaptor molecule apoptosis-associated speck-like protein containing a CARD; ATGL, adipose triglyceride lipase; CEPT1, choline/
ethanolaminephosphotransferase 1; ChREBP, carbohydrate response element binding protein; COX, cyclooxygenase; CPT1,
cholinephosphotransferase 1; CYP, cytochrome P450; DAG, diacylglycerol; DGAT1, diacylglycerol acyltransferase 1; DGAT2, Diacylglycerol
acyltransferase 2; DGK, Diacylglycerol kinase; EET, epoxyeicosatrienoic acids; EPT1, ethanolaminephosphotransferase 1; ER, endoplasmic
reticulum; F6P, fructose 6-phosphate; FAS, fatty acid synthase; FFAs, free fatty acids; G3P, glyceraldehyde 3-phosphate; G6P, glucose 6-
phosphate; GIP, gastric inhibitory peptide; Glcn6P, glucosamine 6-phosphate; GLP1, glucagon-like peptide-1; GLS, glutaminase; GS,
glutathione synthetase; GSDMD, gasdermin D; HETE, hydroxyeicosatetraenoic acids; HIS, hormone-sensitive lipase; IKKb, I-kappa-b-kinase;
IL, interleukin; IRS, insulin receptor substrate; JNK, c-Jun N-terminal kinase; LDH, lactate dehydrogenase; LOX, lipoxygenase; LT,
leukotriene; MCP-1, monocyte chemoattractant protein-1; MGAT1-MGAT3, monoacylglycerol acyltransferases; MOGAT2, monoacylglycerol
O-acyltransferase 2; NAD, nicotinamide adenine dinucleotide; NADPH, nicotinamide adenine dinucleotide phosphate; NF-kB, nuclear factor
kappa B; NLRP3, NOD-like receptor pyrin domain-containing protein 3, cryopyrin, or NALP3; PDK1, phosphoinositide-dependent kinase-1;
PG, prostaglandin; PI3K, phosphatidylinositol 3-kinase; PIP1, phosphatidylinositol 4-phosphate; PIP3, phosphatidylinositol (3,4,5)-
trisphosphate; PLA2, phospholipase A2; PLCs, phospholipases; RBP4, retinol binding protein 4; ROS, reactive oxygen species; SPT, serine
palmitoyl transferase; SREBP-1, sterol regulatory element binding transcription factor 1; TAG, triacylglyceride; TCA, tricarboxylic acid cycle;
TLR4, Toll-like receptor 4; TNF, tumor necrosis factor; cGCS, c-glutamylcysteine synthetase.
620 The FEBS Journal 290 (2023) 620–648 ª 2021 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of
Federation of European Biochemical Societies
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J. M. Sanches et al. Metabolic interorgan crosstalk driving T2D
Introduction T2D, on the other hand, is a heterogeneous and multi-

factorial disease, which affects whole body physiology
Intermediary metabolism affects many functions in [12,21,22]. Among the regulators known to affect
cells, tissues, organs, and the entire organism. Here we metabolism by signaling to different tissues and there-
will focus on the metabolic interorgan crosstalk since fore important for T2D, are hormones (insulin, glucagon
it is important for the pathophysiology of many dis- [23,24], and glucagon-like peptide-1 [25]), organokines
eases [1–5]. In our view, metabolic interorgan crosstalk [adipokines/lipokines (e.g., leptin [26], adiponectin [27],
can be defined as the global effects of secreted factors resistin, Fgf21 [28], and adipsin [29])], and metabolites
from a target tissue that may trigger physiological (amino acids [23,30] like alanine [31,32], lipids, and
responses in one or several other tissues, affecting free fatty acids [32–34]).
homeostasis or the development of diseases. Neverthe- Although T2D most frequently develops in subjects
less, interorgan crosstalk is not only governed by with a family history of diabetes through the interplay
metabolites but also traditionally by hormones [6] and of risk genes expressed mainly in the b-cells and insu-
more recently by organokines (for a summary see lin resistance in target organs, there are many other
below) [7–10], which will not be discussed in detail forms with nongenetic etiology of hyperglycemia. We
here since this has been covered well in the literature. refer to an exhaustive review of the so-called atypical
Therefore, we envision at least three levels of regula- diabetes mellitus [35] and mention just a few of them
tion of interorgan crosstalk: hormones, organokines, here.
and metabolites. The regulation of interorgan crosstalk There are tight functional links between the exocrine
by metabolites in diabetes has not been discussed and endocrine pancreas, resulting in dysregulated pro-
extensively and this is the topic we will focus in this duction of pancreatic enzymes in T1D and T2D
review. [35,36]. Conversely, both acquired and inherited dis-
Since type 2 diabetes (T2D) is considered a complex eases of the exocrine pancreas often lead to diabetes by
and multifactorial metabolic disease that affects more affecting b-cell function. For example, iron overload
than 400 million people worldwide [11–15], we hypoth- that occurs in the hereditary conditions thalassemia
esize that one possible cause of T2D is alterations in and hemochromatosis is associated with progression of
the metabolic interorgan crosstalk. In this review, we b-cell dysfunction and T2D progression [35,37].
will focus especially on the pancreas, liver, adipose tis- While several enteroviruses have been connected to
sue and muscles as major metabolite producers and T1D, T2D has been associated with hepatitis C infec-
highlight selected metabolites, since these target tissues tion; in this case, the initiating event is insulin resis-
and organs play essential roles in glucose and lipid tance in the liver and other target tissues of insulin.
metabolism, as well as in insulin biology. The overrid- Antiviral therapy cures the defect in glucose homeosta-
ing control of metabolic homeostasis by the brain will sis [35]. Several endocrine disorders can lead to mild
not be addressed. Moreover, since T2D can be consid- as well as severe diabetes, among them acromegaly
ered as an inflammatory disease [13], we will summa- with increased plasma growth hormone concentrations
rize the association between metabolites that connect and Cushing’s disease characterized by overproduction
inflammation to T2D. of ACTH [35]. Like glucagon, growth hormones raise
Diabetes mellitus is a devastating chronic metabolic blood glucose and counteract the actions of insulin
disorder characterized by dysregulated insulin secretion and its overproduction causes insulin resistance both
with simultaneously reduced anabolic action on its tar- at the receptor and postreceptor level. Through
get tissues (insulin resistance), leading to altered increased lipolysis, growth hormones promote hepatic
metabolism, reflected among others by hyperglycemia glucose production [35]. Hyperplasia of the adrenal
and dyslipidemia [16,17]. Diabetes mellitus can be cells can also lead to the disease. Drugs like cortisol
divided into type 1 diabetes (T1D) and T2D. Based on and other glucocorticoids alter blood glucose control
clinical parameters, diabetes has been further subdi- by the induction of hepatic gluconeogenic enzymes
vided into five clusters, of which four correspond to and insulin resistance at the postreceptor signaling
T2D [18]. Diabetes reduces life quality through its level as well as b-cell dysfunction [38,39]. Hyperglyce-
many organ complications [19]. T1D, according to the mia is often observed with glucocorticoid therapy,
current hypotheses, is caused by an autoimmune which may result in persistent diabetes in patients with
destruction (through CD4+ and CD8+ T cells and mac- susceptibility to the disease.
rophages) of b-cells, leading to a complete loss of insu- Diabetes is a multifactorial disease where insulin
lin production, although in a small number of patients resistance and increased circulating FFAs collaborate
there is an idiopathic destruction of the b-cells [14,20]. with hyperglycemia, hyperinsulinemia, fat accumulation,
The FEBS Journal 290 (2023) 620–648 ª 2021 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of 621
Metabolic interorgan crosstalk driving T2D J. M. Sanches et al.
oxidative stress, and inflammation in the liver as well LECT2 expression is correlated with fatty liver
as other tissues [40–42]. As a consequence, steatosis is [10,55,56]. Some hepatokines seem to provide benefits
detected in 50% of diabetic patients. In addition, for the regulation of metabolism in T2D.
increased levels of FFAs suppress adipose tissue lipoly- The adipokine, adiponectin, contributes to insulin
sis by insulin, whereas elevated FFAs in the liver lead sensitivity in the liver through the activation of AMP-
to impaired hepatic fatty acid oxidation and insulin activated kinase (AMPK) and also suppresses gluco-
resistance [40]. T2D and NAFLD are likely bidirec- neogenesis (Fig. 1) [57]. Apart from the liver, adipo-
tionally related since NAFLD relates to the develop- nectin acts in muscles activating AMPK, increasing
ment of the insulin resistance [43]. the phosphorylation of ACC, glucose uptake, and
In this review, we will summarize relevant findings fatty acid oxidation [58,59]. In addition, this adipokine
concerning metabolic interorgan crosstalk connected contributes to the regulation of energy homeostasis
to the development and outcomes of T2D. [4,60]. Conversely, several adipokines have been associ-
ated with obesity and metabolic disorders, including
resistin [61,62], TNF-a [63–65], RBP4 [61,66], and
Organokines in type 2 diabetes
others, which impair the homeostasis and lead to com-
Hormones and organokines will not be discussed in plications in metabolic and inflammatory diseases
detail here but to understand the context of interorgan (Fig. 1) [4,61]. Related to T2D, leptin and resistin are
crosstalk, we provide a short summary of organokines. positively associated with insulin resistance, obesity,
Organokines are small secreted proteins produced by and induce a proinflammatory response [4,61,62,67].
target organ/tissues, such as the liver, adipose tissue, Skeletal muscles play an important role in T2D and
and muscles, and are classified as hepatokines, adipo- in the endocrine response through the production of
kines, and myokines, respectively. Organokines act in myokines which promote interorgan crosstalk and can
an endocrine, paracrine, and autocrine fashion, where also be considered as potential biomarkers for the dis-
their actions regulate several metabolic pathways, ease [3]. IL-6, usually associated with inflammatory
which affects the development of diseases. For exam- functions, is the best characterized myokine that plays
ple, hepatokines may act positively in homeostasis but different roles in certain tissues (Fig. 1). Treatment
dysregulation of hepatokines may lead to the develop- with IL-6 in a murine model suggested that insulin sig-
ment of the metabolic syndrome [44]. For example, naling through AKT was improved and reduced
fetuin inhibits the insulin receptor and consequently expression of gluconeogenic genes was observed as
triggers insulin resistance, which leads to inflammation well [68]. In adipose tissue, IL-6 was associated with
[7,44]. In accordance with this, fetuin-A as well as enhanced lipolysis and fat oxidation via AMPK activa-
fetuin-B are related to insulin sensitivity dysregulation tion [69]. IL-15 contributes to reduce visceral adipose
[45,46], impairment in glucose metabolism, and com- tissue and to enhance insulin action [70]. METRNL
plications in T2D [47,48]. In addition to fetuin-A and has been reported to contribute to energy expenditure
NEFA [44], other hepatokines have been linked to gly- through glucose and FFAs oxidation [71]. Thus, eluci-
cemic control, such as SMOC1 [49] and apolipoprotein dation of the roles of myokines, as well as other orga-
J, which improves glucose metabolism and insulin sen- nokines in the regulation of metabolic homeostasis,
sitivity in muscles [50]. holds promise for better understanding of metabolic
Another hepatokine that signals to the adipose tis- diseases such as diabetes.
sue is the selenoprotein P [51]. Selenoprotein P has
been suggested to cause insulin resistance in in vitro
The insulin signaling pathway in the
and in vivo experimental models [52,53], and when sele-
development of T2D
noprotein P levels are low, the levels of adiponectin
are high [51]. Evaluating the effects of FGF-21 in As mentioned earlier, T2D is a complex disease affect-
humans, high levels of FGF-21 were associated with ing the interplay between several metabolic pathways
obesity, NAFLD, and insulin resistance (Fig. 1) [44]. [72]. At physiological concentrations, glucose stimu-
In addition, high levels of sex hormone-binding globu- lates the b-cells to synthesize and release insulin,
lin have also been associated with T2D [54], as well as thereby promoting glucose uptake in muscle, adipose
hepassocin, LECT2, and retinol binding protein 4 tissue, liver, and brain. At the same time, insulin acts
(RBP4), which have been associated with impairment as an inhibitor for hepatic gluconeogenesis, as well as
in insulin signaling and glucose metabolism [10]. More- stimulating glycogen, protein synthesis, and lipogenesis
over, the secretion of LECT2 and RBP4 induces a while inhibiting lipolysis [73]. This illustrates that insu-
proinflammatory response in diabetic patients, and lin beyond its well-known glucose lowering action has
Fig. 1. Metabolic interorgan crosstalk in the development of T2D. Several metabolites from the adipose tissue (yellow), liver (orange),
pancreas (grey), and muscles (green) lead to signaling between tissues and this is connected to the development of type 2 diabetes.
also generalized hormonal effects, explaining why dia- pathways directly affects insulin’s functions. Lipogene-
betes involves several tissues. Insulin signal transduc- sis involves numerous mechanisms, including the
tion starts with the binding of the hormone to the induction of glucose uptake and glycolysis in the liver,
insulin receptor, which results in a series of phosphory- providing intermediates for the de novo synthesis of
lation events. Thus, intracellular protein substrates are fatty acids [75]. Insulin also induces the transcriptional
activated in order to trigger signaling cascades. Subse- activation of lipogenic genes, mediated by AKT2
quently, phosphatidylinositol 3-kinase (PI3K) induces which phosphorylates FOXO1 and SREBP1 [76]. We
the activation of protein kinase B (PKB), known as will touch upon these important pathways that are
AKT. With exception of hepatocytes, which mostly associated with insulin resistance and with the develop-
express the noninsulin-regulated glucose transporter 2 ment of T2D, especially in the context of the discussed
(GLUT2), GLUT4 is then translocated to the plasma metabolites.
membrane, with glycogen synthase and several
enzymes being activated through the action of insulin
Metabolic signature in type 2 diabetes
in target cells. The mitogen-activated protein kinase
pathway is also responsive to insulin signaling which Because of the impairment and imbalance in many
drives gene expression, protein translocation, and cell metabolic pathways in T2D, there is a need to under-
growth [74]. Overall, insulin is a primary driver for stand how amino acids, carbohydrates, nucleotides,
the regulation of carbohydrate, lipid, and protein carnitines, and lipid mediators are related to the devel-
metabolism, explaining why disbalance in metabolic opment and outcomes of T2D. Metabolomics
approaches are a great tool for the molecular charac- on providing a better understanding of how metabo-
terization of disease processes. However, a wide range lites can affect whole body physiology in the develop-
of metabolites were suggested as potential biomarkers ment of T2D. There is a wide range of lipids
leading to contradictory results, which questions the associated with diabetes including phospholipids, cera-
reproducibility of some of the earlier results. For mides, diacylglycerol, FFAs, and carnitine (Table 1).
example, increased levels of numerous amino acids Overall, after statistical meta-analysis, the most promi-
(AAs) have been correlated with IR and diabetes for nent lipids and acyl-carnitines in T2D are palmitic
decades [77–79]. In contrast, other studies have shown acid, myristic acid, stearic acid, linoleic acid, valeryl-
that many of these amino acids are decreased in diabe- carnitine (C5), and hexadecanoylcarnitine (C16),
tes [80–85]. Nonprospective and prospective studies respectively [86]. A recent lipidomics study on serum,
which analyzed plasma, serum, and/or urine in dia- muscle, and visceral adipose tissue of obese and T2D
betic subjects have shown that isoleucine, leucine, subjects emphasized changes in several lipid classes in
valine, tyrosine, phenylalanine, tryptophan [86–89], T2D, including increased deoxy-ceramides [104].
and the lysine metabolite 2-aminoadipic acid [90] were We have selected a few metabolites, which play
positively associated with T2D. Nevertheless, after a essential roles in the pathophysiology of T2D, that we
meta-analysis, the AAs that significantly associated will discuss in more detail (see below).
with T2D were isoleucine, leucine, tyrosine, phenylala-
nine, alanine, and glutamate [86]. Whether these corre-
Free fatty acids, diacylglycerol, and ceramides as
lations are cause or consequences of IR/T2D has not
key metabolites in the development of T2D
been clarified in detail. Thus, these contradictory data
require further analysis and additional technical The synthesis of fatty acids from nonlipid precursors
improvements of the metabolomic analyses including or ‘de novo lipogenesis’ is an enzyme coordinated path-
reproducible standards with which the samples can be way that occurs in the cytoplasm of hepatocytes and
spiked [89]. in adipocytes but FFAs can also be taken up from the
In general, the most prominent carbohydrates diet. Increased levels of glucose and ATP in cells pro-
altered in T2D are hexoses, glucose, mannose, and mote lipogenesis (Fig. 2) [105]. Following glycolysis,
fructose [86,91]. In addition, other carbohydrates have pyruvate enters the mitochondria and is converted into
been suggested as potential biomarkers in T2D acetyl-CoA through oxidative decarboxylation. Alter-
through their increased levels in biological samples. natively, pyruvate can also be converted into lactate in
These include lactate, 1,5-anhydroglucitol, galactose, the cytosol [106]. Subsequently, mitochondrial acetyl-
arabinose, inositol, trehalose, dihexose, phosphate, cit- CoA drives the tricarboxylic acid (TCA) cycle where it
rate, malate, 2-oxoglutaric acid, pyruvate, fumarate, is converted into citrate. High levels of insulin and glu-
cis-aconitate [86], and glucose-6-phosphate [89]. Since cose activate the transcription factors ChREBP and
the liver acts as a major metabolic organ in the human SREBP-1c, which leads to the transcription of lipo-
body, intermediate metabolites, such as glucose-6- genic genes, promoting de novo lipogenesis in the liver
phosphate, were suggested as a potential biomarker and the transport of citrate from mitochondria to the
produced by the liver in T2D (Table 1). In addition, cytosol. In the cytosol, citrate is converted into acetyl-
lactate was also detected at high concentrations in the CoA and oxaloacetate by the ATP-citrate lyase
liver. (ACLY) (Fig. 2). Acetyl-CoA carboxylase (ACC) car-
Besides carbohydrates, nucleotides play important boxylates acetyl-CoA to form malonyl-CoA. Finally,
metabolic roles, acting as cofactors [92] and they can malonyl-CoA (two carbons), acetyl-CoA (as a primer),
be linked to metabolic disorders [93]. Uridine, tri- as well as NADPH (reducing agent) are used to
methylamine, and glyoxylic acid, for example, are synthetize long-chain fatty acids by fatty acid synthase
upregulated in T2D [82,84,94–96]. Interestingly, not (FAS) catalysis (Fig. 2). The most prominent fatty
only in T2D but also in T1D, AMP, GMP, GTP, acid synthetized by FAS is palmitic acid (C16:0). Sub-
IMP, adenosine, guanosine, and inosine were found to sequently, palmitoleic acid is generated by stearoyl-
be increased [97,98]. CoA desaturase-1 and palmitoleic acid can be elon-
Lipids, as well as the lipid transporter carnitine (b- gated to oleoyl-CoA. The desaturation of stearic acid
hydroxy-c-trimethylammonium butyrate), which play leads to oleic acid (C18:0), which is the end product of
essential roles in fatty acid metabolism, have been de novo fatty acid synthesis [105,107].
associated with the development of diabetes [40,89,99– Increased levels of FFAs and deranged de novo lipo-
103]. Because of the relevance of lipid metabolism in genesis cause several metabolic disorders [40,105,108–
diabetes, especially in T2D, many studies have focused 110]. Although it is assumed that insulin resistance
Table 1. Metabolic profile associated with type 2 diabetes. Studies performed in (A) human samples and (B) animal samples. Amino acids,
carbohydrates, lipids, and carnitines detected in the blood (#), urine (&), liver (L), muscle (M), adipose tissue (AT), and islets (i) in T2D.
(A)
Amino acids Carbohydrates Lipids Carnitines
Cysteine # [81,84,110], & [94] Glucose # [86,110], & Phospholipids # [86,89], L/M/AT Propionylcarnitine # [89,301],
[86,91], L [89] [89] L [89]
Pantothenic acid # [81,84,110], & [94] Mannose # [86,110], & Ceramides i [101], L/M [133] Butyrylcarnitine # [89,301], L
[86,91] [89]
Creatine # [81,84,110], & [94] Fructose # [84,86], & Diacylglycerol M [302], L Valerylcarnitine # [86,89,301],
[86,91] [134,135] L [89]
Acetyl carnitine # [81,84,110], & [94] Lactate # [86], L [89] Lauric acid # [160] Octanoylcarnitine # [301], L
[89]
Butyryl carnitine # [81,84,110], & [94] 1 5-Anhydroglucitol # [86] Myristic acid # [160,303–305] Decanoylcarnitine # [89,301],
L [89]
Alanine # [80,81,83,85,306–308], & [82], L Galactose # [309] Pentadecanoic acid # [160,304] Tetradecenoyl # [301], L [89]
[89]
Glutamate # [80,81,83,85,306–308], & [82], Glucose-6-phosphate L 2-Pentadecenoic acid # [160] Hexadecanoylcarnitine #
L/M [89] [89] [86,89,301], L [89]
Glutamine # [80,81,83,85,306–308] & [82], Trehalose # [86] Palmitic acid # [84,160,303–305], Octadecanoylcarnitine # [301],
L [89] AT/L [89] L [89]
histidine # [80,81,83,85,306–308], & [82], dihexose # [110] Palmitoleic acid # [84,160,303– Arachidoylcarnitine # [301]
M [89] 305]
Isoleucine # [80,81,83,85,306–308], & [82], Malate # [86] Margaric acid # [160]
AT [89]
Leucine # [80,81,83,85,89,306–308] & [82] 2-Oxoglutaric acid # [86] 7-Methyl-6e-hexadecenoic acid #
[160]
Proline # [80,81,83,85,306–308], & [82], AT Arachidonic acid # [160], M [89]
[89]
Serine # [80,81,83,85,306–308], & [82] Stearic acid # [84,160,303]
Threonine # [80,81,83,85,306–308], & [82] Oleic acid # [84,160]
Lysine # [80,81,83,85,89,306–308], & [82], Linoleic acid # [160,303–305]
AT [89]
Tyrosine # [80,81,83,85,87–89,306–308], & Gamma linoleic acid #
[82,88], L/M [89] [160,304,305]
Valine # [80,81,83,85,306–308], & [82] 3e 9z 12z 15z-
Octadecatetraenoic acid # [160]
Phenylalanine # [80,81,83,85,87,88,306– Nonadecanoic acid #
308], & [82,88] [160,303,304]
Tryptophan # [80,81,83,85,87,88,306–308], Eicosanoid acid # [160,303,304]
& [82,88] AT [89]
Creatinine # [80,81,83,85,306–308], & [82], 11 14-Eicosadienoic acid # [160]
L [89]
2-Ketocaproic acid # [80,81,83,85,306– 5 8 11-Eicosatrienoic acid #
308], & [82] [160,304]
Pyroglutamic acid # [80,81,83,85,306–308], Eicosatetraenoic acid #
& [82] [160,304,305]
Choline # [80,81,83,85,306–308], & [82] eicosapentaenoic acid #
[160,303,305]
Ornithine # [80,81,83,85,306–308], & [82] 11z-Docosenoic acid # [160]
2-Aminoadipic acid # [90] Docosahexaenoic acid #
[160,304,305]
precedes the hypersecretion of insulin, considered as plasma lipids, in particular, palmitate, stimulate insu-
an adaptation to meet the increased insulin require- lin secretion even under fasting conditions [111]. Pal-
ments, there is evidence to the contrary. Increased mitate raises basal insulin secretion by promoting a
Table 1. (Continued).
(B)
Amino acids Lipids
Cysteine & [94] Ceramides L/M [133]

Pantothenic acid & [94] Diacylglycerol L [134,135]
Creatine & [94] Lauric acid # [160]
Acetyl carnitine & [94] Myristic acid # [160]
Butyryl carnitine & [94] Pentadecanoic acid # [160]
Alanine & [82] 2-Pentadecenoic acid # [160]
Glutamate & [82] Palmitic acid # [160]
Glutamine & [82] Palmitoleic acid # [160]
Histidine # [83] & [82] Margaric acid # [160]
Isoleucine # [83], & [82] 7-Methyl-6e-hexadecenoic acid # [160]
Leucine # [83] & [82] Arachidonic acid # [160]
Proline # [83], & [82] Stearic acid # [160]
Serine #, & [82] Oleic acid # [160]
Threonine # [83], & [82] Linoleic acid # [160]
Lysine # [83], & [82] Gamma linoleic acid # [160]
Tyrosine # [83], & [82] 3e 9z 12z 15z-Octadecatetraenoic acid # [160]
Valine # [83], & [82] Nonadecanoic acid # [160]
Phenylalanine # [83], & [82] Eicosanoid acid # [160]
Tryptophan # [83], & [82] 11 14-Eicosadienoic acid # [160]
Creatinine # [83], & [82] 5 8 11-Eicosatrienoic acid # [160]
2-Ketocaproic acid # [83], & [82] Eicosatetraenoic acid # [160]
Pyroglutamic acid # [83], & [82] Eicosapentaenoic acid # [160]
Choline # [83], & [82] 11z-Docosenoic acid # [160]
Ornithine # [83], & [82] Docosahexaenoic acid # [160]
mitochondrial proton leak in b-cells [112]. According (WAT) and in the liver [116–119], promoting the acti-
to this hypothesis, hyperinsulinism would in turn vation of NF-jB and consequently causing endoplas-
cause insulin resistance. Irrespective of the mechanism mic reticulum (ER) stress in metabolic organs and
of hyperinsulinemia, the consequence of insulin resis- immune cells, as well as inflammation; leading to insu-
tance is decreased glucose uptake in muscle and lin resistance [120,121]. Conversely, it has been sug-
increased production of liver glycogen, contributing to gested that insulin resistance is the initiating event, in
the development of T2D [2,12,40,41,86,113]. Fatty turn leading to inflammation [122]. Although the
acids such as palmitic acid, which is the major lipid molecular mechanisms related to fatty acids and insu-
produced through de novo lipogenesis, has been asso- lin resistance remain unclear, there is a tight associa-
ciated with the risk of T2D [86]. In addition to these tion of FFAs with the impairment of insulin secretion
data, palmitoleic acid, stearic acid, and oleic acid are and FFAs have long been considered a risk factor for
also considered markers associated with pathogenesis the development of T2D [123]. Taken together, fatty
of T2D through the de novo lipogenesis pathway acids act directly and indirectly in the development
[114]. Metabolic changes during the progression of and outcomes of T2D. De novo lipogenesis is a path-
T2D, such as increased free fatty acids, may activate way with a tight coupling to T2D, which is not only
other pathways that could contribute to the progres- due to the production of fatty acids but also due to
sion of T2D. For example, palmitic acid is a lipid fatty acids serving as substrates, playing a key role in
mediator that leads to a proinflammatory response synthesis of other lipids such as diacylglycerol (DAG)
through the toll-like receptor 4 (TLR4), causing toxic and ceramides [72].
effects in the islets, resulting in both impaired insulin Multiorgan involvement in T2D promotes increases
secretion and insulin resistance in the target organs in the production and release of lipid species
[115,116]. Moreover, saturated fatty acids, for exam- [100,124,125], carbohydrates [89,126], and amino acids
ple, palmitic acid, are responsible for the proinflam- [78,89,127]. Convincing evidence suggests that FFAs
matory response via TLR4 in white adipose tissue affect islets in many ways and exacerbates the
Fig. 2. Lipid metabolism and insulin resistance. High levels of glucose, insulin, and ATP promote the activation of the transcription factors
ChREBP and SREBP-1, which drive de novo lipogenesis. Mitochondrial citrate translocates to the cytosol, where it is converted into acetyl-
CoA and oxaloacetate by ACL. Then, malonyl-CoA is converted by FAS to form fatty acids. Thus, triglycerides can be esterified through
MOGAT2, DGAT2, and G3P and be stored in hepatocytes or adipose tissue. Also, TAG can be a major source for DAG synthesis. DAG can
be also synthesized from monoacylglycerol, phosphatidic, and phospholipids. DAG accumulation may inhibit the IRS adaptor protein, which
leads to the blockage of insulin signaling. Ceramides play an important role in insulin resistance through the inhibition of insulin signaling by
dephosphorylating AKT and blocking the action of AKT/PIP3-PDK1, which then affects the insulin receptor. JNK is activated by ER stress
caused by FFAs via TLR4 activation, leading to phosphorylation of IRS1 and IRS2 and this consequently results in insulin resistance. In
addition, ER stress can also activate JNK directly independently of TLR4. While de novo lipogenesis often happens in the liver, ceramides
can be synthesized in the liver, WAT, muscle, or islets. Nevertheless, these pathways are connected through interorgan crosstalk.
development of T2D. Since T2D has been considered liver, adipose tissue, islets, muscles, and probably also
as a multifactorial and complex disease [12,128], it is other organs. Fatty acids are ingested in the form of
reasonable to infer that T2D is a disease involving phospholipids and TAG and during ingestion the
numerous changes in metabolic pathways (Fig. 1). hydrolysis of these lipids are converted into mono-
This disease affects other tissues, such as the adipose and diacylglycerols, as well as FFAs. Short- and
tissue, muscle, and the liver [13,29,40,113,129], through medium-chain length FFAs may be observed in the
the production and distribution of metabolites via intestines and transported by serum albumin in the
blood circulation, leading to interorgan crosstalk. bloodstream and stored in the adipose tissue and liver
Free fatty acids can originate from the diet (15– [130]. Moreover, lipogenesis is another source of FFAs
20%), adipose tissue (~ 60%), and liver (15–25%). At where their synthesis is driven by the excess of carbo-
the same time, FFAs affect several organs including hydrates, triggering de novo lipogenesis, as explained
previously in this review. Lipogenesis occurs in several JNK/IKK-dependent serine phosphorylation of IRS1
cell types, but the liver, adipose tissue, and mammary leads to insulin resistance [145]. Besides that, abnor-
glands are the most active in this process [131,132]. mal levels of FFAs lead to cell stress due to lipotoxi-
In diabetic patients, several lipids species can accu- city inducing ER stress, ROS production, and
mulate in the liver and in the adipose tissue (Table 1). apoptosis [102]. This results in inflammation in adipo-
In the liver, phospholipids, ceramides, diacylglycerol, cytes [146] and causes chronic low-grade inflammation
and FFAs, such as palmitic acid, were increased in and insulin resistance, which contribute to the patho-
T2D [89,118,133–135]. Phospholipids and palmitic acid genesis of T2D [102].
were also found at high concentrations in the adipose The most widely held view is that insulin resistance
tissue [89], while phospholipids, ceramides, and arachi- leads to compensatory hypersecretion of the hormone
donic acid were elevated in T2D muscle samples from the b-cells, however, long term of exposure to
[89,133]. In addition, pancreatic islets displayed high FFAs at high levels results in b-cells dysfunction by
levels of ceramides in the diabetic condition [101]. lipotoxicity, which together with dysregulated blood
Interestingly, the total carnitine content in the human glucose control (glucotoxicity) eventually induce T2D
body is mostly stored in the heart and skeletal muscle [147]. Long-chain fatty acids, such as palmitate
[136]. Conversely, the levels of carnitines were most (C16:0) and stearate (18:0), and to a lesser extent myr-
prominent in the liver of T2D patients [89]. istate (C14:0) and laurate (C12:0), induce cytotoxicity
Elevated levels of FFAs released from the liver have in b-cells [148]. Chronic FFAs exposure of isolated
been linked to the development of T2D (Fig. 1) pancreatic islets at stimulatory glucose concentrations
[100,102,124,137]. T2D and NAFLD are likely bidirec- causes inhibition of glucose-stimulated insulin secre-
tionally related since NAFLD relates to the develop- tion (GSIS), altering gene expression, as well as pro-
ment of the insulin resistance [43] and up to 50% of moting apoptosis [149]. The b-cells are very sensitive
diabetic patients develop a fatty liver. The accumula- to ER stress and unfolded protein response with satu-
tion of FFAs in the liver is considerably increased in rated fatty acids inducing ER stress eventually leading
patients with T2D and NAFLD [138] often as a result to b-cells apoptosis [150]. Thus, chronic exposure of
of obesity. The liver is the metabolic center of the pancreatic islets to FFAs contributes to the develop-
human body, which plays essential roles in the detoxi- ment of T2D. Moreover, an in vitro study proposed
fication, digestion, and controlling many metabolic metabolic interorgan crosstalk between a fatty pan-
pathways and biological processes [139]. Because the creas and fatty liver, where the hepatokine fetuin-A
liver is functionally related to energy homeostasis and palmitate induced the expression of IL-6, CXCL8,
through lipid and glucose metabolism, and its links to and CCL2 in pancreatic adipocytes in a TLR4-
the gastrointestinal tract, disequilibrium of the liver dependent manner [2]. In the islets, the expression of
homeostasis and exposure to toxins can lead to liver IL-6 and CXCL8 was significantly higher after fetuin-
damage and diseases [113,140]. NAFLD is character- A and palmitate treatment, and when co-cultured with
ized by lipid deposition in the liver without alcohol macrophages, IL-1b was also released. Fetuin-A was
abuse or other etiologies related to viral or autoim- responsible for causing an impairment in glucose-
mune hepatitis [113]. The progression of NAFLD can induced insulin secretion (Fig. 1) [2]. Taken together,
lead to simple steatosis, nonalcoholic steatohepatitis this study suggests potential interorgan crosstalk
(NASH), liver fibrosis, cirrhosis, and eventually HCC between a fatty liver and pancreas leading to impair-
[42,141]. Conversely, due the lipid influx into the liver, ments in b-cells, with a fatty pancreas inducing a local
the liver contributes to increase in the levels of circu- inflammatory reaction [2].
lating lipid mediators that trigger metabolic crosstalk Regarding the adipose tissue, high levels of FFAs
and induce insulin resistance in other tissues [142]. promote its storage in adipocytes; however, increased
Stearic acid, for example, has been considered a pre- amount of fat in adipocytes may lead to cell and tissue
dictor of peripheral insulin resistance and glycemia in hypoxia and consequently to inflammation [132]. In
T2D [143]. Additional to insulin resistance that FFAs this context, due to the fat accumulation in the adi-
promote in several tissues, high levels of FFAs trigger pose tissue, TNF-a plays an important role through
several pathways that may collaborate to the out- the production and release by the adipose tissue during
comes of T2D. Increased levels of palmitate induce inflammation, increasing lipolysis and promoting insu-
the activation of the inflammasome and promote IL- lin resistance [151,152]. In addition, TNF-a acts in an
1b and IL-18 maturation and secretion, and conse- autocrine manner in the adipose tissue and reduces the
quently trigger a proinflammatory response [144]. The insulin sensitivity through the inhibition of IRS1 and
action of proinflammatory cytokines by inducing downregulating PPAR-c [153,154]. Due to increased
lipolysis promoted by adipocytes and high levels of promotes the expression of lipogenic genes, resulting
FFAs in the bloodstream, crosstalk between FFAs in in steatosis [160]. In this system, we consider FFA to
muscles, liver, and pancreas may lead to lipoapoptosis be the signaling molecule that drives crosstalk between
and organ failure [155]. Lipotoxicity in other tissues the liver, islets, WAT, and muscle [160]. Our study
and organs provokes several metabolic perturbations, indicates that defects in the liver may initiate the devel-
such as ROS production, leading to ER, lysosomal, opment of diabetes.
and mitochondrial stress, resulting in tissue damage Metabolic disbalance in the liver and muscles is
and loss of important functions of those target tissues often related to metabolic diseases and inflammation
and organs [156]. In fact, it is of interest in this con- [163,164], with DAG and ceramides playing important
text that T2D patients display impairment in mito- roles [165,166]. DAG accumulation in muscle and liver
chondrial activity in the deep subcutaneous adipose promotes the activation of PKC and blocks insulin
tissue, which leads to muscle insulin resistance and receptor activation, leading to insulin resistance [167–
increased substrate flux to the liver [157]. 169]. Abnormal lipid accumulation in the liver and
Skeletal muscle use glucose and FFAs as main meta- muscle correlates positively with insulin resistance
bolic energy source, and, since in T2D the flux of [170]. Conversely, insulin resistance seems to stimulate
TAG and FFAs is increased, the increased uptake of increased lipid deposition in these tissues [72]. Elevated
FFAs into myocytes is common, as well as their stor- concentrations of plasma FFAs result in fat accumula-
age as TAG [132,158]. The accumulation of FFAs in tion in the liver, WAT, and muscle by controlling the
myocytes, the synthesis of diacylglycerols and cera- amount of diacylglycerol (DAG), triglycerides (TAG),
mides, results in several consequences, including lipo- and long-chain acyl-CoA [171]. DAG is a precursor of
toxicity, inflammation, insulin resistance, and cell TAG, and by activation of protein kinase C (PKC)
damage [132]. In C2C12 myotubes, palmitate (C16:0) isoforms, modulates the phosphorylation of insulin
decreased the diameter of the myotubes and insulin pathway molecules [99]. The synthesis of DAG starts
signaling was affected [159], suggesting a direct effect with the catalysis of monoacylglycerol through monoa-
of FFAs on the physiology of muscle. cylglycerol acyltransferase, promoting the esterification
To illustrate how FFAs are involved in interorgan of monoacylglycerol (Fig. 2) [72,168]. On the other
crosstalk, we will now discuss one of our recent stud- hand, DAG can be synthesized by the hydrolysis of
ies. Using a mouse knockout model for cyclin- triacylglycerol and phospholipids by adipose triglycer-
dependent kinase 1 (Cdk1 cKO; Cdk1flox/flox Alb-Cre), ide lipase and phospholipases, respectively [72,168].
which is defective in hepatocyte proliferation and Another possibility to generate DAG is from phospha-
shows impairments in mitochondrial functions, our tidic acid where lipins (LPIN1 and LPIN3) mediate
group has uncovered impairments in fatty acid oxida- the dephosphorylation, consequently synthetizing
tion (FAO) and increased lipolysis, promoting high DAG (Fig. 2) [72]. In T2D, increased levels of DAG
levels of FFAs in the bloodstream, which caused promote the activation of PKCh and PKCe, phosphor-
enhanced insulin secretion by b-cells in young Cdk1 ylating the insulin receptor, and consequently leading
cKO mice [160]. Homeostatic levels of insulin in the to insulin resistance (Fig. 2) [167–169]. PKC isoforms
blood are essential for sugar metabolism, but at ele- have long been associated with insulin resistance
vated levels, classified as hyperinsulinemia or chronic [172,173] and their activation was also observed in dia-
hyperinsulinemia, insulin resistance develops [161,162]. betic rodent models [174,175]. Although increased
Hyperinsulinemia was observed in aged Cdk1 cKO levels of DAG were associated with insulin resistance,
mice associated with insulin resistance through reduced different DAG species may act in various ways regu-
INSRB expression as well as the reduction in insulin lating PKC activities. Nevertheless, the activation of
receptor autophosphorylation, high levels of glucose in PKCs through DAG accumulation in muscle and liver
the blood, decrease in glucose tolerance, and response modulates insulin sensitivity and seems to be an
to insulin [160]. Thus, in this mouse model, there is a important lipid mediator in the development of T2D
relationship between loss of hepatocyte proliferation [72,176,177].
and/or the Cdk1 gene and lipid metabolism, leading to Ceramides are sphingolipid-derived lipids that have
a diabetes-like phenotype. Mitochondrial dysfunction been linked to the pathogenesis of T1D and T2D
in hepatocytes results in excessive plasma FFAs that [101]. Although ceramides can play important roles in
are stored in the WAT leading to hyperinsulinemia. insulin resistance, not all ceramide species are associ-
Over time, Cdk1 cKO mice become insulin resistant ated with this condition and the development of T2D
and elevated blood glucose levels contribute to the [178]. Ceramides have been linked to muscle insulin
activation of the transcription factor LXR/RXR which resistance through their action downstream of IRS1 to
inhibit the phosphorylation and activation of PKB/ been described as potential biomarkers in T2D
Akt [179]. In vitro studies have shown that ceramides [86,96,199], and glutathione is an important scavenger
play important roles in insulin resistance in muscle of free radicals generated during oxidative stress [200],
cells [180,181], and there are data that link elevated we chose these pathways to highlight their important
levels of ceramides in muscles to T2D risk in roles in the development of T2D (Fig. 3).
men [182]. Thus, many more studies are needed to
investigate the relationship of lipid metabolism and
Lactate and alanine contribute to
insulin resistance in different tissues. Previous data
gluconeogenesis and the development of T2D
suggested that ceramides inhibit glucose uptake and
glycogenesis in muscle cells [183,184]. In an animal Lactate and alanine are a major source for gluconeo-
model of lipid infusion, ceramides were increased genesis [201]. The release of considerable amounts of
in muscles and the peripheral insulin sensitivity was lactate in plasma is the result of glycolysis in muscle
decreased [133]. and other tissues, and is inversely correlated with the
High levels of ceramides have been correlated with oxidative activity in mitochondria [202]. The mito-
inflammation driving insulin resistance, caused by the chondrial oxidative capacity is lower in T2D compared
reduction of adiponectin levels and the increased levels with healthy people [203] and the association between
of ceramide precursors [65,185,186]. Several studies high levels of lactate in the plasma with insulin resis-
have provided a better understanding on how ceramides tance has been observed [204] in T2D patients [205].
can affect insulin biology in cells and tissues [118,186– In addition, high concentrations of alanine were found
188]. Although the specific molecular mechanism of in diabetic patients including in the liver, blood, and
how ceramides trigger insulin resistance has not been urine [89,199,206]. There are two stereoisomers of lac-
elucidated, some studies have shown the association tate (2-hydroxypropanoate), L-lactate and D-lactate,
between insulin resistance and ceramides [101,186–194]. with L-lactate being prominent in physiological condi-
Ceramides promote the activation of phosphatase 2A tions through its production by glycolysis (Fig. 3)
[187,189], which dephosphorylates AKT [187,193], [207,208]. In the cytosol, pyruvate is reduced to L-
thereby blocking insulin-stimulated AKT attenuating lactate by lactate dehydrogenase (LDH) (Fig. 3) [209].
the translocation of the PIP3-PDK1 complex at the Evidence suggests that high concentrations of lactate
plasma membrane of target cells (Fig. 2) [191,194]. In lead to increased hepatic glucose production, which in
addition to these mechanisms, the accumulation of cer- association with the imbalance in lipid metabolism in
amides in membrane domains induces caspase activa- the liver triggers insulin resistance that may inevitably
tion leading to proinflammatory cytokine production contribute to the development of hyperglycemia and
and release, ROS generation, and cell death [195,196]. T2D [210]. Related to lactate metabolism, the high
Thus, ceramides are bioactive lipids that play essential concentrations of alanine in diabetic patients have
roles in cell signaling and also may affect the insulin been associated with the progression of T2D. The
pathway in target tissues. Intriguingly, the correlation reversible catalysis of alanine aminotransferase (AAT),
between ceramides and T2D needs further study since also known as glutamate pyruvate transaminase
ceramides may be induced by inflammation or could (GPT), promotes the transamination of L-alanine and
cause inflammation as a consequence of progression of a-ketoglutarate to convert them into pyruvate and glu-
T2D [65,101,185,197,198]. tamate. In addition, alanine can also stimulate gluco-
In general, lipids play essential roles in whole body neogenesis [211–213]. Being a glucogenic amino acid,
physiology as well as in the development of several alanine may act as an intermediate metabolite to form
diseases. In T2D, lipid mediators act through different glucose in the liver by the catalysis of alanine transam-
pathways and when the concentration of FFAs is high inase (ALT), with ALT using alanine and a-
and the synthesis of lipids is upregulated, metabolic ketoglutarate to form glutamate and pyruvate. Pyru-
changes occur that consequently affect physiology, vate then serves as a substrate for the gluconeogenesis
leading to cellular stress, ROS, and inflammation. pathway [211,212].
Thus, disorders of lipid metabolism play an important Since alanine induces gluconeogenesis in muscle
role in the development of T2D. In order to emphasize [211] as well as in liver [212,213], alanine may be a
the importance of a better understanding of the molec- potential biomarker for glucose synthesis in T2D.
ular mechanisms of metabolic pathways associated Overall, elevation of alanine seems to play a role in
with T2D, we will present next the pathways focusing the interorgan crosstalk in T2D. Alanine is produced
on lactate, alanine, glutamate, glutathione, and inflam- by ALT in a reaction including a-ketoglutarate, pyru-
mation. Since lactate, alanine, and glutamate have vate, and glutamate. From this reaction, it is clear that
Fig. 3. Lactate, alanine, glutamate, and glutathione metabolism. After glucose uptake in the liver and its oxidation through glycolysis,
pyruvate can be used to form lactate or alanine, both being major sources for gluconeogenesis. Glutamate is synthesized by different
pathways and serves as an intracellular as well as extracellular stimulus for insulin secretion, participating in incretin actions in b-cells.
Hyperglutamatemia is associated with the production of oxidative stress and leads to inflammation and insulin resistance. Altered
glutathione synthesis may play essential roles in the defense against proinflammatory cytokine expression and oxidative stress. On the
other hand, lipids, proinflammatory cytokines, and oxidative stress may block the synthesis of glutathione. The balance of these pathways
leading to oxidative stress and inflammation may determine the outcome of T2D.
alanine can be generated in all organs but larger 79 women using magnetic resonance imaging for fat
amounts are generated in organs with a high-energy content in the liver, and statistical correlations indi-
turnover. Liver and muscles may be considered major cated that liver and pancreas may communicate with
producers of several amino acids species where high each other [32]. Although not all individuals with T2D
concentrations are found in T2D (Table 1). Glutamate display hyperglucagonemia [214], which is related to
and tyrosine concentrations were reported to be ele- the secretory activity of a-cells in the pancreatic islets,
vated in the liver and muscles in patients under T2D increased levels of glucagon in the plasma have been
condition [89]. In the liver, alanine, glutamine, and cre- associated with the development of T2D [32]. A cohort
atinine were increased in comparison to other tissues study proposed that the glucagon–alanine index is
and organs, and histidine increased in the muscles [89]. associated with liver fat and this association was also
Adipose tissue also played an important role as major related to insulin resistance, indicating a risk factor for
producer of some amino acids, where the concentra- T2D [32]. Evaluating metabolism during liver regener-
tion of isoleucine, proline, lysine, and tryptophan was ation in a model with mitochondrial impairments in
more prominent [89]. hepatocytes, our group provided data that alanine pro-
An interaction between the fatty liver and pancreas duction from pyruvate is increased by the metabolic
was also shown through the liver-a-cell axis in a study flux through alanine transaminase [213]. Moreover,
that evaluated glucagon and alanine from plasma of elevated levels of a-ketoglutarate and glutamine were
observed, with increased concentrations of glutamine secretion, as well as in neuronal communication and
possibly related to a compensatory anabolic mecha- brain plasticity [223]. Glutamate is synthesized in sev-
nism in the context of mitochondrial impairment [215]. eral tissues, including the brain, skeletal muscle, liver,
Regarding muscles, T2D patients develop high sys- kidney, and pancreas, while acting both in intra- and
temic levels of amino acids and protein metabolic turn- extracellular signaling [223]. Glutamate can be gener-
over [216]. An interorgan crosstalk between the liver ated in the cytosol and in mitochondria (Fig. 3). In
and muscles suggests that the catabolism of alanine in the cytosol, glutamate is synthesized by using fructose-
the liver by ALT promotes an endocrine and meta- 6-phosphate (F6P) from the glycolysis pathway, where
bolic interaction that links hyperglycemia and muscle F6P and glutamine are converted by fructose-6-
atrophy in the diabetic condition [217]. ALT expres- phosphate aminotransferase; consequently forming
sion was upregulated in BKS-db/db mice with obesity glutamate. Moreover, through glutaminase, glutamine
and diabetes. Therefore, by silencing GPT and GPT2, can be deaminated to form glutamate (Fig. 3). In
the ALT isoforms, alanine tolerance was reversed, mitochondria, glutamate is formed by glutamate dehy-
linked to the lower glycemic response to alanine, as drogenase (GDH1 and GDH2), where a-ketoglutarate
well as polydipsia, glycosuria, and blood glucose levels is converted into glutamate (Fig. 3) [223]. Glutamate
were reduced by ALT silencing in the liver [217]. has been associated with glucose-induced insulin secre-
Moreover, the lack of ALT contributed to improve- tion for many years [224,225]. The synthesis of gluta-
ments in skeletal muscle mass in diabetic mice. The mate following glucose metabolism occurs either in
endocrine–liver–amino acid catabolic axis provides mitochondria of b-cells through GDH or in the cyto-
intriguing evidence that links hyperglycemia and mus- sol by transamination from aspartate [226–228]. In the
cle atrophy in T2D [217], providing a novel view former case, glutamate is transported to the cytosol by
regarding the metabolic interorgan crosstalk, which the glutamate carrier (GC1) [229]. Insulin exocytosis is
could serve as tools for new therapeutic approaches in primed following glutamate uptake into the insulin
T2D. secretory granules (Fig. 3). After glucose uptake into
Interestingly, alanine can be used as an intermediate b-cells, glutamate thus acts as a messenger molecule by
metabolite to form 1-deoxysphingolipids, which is an triggering insulin secretion [227,228]. Later, glutamate
atypical sphingolipid with toxic effects in neurons and was also linked to the potentiation of glucose-
b-cells. Sphingolipids have been associated with neuro- stimulated insulin secretion by the incretin hormones
logical diseases and T2D [218]. Their levels are also GLP1 and GIP. These gut hormones bind to their
increased in serum and visceral adipose tissue from respective receptors in the membrane of b-cells, gener-
T2D patients [104]. The synthesis of these sphingoli- ating cAMP and activating PKA [230,231]. This pro-
pids occurs when serine palmitoyltransferase condenses motes glutamate uptake by the insulin granules,
palmitoyl-CoA with alanine rather than serine [218]. facilitating insulin secretion [230,231]. Mechanistically,
In pancreatic a-cells, a study showed that a mixture of the high levels of glucose and consequently ATP pro-
amino acids (alanine, arginine, cysteine, and proline) duction lead to closure of the ATP-sensitive potassium
promoted increased levels of glucagon in the plasma in channel, which results in the depolarization of b-cells
female mice, as well as increased blood glucose and the opening of voltage-sensitive calcium channels.
through a glucagon receptor-dependent way [219]. Ala- The increase in cytosolic Ca2+ is the main trigger for
nine and other amino acids have been associated with insulin secretion [223]. Thus, intracellular glutamate
increases in a-cell proliferation [23,220,221]. Therefore, plays an important role in glucose- and incretin-
inhibition of glucagon signaling has been observed in stimulated insulin secretion [227,229]. VGLUT1 and
a-cell hyperplasia as well as hyperaminoacidemia VGLUT2 are the major glutamate transporters that
[23,220,222]. Thus, alanine seems to be a pivotal bio- are associated with the potentiation of insulin secretion
marker in pancreatic islet dysfunction, promoting met- [229].
abolic and structural changes that may participate in It is noteworthy that impaired b-cell responsiveness
the development of metabolic diseases, such as to incretin hormones is an early defect in T2D [231].
diabetes. Moreover, glutamate is cosecreted with insulin, caus-
ing high concentrations of glutamate in the extracellu-
lar space of the pancreatic islets. Therefore, the
Involvement of glutamate in health and disease
NMDA receptors in b-cells may be activated, which
Glutamate is a nonessential amino acid abundant in leads to depolarization and increases in cytosolic Ca2+,
the human body, which plays important roles in eventually resulting in b-cell dysfunction and death
metabolism, in the control of insulin and glucagon [232,233]. NMDA receptor antagonists have therefore
been suggested as treatment in T2D [234]. Concerning Type 2 diabetes as an inflammatory disease:
receptor-mediated effect of glutamate, it is worth men- metabolic association and outcomes
tioning that an inhibitory effect of glutamate on insu-
Several metabolites may cause inflammation during
lin secretion has also been associated with another
the progression of T2D. As we have already men-
membrane receptor, that is, GPRC5B [225].
tioned, high levels of FFAs, DAG, ceramides, and glu-
Obesity, aging, and T2D are characterized by insulin
tamate may collaborate with ROS and reactive
resistance, which not only affects glucose and lipid
nitrogen species production inducing a proinflamma-
homeostasis but also protein metabolism, resulting in
tory response in T2D [99,100,102,165–167,238,251]. In
diminished anabolic actions of insulin and increased
this section, we will summarize how metabolites trigger
plasma glutamate [235–237]. Hyperglutamatemia is
inflammation and how the proinflammatory response
associated with increased oxidative stress and inflam-
can affect the development of T2D (Fig. 4).
mation (Fig. 3), as is the case in diabetes [238–240].
High concentrations of free fatty acids have been
Proinflammatory factors and insulin resistance may
associated with increased plasma free radicals in
collaborate leading to cytotoxicity through high levels
humans [137], as well as ROS production in adipocytes
of glutamate [241]. Thus, more studies are needed in
through NADPH oxidase, which consequently resulted
order to uncover the effects of glutamate in the patho-
in proinflammatory cytokine production and release
physiology of T2D and its potential as a drug target.
from white adipose tissue [252]. ROS plays a key role
in signaling and inflammation [253]. The production
and release of proinflammatory cytokines may affect
Impairments in glutathione production may lead
not only the tissue where they were produced, such as
to disbalance of homeostasis
the adipose tissue and/or the liver, but also, by circu-
Glutathione (GSH) is a tripeptide synthesized from lating in the blood, may affect other tissues and lead
glutamate, cysteine, and glycine in the cytosol of all to an exacerbated proinflammatory response, cell
cell types, but especially in the liver which plays a death, and tissue damage [13].
major role in producing and exporting glutathione Lipid mediators, TNF-a, ROS, the activation of
[242]. First, c-glutamylcysteine is formed from gluta- Iҡba kinase b (IKKb) by hypoxia, as well as JNK
mate and cysteine by the c-glutamylcysteine synthetase induce the inhibition of IRS1 in adipose tissue and
(Fig. 3). Then, GSH is synthesized through GSH syn- liver (Fig. 4) [125,254,255]. Mechanistically, IKKb and
thetase which catalyzes c-glutamylcysteine and glycine JNK1 promote serine phosphorylation of IRS1 and
to form glutathione (Fig. 3) [243,244]. The amount of IRS2, driving the transcriptional activation of genes
GSH in the human body plays an important role in related to inflammation and consequently resulting in
many metabolic processes, especially since oxidative insulin resistance (Fig. 4) [255,256]. The NF-jB path-
stress triggers cellular and tissue damage via the way is also activated by high concentrations of FFAs
increased production of oxidizing free radicals. Several leading to proinflammatory cytokine production and
studies have demonstrated that reduced levels of GSH release, such as TNF-a, IL1b, IL-6, and MCP1
contribute to metabolic disorders [245]. Impairments (Fig. 4) [100]. Increased levels of circulating MCP1 are
and/or reduced levels of GSH are associated with associated with macrophage recruitment to tissues, in
aging, fibrotic diseases, liver diseases, and diabetes part mediating the inflammatory response [257].
mellitus [242,246]. In diabetes, nonglycemic mecha- Increased production of MCP1 by pancreatic islets
nisms are likely to alter GSH metabolism. For exam- during pathophysiological conditions has been associ-
ple, circulating fatty acids, high concentrations of ated with pancreatic b-cell dysfunction [258].
triglycerides, oxidative stress, and proinflammatory Free fatty acids can induce insulin resistance
cytokines may affect glutathione levels (Fig. 3) [247]. through different ways. First, FFAs are associated
In young mice deficient for Cdk1, an essential gene for with insulin resistance by increased lipid metabolism
hepatocyte proliferation and mitochondrial functions which leads to the inhibition of the insulin receptor
[213,248], oxidative stress activated FOXO1, which [259,260]. In addition, high concentrations of FFAs
leads to Pnpla2/ATGL expression resulting in high trigger ER stress in adipocytes [261], liver [262], and b-
concentrations of plasma FFAs [160]. Diabetic patient cells [263], and as a consequence, ER stress activates
samples display lower GSH concentrations [242,245– JNK leading to insulin resistance (Fig. 4) [264]. Not
247,249], possibly related to dyslipidemia and contrib- only are cytokines produced by NF-jB activation
uting to T2D complications [250]. Therefore, glutathi- stimulating JNK, which leads to insulin resistance, but
one metabolism in T2D is an important research area. they can also self-activate NF-jB in a feedback loop
Fig. 4. Metabolic connections in inflammation and insulin resistance. Several metabolites act as essential factors to trigger a
proinflammatory response. FFAs can promote the activation of NF-kB, induce ER stress, and consequently lead to ROS production. NF-kB
induces transcription factors that produce cytokines and chemokines, which leads to further activation of NF-kB. The release of cytokines
and chemokines induces the recruitment of macrophages and triggers a proinflammatory response. NF-kB, ROS, and lipid mediators, such
as ceramides, induce the activation of NLRP3 inflammasome and its oligomerization promotes the activation of caspase. Thus, caspase 1
promotes the cleavage of pro-IL-1b and pro-IL-18, and GDSMD. GDSMD microdomains form pores in the plasma membrane and IL-1b and
IL-18 are released, leading to a proinflammatory response. Hyperglycemia and hyperlipidemia can activate IKK which leads to insulin
resistance. Several factors may trigger insulin resistance including ceramides, DAG, ROS, ER stress, and NF-kB, which play important roles
in the blockage of insulin signaling. Proinflammatory stimuli or external factors can activate PLA2 and promote the synthesis of arachidonic
acid and consequently eicosanoid production, resulting in rapid release at the local site of inflammation.
(Fig. 4) [13]. This may trigger other proinflammatory production [116,124], as well as in the activation of the
pathways that consequently drive the detrimental out- inflammasome NLRP3 in obesity and T2D (Fig. 4)
comes in T2D. Liver and adipose tissue play an impor- [102]. Ceramides play roles in inflammation and insu-
tant role in the activation of proinflammatory lin resistance [186,194] and also activate the NLRP3
pathways through macrophages, for example, which inflammasome [197]. The NLRP3 inflammasome pro-
when activated, produce and release TNF, IL-6, and motes a proinflammatory response through the release
IL-1b [265–269]. IL-1b can be produced through the of IL-1b and IL-18 (Fig. 4) [273–275], which may be
expression of the proapoptotic receptor FAS in b-cells associated with an upregulated inflammation response
due to high concentrations of glucose [270,271]. The in diabetic patients.
activation of FAS and IL-1b contributes to glucose- In concert with the harmful effects of glucose in dia-
induced impairment in b-cells and may lead to cell betes, which lead to proinflammatory responses involv-
death [126,272]. FFAs also play a key role in IL-1b ing IL-1b transcription, production, and its release,
eicosanoids such as prostaglandin E2 can also induce Overall, the association between inflammation and
IL-1b production [276]. Prostaglandins and leukotri- T2D is convincing but is still under investigation.
enes are eicosanoid lipid mediators synthesized from From the data in the past and present literature
arachidonic acid, playing an important role in the emerges a close relationship between the inflammatory
acute and chronic inflammatory response. Eicosanoids process and the development of T2D, but how inflam-
are rapidly released by proinflammatory cytokines, mation promotes insulin resistance in target tissues, as
ROS, and external factors, resulting in pathological well as how the inflammation affects the outcomes of
consequences related to inflammation [277,278]. In T2D, needs to be further explored. Therefore, we
addition to their role in inflammation, arachidonic hypothesize that lipid metabolism plays important
acid and eicosanoids play important roles in tissue roles in the development of T2D through the synthesis
homeostasis, cellular signaling, and inducing vasodila- of lipid mediators related to inflammation and insulin
tation [279,280]. The synthesis of arachidonic acid can resistance. For example, diacylglycerol, ceramides, and
occur through the phospholipase A2 (PLA2) superfam- eicosanoids in high concentrations in cells and/or in
ily, where the enzymatic action on phospholipids of plasma may provoke changes in metabolism and affect
the membrane promotes its production (Fig. 4) several pathways, resulting in the progression of T2D.
[279,281]. In addition, arachidonic acid can also be In addition, changes in metabolism may also induce
formed via the activity of phospholipases C and D, proinflammatory responses through the production
which catalyze DAG production [282], as well as from and release of cytokines and chemokines, triggering
anandamides [283,284]. Eicosanoids are mainly gener- inflammation in different tissues and consequently pro-
ated from arachidonic acid by cyclooxygenase 1 or 2 voking tissue damage. Altogether, T2D can be consid-
(COX1/COX2), lipoxygenase (LOX), and cytochrome ered an inflammatory disease where several pathways
P450 (CYP) [285–288]. COX1 is expressed in most cell may lead to the inflammation process which is associ-
types and can be considered as a physiological enzyme ated with T2D development. Therefore, further studies
which is important for tissue homeostasis [286,287]. are needed in order to provide a better understanding
COX2 is required and is activated by proinflammatory of the immunometabolism in T2D.
processes and/or stimuli or tissue damage [289,290].
Through the catalysis of COX2 using arachidonic acid,
Conclusions and perspectives
the major eicosanoids synthesized are the prostaglan-
dins PGD2, PGE2, PGI2, PGF2a, and the thromboxane T2D is a disease that affects hundreds of millions of
TXA2 with their actions occurring through binding people and despite thorough research, we still do not
membrane receptors. In the context of T2D, it has fully understand this multifactorial disease. The dysre-
been demonstrated that high levels of glucose or pal- gulated secretory functions of islets and a reduced
mitic acid promote the expression of COX2 in human peripheral insulin action are central in T2D patho-
islets [291,292]. Palmitic acid also induces the expres- physiology. This has been studied extensively both
sion of the PGE2 receptor subtype 3, which is also in vitro using isolated islets and single b-cells as well as
upregulated in islets from T2D organ donors [293]. how the hormone insulin affects its target tissues
Inhibition of PGE2 synthesis or of its receptor pre- in vivo in animals and humans. One aspect that has
vents b-cell dysfunction and apoptosis [293]. Since drawn less attention is that liver and adipose tissue, in
COX is one of the enzymes responsible for eicosanoid addition to their well-documented properties of
synthesis, which can be associated with a proinflamma- increasing blood glucose and lipids, also release metab-
tory response, COX2 activation may also contribute olites and organokines that in turn affect the biology
to the development of inflammation in T2D. The of islets and insulin in a direct and indirect way. This
major eicosanoids derived from the LOX pathway is the main reason why we focused this review article
are hydroxyeicosatetraenoic acids (HETEs), such as on interorgan crosstalk and how this is involved in the
15(S)-HETE; 5(S)-HETE; 19(S)-HETE; 20-HETE; development and outcome of T2D. For example, as
()8-HETE; 12(S)-HETE; and also the leukotrienes the major organ for metabolism and energy produc-
LTA4, LTB4, LTC4, LTD4, and LTE4 [294,295]. The tion, the liver acts in several pathways in biological
LOX pathway is associated with the regulation of cyto- systems, contributing to the metabolic interorgan
kines and chemokines in several tissues, such as in islets crosstalk and triggering numerous responses in
and adipose tissue [296,297]. Previous data related 12- humans. Metabolites and hepatokines from the liver
LOX expression with hyperglycemia [298] and suggested affect metabolism of several tissues and may lead to
12-LOX to be involved (as well as 15-LOX) in insulin metabolic changes that drive ROS production, inflam-
resistance and adipose tissue inflammation [299,300]. mation, and cell death in other tissues, prompting the
development of T2D. The adipose tissue also plays an thank Maria Peleli for comments on the manuscript.
important role in the metabolic crosstalk since many The research work of PK and AS was supported by
metabolites produced in the adipose tissue contribute the Faculty of Medicine, Lund University, the Swedish
to obesity, inflammation, and T2D. Because of their Foundation for Strategic Research Dnr IRC15-0067,
participation in energy metabolism and positive effects and Strategic Research Area EXODIAB, Dnr 2009-
for liver and pancreas biology, muscle has also been 1039; PK was supported by the Swedish Research
under study for the past decades due to interaction Council (2021-01331) and the Swedish Cancer Society
with other tissues. In summary, there is a long road to (21 1566 Pj); AS was supported by the Swedish Research
go in order to determine how interorgan crosstalk Council, the Novo Nordic Foundation, the Swedish Dia-
affects the development and outcomes of T2D. betes Foundation, the Forget Foundation, and the
There are several limitations that affect the study of EFSD/Lilly Foundation; LNZ was supported by the
interorgan crosstalk: Crafoord Foundation and the IngaBritt och Arne Lund-
bergs Forskningsstiftelse LU2020-0013. The funders had
(1) Interorgan crosstalk is very difficult to study in
no role in study design, data collection and interpreta-
patients since biopsies from multiple organs are
tion, or the decision to submit the work for publication.
rarely available and when they are available, the
quantity of the biopsies only allows testing of sin-
gle parameters. Conflict of interest
(2) Ideally, interorgan crosstalk is investigated in an ani-
JMS, LNZ, and PK declare no conflict of interest. AS
mal system, which allows sampling of several organs
and CBW are founders of Abarceo Pharma, Malm€ o,
simultaneously and at any time of the experimental
Sweden, and hold stock in the company. CBW is a
setup. Nevertheless, one could argue that animals
member of its board.
(e.g., mice or rats) fundamentally differ from
humans, especially in the terms of metabolism.
(3) A further limitation is that there are ample data Author contributions
which associate metabolites (as well as protein and
PK conceptualized this review; JMS wrote the first
gene expression) with certain diseases or biological
draft of the manuscript and prepared the figures with
processes. Nevertheless, associations are not always
input from PK; JMS, LNZ, AS, CBW, and PK revised
reliable and they certainly do not allow us to
the manuscript; and all authors approved the final ver-
determine causality. Therefore, associations need
sion of this manuscript.
to be considered with a pinch of salt.
(4) In general, interorgan crosstalk is very difficult to
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STATE-OF-THE-ART REVIEW

Pathophysiology of type 2 diabetes and the impact of

Keywords Diabetes is a complex and multifactorial disease that affects millions of

Introduction T2D, on the other hand, is a heterogeneous and multi-

Amino acids Carbohydrates Lipids Carnitines

Amino acids Lipids

Cysteine & [94] Ceramides L/M [133]

7 Choi KM (2016) The impact of organokines on insulin 23 Solloway M, Madjidi A, Gu C, Eastham-Anderson J,

A, Chrousos G, de Herder WW, Dhatariya K, 48 Meex R, Hoy A, Morris A, Brown R, Lo J, Burke M,

differentiates nonalcoholic steatohepatitis (NASH) 122 Shimobayashi M, Albert V, Woelnerhanssen B, Frei

hyperinsulinemia contributes to insulin resistance inhibiting glycogen synthesis. Diabetes 45,

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