Adipokines in gestational diabetes

Review

Adipokines in gestational diabetes Mathias Fasshauer, Matthias Blüher, Michael Stumvoll Lancet Diabetes Endocrinol 2014; 2: 488–99 Published Online December 30, 2013 http://dx.doi.org/10.1016/ S2213-8587(13)70176-1 Department of Endocrinology and Nephrology (Prof M Fasshauer MD, Prof M Blüher MD, Prof M Stumvoll MD); and IFB Adiposity Diseases (M Fasshauer), University of Leipzig, Leipzig, Germany Correspondence to: Prof Michael Stumvoll, Department of Endocrinology and Nephrology of the University of Leipzig, Liebigstr 20, 04103 Leipzig, Germany michael.stumvoll@medizin. uni-leipzig.de

488

Gestational diabetes is characterised by glucose intolerance with onset or first recognition during pregnancy. The disease shows facets of the metabolic syndrome including obesity, insulin resistance, and dyslipidaemia. Adipokines are a group of proteins secreted from adipocytes, which are dysregulated in obesity and contribute to metabolic and vascular complications. Recent studies have assessed the role of various adipokines including leptin, adiponectin, tumour necrosis factor α (TNFα), adipocyte fatty acid-binding protein (AFABP), retinol-binding protein 4 (RBP4), resistin, NAMPT, SERPINA12, chemerin, progranulin, FGF-21, TIMP1, LCN2, AZGP1, apelin (APLN), and omentin in gestational diabetes. This Review provides an overview of these key adipokines, their regulation in, and potential contribution to gestational diabetes. Based on the evidence so far, the adipokines adiponectin, leptin, TNFα, and AFABP seem to be the most probable candidates involved in the pathophysiology of gestational diabetes.

Introduction Gestational diabetes is a frequent metabolic disorder in pregnancy, which includes facets of the metabolic syndrome and leads to adverse short-term and long-term metabolic and vascular disease states in both the mother and offspring. In recent years, various adipokines (adipocyte-secreted proteins) have been introduced as novel links between obesity and its complications, including insulin resistance, hypertension, and dyslipidaemia. However, only a few adipokines have been studied with respect to their potential involvement in the pathophysiology of gestational diabetes. First recognition of glucose intolerance is a frequent finding in pregnancy, with about 2–10% of pregnancies affected by gestational diabetes in the USA and Europe.1 Starting in midpregnancy, insulin sensitivity progressively decreases to levels that approximate insulin resistance seen in type 2 diabetes (figure 1). Despite this physiological insulin resistance, most women remain normoglycemic throughout pregnancy because of adequate β-cell compensation (figure 1). Gestational diabetes develops if insulin resistance is excessive, β-cell compensation is inadequate, β-cell function decreases, or any combination of these (figure 1). Although a remission of glucose intolerance is a frequent finding after delivery, patients with a history of gestational diabetes have a high risk of developing diabetes in later life, ranging from 17% to more than 50% risk depending on the population studied and the follow-up period.1 The risk of atherosclerotic disease is also significantly increased after a pregnancy with gestational diabetes. Neonates of mothers with gestational diabetes are at increased risk of acute perinatal complications including hypoglycaemia, jaundice, and being large for gestational age. Interestingly, offspring resulting from a pregnancy in a woman with gestational diabetes, have an increased risk of developing obesity, hypertension, diabetes, and cardiovascular disease.1–3 Since the discovery of leptin in 1994, adipose tissue has been established as an endocrine organ secreting various proteohormones, which are collectively called adipokines or adipocytokines. Adipokines participate in various metabolic processes including insulin sensitivity, insulin secretion, appetite control, fat distribution, energy

expenditure, inflammation, regulation of adipogenesis, and chemoattraction of immune cells into adipose tissue. In principle, there are direct and indirect mechanisms by which altered adipokine secretion might contribute to changes in glucose homoeostasis in pregnancy subsequently causing gestational diabetes (figure 1). Direct mechanisms include a role of adipokines in the regulation of insulin secretion and insulin sensitivity both at the level of the whole body and in specific organs including in the liver, brain, muscle, and other tissues. Indirect mechanisms are mainly related to the fact that adipokines play a part in inflammation, adipose tissue accumulation, and adverse fat distribution, which subsequently affect glucose metabolism.4 This Review provides a comprehensive overview of our present knowledge about the pathogenetic role and regulation of adipokines in gestational diabetes. We focus on the adipokines leptin, adiponectin, tumour necrosis factor α (TNFα), adipocyte fatty acid-binding protein (AFABP), retinol-binding protein 4 (RBP4), resistin, NAMPT, SERPINA12, chemerin, progranulin, fibroblast growth factor 21 (FGF21), TIMP1 metallopeptidase inhibitor 1 (TIMP1), lipocalin 2 (LCN2), AZGP1, apelin (APLN), and omentin. For the purpose of this Review, we defined the following four criteria to select adipokines potentially involved in the pathogenesis of gestational diabetes and specifically address these points: the adipokine affects key pathways crucial for the pathophysiology of gestational diabetes—eg, insulin resistance, β-cell dysfunction, and bodyweight gain; maternal circulating adipokine concentrations are upregulated or downregulated in gestational diabetes; maternal circulating adipokine concentrations predict the development of gestational diabetes; and expression of the adipokine in placenta or adipose tissue is upregulated or downregulated in gestational diabetes. Because an in-depth discussion of the role of adipokines in insulin resistance, β-cell dysfunction, and bodyweight gain is beyond the scope of this Review, the pathophysiological relevance of each adipokine is only briefly summarised and at least one excellent and recent review is given for each candidate protein as a reference for further reading. Moreover, results from www.thelancet.com/diabetes-endocrinology Vol 2 June 2014

Review

clinical cross-sectional studies (table 1, appendix), prospective studies (table 2), and basic experiments are summarised for each adipocyte-secreted protein. Additionally, we discuss whether circulating adipokine concentrations might be useful and clinically relevant biomarkers to predict risk of gestational diabetes in pregnant women. Furthermore, topics of uncertainty and need for additional studies are presented. Based on the evidence thus far, the adipokines adiponectin, leptin, TNFα, and AFABP seem to be the most probable candidates involved in the pathophysiology of gestational diabetes.

Adipokines involved in gestational diabetes pathophysiology Leptin Leptin was discovered in 1994 and is regarded as the prototypical adipokine. Leptin is a potent appetite suppressive and energy expenditure-inducing hormone that controls bodyweight and energy balance mainly through neurons in the arcuate nucleus of the hypothalamus. Furthermore, leptin suppresses insulin secretion from pancreatic β cells. Leptin deficiency and genetic defects in leptin signalling pathways cause hyperphagia and obesity. In clinical studies, serum leptin concentrations are directly proportional to fat mass, and decreased central leptin responsiveness—so-called leptin resistance—is seen in obesity.58 Studies of regulation of circulating leptin in gestational diabetes have shown varied results (table 1). Several studies have shown that leptin concentrations are not changed in gestational diabetes compared with pregnant controls.5–18 By contrast, other groups have described increased circulating concentrations of leptin in women with gestational diabetes.19–28 Only a small cross-sectional study showed decreased leptin concentrations in gestational diabetes.29 In keeping with studies in nonpregnant individuals,58 leptin is independently and positively associated with features of the metabolic syndrome including increased bodyweight,5,10,20 insulin resistance,5,10,20 blood pressure,21 and inflammation.10 In a large prospective cohort study, increased first trimester leptin concentrations were associated with increased risk of later developing gestational diabetes (table 2).46 These results were not confirmed in an independent nested case-control cohort; however, only 14 cases and 14 controls were included in this study.47 Both leptin and the leptin receptor are expressed in the placenta.59 Furthermore, leptin expression in the placenta of women with gestational diabetes was upregulated in several59–61 but not all62,63 studies. Similarly, some studies show that the leptin receptor is upregulated in the placenta of women with gestational diabetes,59,61,64 whereas other studies60,62 show no difference. Leptin mRNA expression is significantly upregulated in visceral adipose tissue, but not in subcutaneous adipose tissue of patients with gestational diabetes compared with pregnant controls in one study.62 www.thelancet.com/diabetes-endocrinology Vol 2 June 2014

See Online for appendix

β-cell function

β-cell dysfunction • Adipokines • Other factors (eg, genetic predisposition)

Insulin sensitivity Insulin resistance • Adipokines • Others (eg, fluid imbalance) Physiological insulin resistance with adequate β-cell compensation Excessive insulin resistance with inadequate β-cell compensation Normal glucose tolerance Gestational diabetes

Physiological insulin resistance without β-cell compensation Physiological insulin resistance and β-cell dysfunction

Figure 1: Pathogenesis of gestational diabetes Starting in midpregnancy, insulin sensitivity progressively decreases to levels that approximate insulin resistance seen in type 2 diabetes. Despite this physiological insulin resistance, most pregnant women remain normoglycemic throughout pregnancy because of adequate β-cell compensation (purple arrow, individuals remain on the dotted blue line). Gestational diabetes (dotted red line) develops if insulin resistance is excessive (green arrow), β-cell compensation is not present (blue arrow), β-cell secretion even decreases (grey arrow), or a combination of these. Adipokines in addition to genetic and other factors could contribute to excessive peripheral insulin resistance and impair β-cell compensation.

However, in another study, leptin mRNA synthesis did not significantly differ in both adipose tissue depots between patients with gestational diabetes and pregnant controls.63 Leptin treatment in db/+ mice, an animal model of gestational diabetes, reduced energy intake and improved glucose tolerance in the pregnant state.65 However, fetal overgrowth, and fetal and placental leptin concentrations, were not reduced by leptin treatment.65 These results show that leptin secreted from the placenta might contribute to the regulation of fetal growth independently of maternal glucose concentrations.65

Adiponectin Adiponectin is an adipokine that is almost exclusively synthesised by adipocytes. Adiponectin has potent insulinsensitising and anti-atherogenic properties. Furthermore, adiponectin enhances insulin secretion by stimulating both the expression of the insulin gene and exocytosis of insulin granules. In clinical studies, circulating adiponectin is independently and negatively related to facets of the metabolic syndrome including insulin resistance, bodyweight, blood pressure, and serum lipids.66 Circulating adiponectin in gestational diabetes has been extensively studied in more than 20 independent cohorts (table 1). Most studies show decreased adiponectin concentrations in gestational diabetes.7,12–15,17,22,23,27,28,30–42 In five studies,8,9,17,18,29 adiponectin concentrations did not significantly differ between patients with gestational 489

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Gestational age (weeks) of patients with gestational diabetes/ controls

Multivariate correlation Circulating adipokine concentration in gestational diabetes

55/166

26·0/25·4

↔

+ BMI, + fasting insulin – Gestational diabetes

Number of patients with gestational diabetes/controls Leptin Festa et al (1999)5 Mokhtari et al (2011)6

26/22

Not given

↔

ND

Horosz et al (2011)7

86/48

Both 27–32

↔

ND

Saucedo et al (2011)8

60/60

Both 30

↔

ND

Skvarca et al (2012)9

30/25

27·1/27·2

↔

ND

29/30

↔

+ BMI, + fasting insulin, + weight gain, + CRP – Parity ND

Maple-Brown et al (2012)10

198/477

Ranheim et al (2004)11

22/29

38·1/38·5

↔

Thyfault et al (2005)12

22/27

39·3/39·2

↔

ND

29/30

↔

+ Post-P β-cell function

Retnakaranet al (2010)13

137/259

Ortega-Sanovilla et al (2011)14

98/86

26·4/26·9

↔

ND

Lappas et al (2005)15

11/9

38·8/38·7

↔

ND

Tepper et al (2010)16

12/10

Both 24–28

↔

ND

Park et al (2013)17

98/395 (NW)

Both 24–28

↔

ND

Park et al (2013)17

117/136 (OW)

Both 24–28

↔

ND

40/80

29·3/28·3

↔

ND

Vitoratos et al (2001)19

17/17

28·2/30·6

↑

ND

Kautzky-Willer et al (2001)20

55/25

Both 28

↑

+ BMI, + FG, + HbA1c

Buhling et al (2005)21

34/61

32·1/34·0

↑

+ BP

Atègbo et al (2006)22

59/60

At delivery

↑

ND

Gao et al (2008)23

22/20

16·0/16·5

↑

ND

Gao et al (2008)23

22/20

29·3/28·0

↑

ND

Yilmaz et al (2010)24

56/42

30·9/31·2

↑

ND

Chen et al (2010)25

20/20

37·1/39·0

↑

ND

Soheilykhah et al (2011)26

29/27

25·6/26·1

↑

ND

López-Tinoco et al (2012)27

56/48

29·2/29·3

↑

ND

Palik et al (2007)28

30/15

27·4/28·9

↑

ND

McLachlan et al (2006)29

19/19

Both 34·0

↓

+ IS

Stepan et al (2010)18

Adiponectin Horosz et al (2011)7

86/48

Both 27–32

↓

ND

Saucedo et al (2011)8

60/60

Both 30

↔

ND

Skvarca et al (2012)9

30/25

27·1/27·2

↔

ND

Ranheim et al (2004)11

22/29

38·1/38·5

(↓) p=0·06

ND

Thyfault et al (2005)12

22/27

39·3/39·2

↓

ND

29/30

↓

+ Post-P IS, + post-P β cell function – Post-P FG

Retnakaranet al (2010)13

137/259

Ortega-Sanovilla et al (2011)14

98/86

26·4/26·9

↓

ND

Lappas et al (2005)15

11/9

38·8/38·7

↓

ND

Park et al (2013)17

98/395 (NW)

Both 24–28

↔

ND

Park et al (2013)17

117/136 (OW)

Both 24–28

↓

– Gestational diabetes

29·3/28·3

↔

ND

Stepan et al (2010)18

40/80

Atègbo et al (2006)22

59/60

At delivery

↓

ND

Gao et al (2008)23

22/20

16·0/16·5

↓

ND

Gao et al (2008)23

22/20

29·3/28·0

↓

ND

López-Tinoco et al (2012)27

56/48

29·2/29·3

↓

– Gestational diabetes

Palik et al (2007)28

30/15

27·4/28·9

↓

– C-peptide

McLachlan et al (2006)29

19/19

Both 34·0

↔

ND

Retnakaran et al (2004),30 Retnakaran et al (2005)31

48/93

29·1/29·2

↓

+ ISSI – Gestational diabetes, – fasting insulin, – South Asian ethnicity (Continues on next page)

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Number of patients with gestational diabetes/controls

Gestational age (weeks) of patients with gestational diabetes/ controls

Multivariate correlation Circulating adipokine concentration in gestational diabetes

(Continued from previous page) Worda et al (2004)32

20/21

32·1/32·2

↓

+ Gestational week – Gestational diabetes

Kinalski et al (2005)33

80/30

26·6/26·3

↓

– Pre-P BMI, – triacylglycerol (patients with gestational diabetes) – Triacylglycerol (controls) ND

Tsai et al (2005)34

34/219

Both 24 31

↓

Cortelazzi et al (2007)35

18/13

Both 37–41

↓

ND

Altinova et al (2007)36

34/31

26·2/25·2

↓

– HOMA-IR

Vitoratos et al (2008)37

22/22

30/31

↓

ND

Soheilykhah et al (2009)38

30/31

28/28

↓

ND

Ballesteros et al (2011)39

80/132

27·5/27·5

↓

ND

Matuszek et al (2013)40

36/28

Both 24–28

↓

ND

Näf et al (2012)41

77/130

28/27

↓

ND

Mazaki-Tovi et al (2009)42

72/149

37·6/37·6

↓

– Gestational diabetes, – first trimester BMI

Saucedo et al (2011)8

60/60

Both 30

↔

ND

Atègbo et al (2006)22

59/60

At delivery

↑

ND

Gao et al (2008)23

22/20

16·0/16·5

↑

ND

Gao et al (2008)23

22/20

29·3/28·0

↑

ND

López-Tinoco et al (2012)27

56/48

29·2/29·3

↑

ND

Palik et al (2007)28

30/15

27·4/28·9

↑

ND

McLachlan et al (2006)29

19/19

Both 34·0

↑

ND

Kinalski et al (2005)33

80/30

26·6/26·3

↑

+ Pre-P BMI, + insulin sensitivity (patients with gestational diabetes) + Pre-P BMI, + BMI, + triacylglycerol (controls)

Altinova et al (2007)36

34/31

26·2/25·2

↑

+ Pre-P BMI

Ma et al (2010)43

20/22

39·1/38·7

↑

ND

Salmi et al (2012)44

22/31

29·6/29·0

↑

ND

Ortega-Sanovilla et al (2011)14

98/86

26·4/26·9

↑

ND

Kralisch et al (2009)45

40/80

29·3/28·3

↑

+ Leptin, + BMI, + creatinine, + triacylglycerol, + gestational diabetes

TNFα

AFABP

ND=not determined. CRP=C-reactive protein. Post-P=post-pregnancy. FG=fasting glucose. BP=blood pressure. ISSI=insulin secretion-sensitivity index. NW=normal weight. OW=overweight. HOMA-IR=homoeostasis model assessment of insulin resistance. Pre-P=pre-pregnancy. TNFα=tumour necrosis factor α. AFABP=adipocyte fatty acid-binding protein. ↑=increased circulating concentrations of indicated adipokine in gestational diabetes compared with pregnant controls. ↔=unaltered circulating levels of indicated adipokine in gestational diabetes as compared to pregnant controls. ↓=decreased circulating concentrations of indicated adipokine in gestational diabetes compared with pregnant controls. +=significant and independent positive association between adipokine and indicated parameter. –=significant and independent negative association between adipokine and indicated parameter.

Table 1: Main findings of circulating concentrations of four adipokines most likely involved in pathophysiology of gestational diabetes from cross-sectional studies

diabetes and controls, and no study has shown that the adipokine is upregulated in patients with gestational diabetes. Furthermore, in various cross-sectional studies,17,27,30–32,42 adiponectin is an independent and negative predictor of gestational diabetes. In accordance with studies in non-pregnant individuals,66 circulating adiponectin concentrations are independently and negatively associated with features of the metabolic syndrome in pregnancy including insulin resistance,13,28,30,31,36 bodyweight,33,42 and serum lipids.33 Five47–51 of six prospective www.thelancet.com/diabetes-endocrinology Vol 2 June 2014

studies have shown that low circulating adiponectin concentrations in the first trimester of pregnancy were associated with an increased risk of development of gestational diabetes (table 2). Similar findings have also been seen in women in the second trimester of pregnancy.52 Only one study has not described an independent relation between first trimester adiponectin and risk of gestational diabetes.53 Adiponectin is expressed in the human placenta, primarily in the syncytiotrophoblast.67 In the placenta, 491

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Number of cases/controls

Risk of gestational diabetes Variables associated with gestational in cases of high baseline diabetes adipokine concentrations

Study design

Weeks of gestation

Qiu et al (2004)46

PCS

<16

47/776

↑

ND

Georgiou et al (2008)47

NCC

11

14/14

↔

ND

Leptin

Adiponectin Georgiou et al (2008)47

NCC

11

14/14

↓

ND

Williams et al (2004)48

NCC

13

41/70

↓

Pre-P overweight status

Lain et al (2008)49

NCC

30/29

↓

ND

Ferreira et al (2011)50

NCC

11–13·6

100/300

↓

ND

Lacroix et al (2013)51

PCS

6–13

38/407

↓

ND

Weerakeit et al (2006)52

PCS

21–27

60/299

↓

BMI

Paradisi et al (2010)53

PCS

<13·6

12/38

↔

HOMA, FG, BMI, TG

NCC

11

14/14

↔

ND

Abetew et al (2013)54

NCC

16

173/187

↔

ND

Nanda et al (2013)55

NCC

11–13·6

60/240

↔

ND

Georgiou et al (2008)47

NCC

11

Lain et al (2008)49

NCC

Nanda et al (2012)56

NCC

9·3

TNFα Georgiou et al (2008)47 RBP4

Resistin 14/14

↔

ND

30/29

↔

ND

11–13·6

60/240

↔

ND

NCC

11–13·6

100/300

↑

ND

NCC

9–12

41/82

↑

ND

9·3

NAMPT Ferreira et al (2011)50 LCN2 D’Anna et al (2009)57

PCS=prospective cohort study. ND=not determined. NCC=nested case-control. Pre-P=pre-pregnancy. HOMA=homoeostasis model assessment. FG=fasting glucose. TG=triacylglycerol. TNFα=tumour necrosis factor α. RBP4= retinol-binding protein 4. LCN2=lipocalin 2. ↑=increased. ↔=unaltered. ↓=decreased.

Table 2: Main findings of circulating adipokines in women who later developed gestational diabetes from prospective studies

adiponectin is differentially regulated by various cytokines including TNFα, interferon γ, interleukin 6, and leptin.67 Results from studies of the regulation of adiponectin in the placenta in patients with gestational diabetes are conflicting. One study67 reported that expression of adiponectin was downregulated in patients with gestational diabetes. By contrast, in another study,15 adiponectin release from the placenta, fetal membranes, maternal subcutaneous adipose tissue, and skeletal muscles did not differ between gestational diabetes and controls. Furthermore, in a different study,62 expression of adiponectin mRNA did not significantly differ in visceral or subcutaneous adipose tissue of patients with gestational diabetes compared with controls. The role of circulating maternal adiponectin on placental physiology is far from clear. Evidence is emerging that maternal adiponectin decreases fetal growth by impairing placental insulin signalling and reducing insulin-stimulated aminoacid transport.68 In addition, lower placental adiponectin gene DNA methylation levels on the fetal and maternal side of the placenta are associated with impaired maternal glucose status and with higher maternal circulating adiponectin.69 492

TNFα TNFα is a proinflammatory adipokine that is expressed in monocytes and macrophages. Besides its central role in inflammation and autoimmune diseases, TNFα impairs insulin signalling in insulin-sensitive tissues and inhibits insulin secretion from β cells. In human beings, TNFα mRNA and protein expression in adipose tissue are low, but correlate positively with adiposity and decrease in obese individuals after weight loss.70,71 Consistent evidence suggests that circulating TNFα concentrations are elevated in women with gestational diabetes (table 1). Nine of ten published studies show significantly increased circulating TNFα concentrations in patients with gestational diabetes in the second and third trimesters of pregnancy. Furthermore, two studies33,36 have shown that TNFα is independently and positively associated with prepregnancy BMI. Moreover, increases in TNFα concentration from pregravid to late pregnancy are independently and negatively associated with changes in insulin sensitivity in pregnant women.72 Only one small nested case-control study47 assessed the predictive value of TNFα concentrations in the first trimester (table 2). In this study, TNFα quantified at 11 weeks of gestation was not significantly associated www.thelancet.com/diabetes-endocrinology Vol 2 June 2014

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with the risk of developing gestational diabetes;47 however, only 14 cases and 14 controls were included in the study. TNFα mRNA and protein are expressed in human placental and uterine cells.72 In vitro, most of the placental TNFα (94%) is released into the maternal circulation, whereas 6% is released into the fetal circulation.72 TNFα treatment in mouse models  of gestational diabetes (db/+ mice) raises the number of  apoptotic cells in the placenta and increases retention  of uterine natural killer cells.73 Two studies have shown no difference in placental TNFα expression between patients with gestational diabetes and controls.62,74 Similarly, TNFα mRNA synthesis is not significantly different in visceral and subcutaneous adipose tissue of women with gestational diabetes compared with pregnant controls.62 By contrast, another study showed that expression of the TNFα receptor is increased in the placenta of patients with gestational diabetes compared with controls.75

AFABP AFABP belongs to the fatty acid-binding protein superfamily and is highly expressed in adipocytes, macrophages, and endothelial cells. This adipokine impairs glucose tolerance in mice by upregulating hepatic glucose production. Furthermore, high circulating AFABP concentrations independently predict the risk of developing metabolic syndrome, type 2 diabetes, and cardiovascular disease in human beings.76 Two studies analysed regulation of circulating AFABP concentrations in patients with gestational diabetes (table 1). AFABP serum concentrations were significantly increased in 40 patients with gestational diabetes compared with 80 controls who were matched for gestational age and insulin sensitivity.45 Furthermore, markers of the metabolic syndrome including leptin, BMI, and triacylglycerols were significantly associated with serum AFABP concentrations, gestational diabetes, and serum creatinine in multivariate analysis.45 Similarly, another study14 showed that circulating AFABP concentrations were increased in patients with gestational diabetes. So far, no study has assessed whether baseline AFABP concentrations predict the risk of gestational diabetes. AFABP is expressed in the human placenta, and exposure to hypoxia enhances expression.77 Increased AFABP synthesis is associated with accumulation of lipid droplets in hypoxic trophoblasts, suggesting a possible role for this adipocyte-secreted factor in the uptake or accumulation of lipids during hypoxic stress.77 In accordance with these findings, AFABP inhibition reduces triacylglycerols content in human trophoblasts.78 No study so far has investigated whether the expression of AFABP in the placenta, visceral adipose tissue, or subcutaneous adipose tissue differs between patients with gestational diabetes and controls. www.thelancet.com/diabetes-endocrinology Vol 2 June 2014

Adipokines probably not involved in pathophysiology of gestational diabetes RBP4 Although the evidence discussed above suggests that some adipokines are associated with gestational diabetes, the evidence for other adipokines is lacking, as detailed in the next sections. We only briefly summarise the major results from cross-sectional studies in gestational diabetes. A complete overview on all cross-sectional studies with references is given in appendix; results from prospective studies are summarised in table 2. Similar to LCN2, RBP4 is a member of the lipocalin family of proteins that transports small hydrophobic molecules. Transgenic overexpression of RBP4 or injection of the adipokine causes insulin resistance in mice.79 Some but not all studies suggest that RBP4 is positively and independently correlated with markers of insulin resistance and obesity in human beings.79 Conflicting data have been published concerning the regulation of circulating RBP4 in gestational diabetes. Seven studies have shown increased RBP4 concentrations in gestational diabetes, whereas five have not shown dysregulation of the adipokine, and one study showed decreased concentrations in gestational diabetes (appendix). Two prospective studies have shown that RBP4 concentrations in the first trimester did not predict the risk of developing gestational diabetes (table 2).54,55 RBP4 is expressed in the human placenta.80 However, expression of RBP4 mRNA in the placenta did not significantly differ between patients with gestational diabetes and controls.80 By contrast, expression of the adipokine was significantly upregulated in subcutaneous but not visceral adipose tissue of women with gestational diabetes compared with pregnant controls.80

Resistin Originally described as an insulin resistance-inducing adipokine, resistin is upregulated in obesity. Studies show convincingly that the adipokine also induces inflammation, endothelial dysfunction, thrombosis, angiogenesis, and smooth muscle cell dysfunction.81 In human beings, circulating resistin concentrations are positively associated with markers of obesity, insulin resistance, and inflammation.81 Several studies have quantified circulating resistin in gestational diabetes, however, data are conflicting. Most studies show that resistin concentrations do not significantly differ between women with gestational diabetes and pregnant controls, but other studies have described increased and decreased resistin concentrations in gestational diabetes (appendix). Three independent prospective studies have shown that resistin does not contribute to the risk prediction of gestational diabetes (table 2).47,49,56 Resistin is expressed in the human placenta, and gene expression in term placental tissue is more prominent than in first trimester chorionic tissue.82 However, resistin release from the placenta, fetal membranes, maternal 493

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subcutaneous adipose tissue, and skeletal muscles does not differ between patients with gestational diabetes and controls.15

NAMPT NAMPT, also known as pre-B cell colony-enhancing factor, was first described as an adipokine predominantly secreted from visceral fat that exerts insulin-mimetic effects. However, other tissues and adipose tissue depots also express NAMPT, and the effects of this molecule as an insulin-mimetic are controversial. Recent evidence suggests that NAMPT affects glucose homoeostasis by affecting β-cell function and the regulation of genes related to oxidative stress, the inflammatory response, and the circadian rhythm.83 In human beings, circulating NAMPT concentrations are increased in overweight or obese patients, and patients with type 2 diabetes, metabolic syndrome, or cardiovascular disease.83 Studies of the regulation of NAMPT in gestational diabetes have been highly conflicting with almost an equal number of studies showing upregulation, downregulation, or no regulation in gestational diabetes compared with pregnant controls (appendix). In a nested case-control setting, first trimester NAMPT was shown to predict the risk of developing gestational diabetes beyond BMI, gestational age, ethnicity, parity, previous gestational diabetes, and family history of the disease (table 2).50 NAMPT is expressed in human placenta, but expression is significantly lower than in subcutaneous adipose tissue and visceral adipose tissue.84 Furthermore, expression of NAMPT mRNA in the placenta, subcutaneous adipose tissue, and visceral adipose tissue does not differ between women with gestational diabetes and controls.84 By contrast, in another study,43 the adipokine was upregulated at the mRNA and protein level in the placenta, but not in subcutaneous adipose tissue and visceral adipose tissue in gestational diabetes compared with controls. In accordance with its proinflammatory properties, NAMPT treatment of human fetal membranes induces key proinflammatory cytokines—eg, TNFα and interleukin 6—and chemokines—eg, macrophage inflammatory protein 1α, macrophage inflammatory protein 1β, and macrophage inflammatory protein 3α.85

SERPINA12 SERPINA12 (visceral adipose tissue-derived serpin) was originally identified as an insulin-sensitising adipokine that was predominantly secreted from visceral adipose tissue. SERPINA12 administration improves glucose tolerance, insulin sensitivity, and reduces food intake in obese db/db mice via unknown mechanisms.86 Elevated serum concentrations and mRNA expression of SERPINA12 in adipose tissues are associated with obesity, insulin resistance, and type 2 diabetes in human beings.86 Two independent cross-sectional studies (appendix) showed that serum concentrations of 494

SERPINA12 did not significantly differ between women with gestational diabetes and pregnant controls. To the best of our knowledge, no study has assessed the role of circulating SERPINA12 in the prediction of risk of gestational diabetes. SERPINA12 is expressed in human placenta.87 Furthermore, it has been shown that SERPINA12 concentrations significantly decrease after placental elimination, suggesting that the  placenta probably contributes to circulating concentrations of the adipokine.88 So far, no study has assessed the expression of SERPINA12 in the placenta and adipose tissue of women with gestational diabetes compared with controls.

Chemerin Chemerin has traditionally been implicated in the regulation of adaptive and innate immunity. However, recent evidence suggests that chemerin is also an adipokine that induces insulin resistance in human myocytes in vitro and impairs glucose tolerance in ob/ ob, db/db, and diet-induced obese mice in vivo. In glucose tolerant individuals, circulating chemerin is significantly associated with BMI, triacylglycerol, and blood pressure.89 Three independent cross-sectional studies (appendix) have shown that circulating chemerin concentrations did not significantly differ between women with gestational diabetes and healthy pregnant controls. So far, no study has determined the predictive value of baseline chemerin concentrations on the risk of gestational diabetes. Chemerin is expressed in human placenta with comparable mRNA expression in trophoblasts, and arterial and venous endothelial cells.90 Furthermore, mRNA expression in and protein secretion from placenta and adipose tissue did not significantly differ between gestational diabetes and controls in accordance with the findings for circulating chemerin.91

Progranulin The most recently identified adipokine is progranulin, which induces insulin resistance. Thus, progranulinknockout mice are resistant to high fat diet-induced insulin resistance, adipocyte hypertrophy, and obesity. Circulating progranulin concentrations are markedly increased in patients with obesity and type 2 diabetes.92 In the only cross-sectional study published to date (appendix), concentrations of circulating progranulin were not changed in patients with gestational diabetes compared with controls. No prospective data are available elucidating circulating progranulin as a risk predictor of gestational diabetes. Progranulin is synthesised in human placenta with the strongest expression seen in syncytiotrophoblasts.93 Furthermore, the adipokine significantly stimulates cell proliferation in the human choriocarcinoma-derived BeWO cell line.93 Expression of progranulin in the placenta or adipose tissue of patients with gestational diabetes has not been assessed so far. www.thelancet.com/diabetes-endocrinology Vol 2 June 2014

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FGF21 FGF21 is a member of the FGF superfamily that is primarily produced by the liver and adipose tissue. FGF21 elicits antihyperglycaemic, antihyperlipidaemic, and thermogenic effects through interaction with specific FGF receptors and a cofactor called β-Klotho. Circulating FGF21 concentrations are elevated in insulin resistance and obesity in human beings, and FGF21 resistance has been discussed as a mechanism for this paradoxical finding.94 A cross-sectional study (appendix) showed that circulating concentrations of FGF21 did not significantly differ between patients with gestational diabetes and pregnant controls. No studies are available regarding the role of circulating FGF21 in the risk prediction of gestational diabetes or on FGF21 expression in placenta.

TIMP1 TIMP1 is an adipokine that decreases adipogenesis and impairs glucose tolerance. Recombinant TIMP1 induces insulin resistance and hepatic triacylglycerol accumulation in mice on a high-fat diet. Circulating TIMP1 concentrations are increased in overweight individuals.95 A small cross-sectional study (appendix) showed that TIMP1 serum concentrations did not differ between women with gestational diabetes and controls. So far, the potential role of TIMP1 in the risk prediction of gestational diabetes has not been assessed. It has long been known that TIMP1 is abundantly expressed in the human placenta throughout gestation.96 However, gestational diabetes-dependent regulation of TIMP1 in the placenta has not been determined.

human beings, AZGP1 expression in adipose tissue and circulating concentrations are negatively correlated with adiposity.99 In a cross-sectional study (appendix), AZGP1 serum concentrations did not differ between patients with gestational diabetes and pregnant controls. Prospective studies about AZGP1 and risk prediction of gestational diabetes, and data for expression of the adipokine in placenta have not been published so far.

Apelin APLN is the ligand of the G-protein-coupled receptor APLNR and exists in several active forms. As well as its role in cardiovascular and fluid homoeostasis—ie, as a peripheral vasodilator, powerful inotrope, and antidiuretic—high APLN leads to beneficial effects on bodyweight and glucose control. Several, but not all, clinical studies show increased circulating APLN concentrations in obese individuals and patients with type 2 diabetes.100 Cross-sectional studies of circulating APLN in gestational diabetes have contradictory results; one study showed unaltered adipokine concentrations in two cohorts of patients with gestational diabetes, whereas another study showed increased concentrations of APLN in patients with gestational diabetes compared with pregnant controls (appendix). No study has assessed the role of APLN in the risk prediction of gestational diabetes. APLN and its receptor APLNR are expressed in the human placenta.101 However, mRNA synthesis of APLN and APLNR does not differ between patients with gestational diabetes and controls in the placental tissue, subcutaneous adipose tissue, and visceral adipose tissue.101

LCN2 Similar to RBP4, LCN2 is a member of the large family of lipocalins, which exhibit high affinity for small hydrophobic ligands such as steroids and pheromones. LCN2-knockout mice show improved insulin sensitivity in conditions of ageing or obesity. In clinical studies, LCN2 is positively and independently correlated with markers of insulin resistance and inflammation.97 No cross-sectional study of LCN2 in patients with gestational diabetes is available. However, in a nested case-control study, first trimester LCN2 concentrations were almost three-fold higher in women who later developed gestational diabetes compared with controls who were matched for age, gestational age, parity, and prepregnancy BMI (table 2).57 LCN2 is expressed in trophoblasts, but not in the decidua under basal conditions, and trophoblast expression of the adipokine is further increased by intra-amniotic infection.98 No study has elucidated gestational diabetes-dependent synthesis of LCN2 in the human placenta.

AZGP1 In 2005, AZGP1 was identified as an adipokine that regulates bodyweight. Thus, AZGP1-knockout mice are susceptible to weight gain, whereas transgenic mice overexpressing AZGP1 show pronounced weight loss. In www.thelancet.com/diabetes-endocrinology Vol 2 June 2014

Circulating concentrations Circulating concentrations Expression in placenta or adipose tissue is dysregulated predict development of are dysregulated in in gestational diabetes gestational diabetes gestational diabetes Leptin*

+

+

+

Adiponectin*

+

+

+

TNFα*

+

?

–

AFABP*

+

?

?

RBP4

–

–

–

Resistin

–

–

–

NAMPT

–

+

–

SERPINA12

–

?

?

Chemerin

–

?

–

Progranulin

–

?

?

FGF21

–

?

?

TIMP1

–

?

?

LCN2

?

+

?

AZGP1

–

?

?

APLN

–

?

–

Omentin

–

?

–

+=most studies support. TNFα=tumour necrosis factor α. ?=no study or insufficiently powered studies have addressed this question. –=most studies do not support. AFABP=adipocyte fatty acid-binding protein. RBP4=retinol-binding protein 4. FGF21=fibroblast growth factor 21. TIMP1=tissue inhibitor of metalloproteinase 1. LCN2=lipocalin 2. *Adipokines that are likely to contribute to the pathogenesis of gestational diabetes.

Table 3: Summary of major published findings on adipokines in gestational diabetes

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Omentin

Summary and conclusions

Omentin is preferentially synthesised by visceral adipose tissue and shows insulin-sensitising effects. In most clinical studies, circulating omentin concentrations are decreased in obesity and people with diabetes.102 Data from three cohorts of patients with gestational diabetes have been published, with similar omentin concentrations between those with gestational diabetes and pregnant controls in two of the cohorts, and decreased concentrations observed in one cohort (appendix). Prospective studies of omentin and risk prediction of gestational diabetes have not been published. Omentin is expressed and secreted by the human placenta; however, mRNA expression in and secretion from the placenta and omental adipose tissue do not differ between patients with gestational diabetes and pregnant controls.103

Despite the high number of studies assessing the role of specific adipokines in gestational diabetes, interpretation of results is difficult because of several limitations. First, diagnostic criteria used to define gestational diabetes vary greatly among expert groups such as national medical associations or WHO. Furthermore, some studies focus on insulin-treated (ie, more severe) gestational diabetes, whereas others exclusively include women with gestational diabetes controlled by diet only. As a result, pregnant women with different degrees of hyperglycemia are defined as having gestational diabetes. Moreover, controls are often poorly defined and whether gestational diabetes was in fact excluded by oral glucose tolerance testing remains unclear in many instances. Additionally, gestational age at blood sampling in cross-sectional studies ranges from early second trimester to late third trimester (table 1, appendix). Because several adipokines are also regulated by pregnancy, comparisons between studies are difficult. Differences in assay methods are another cause of heterogeneous results—eg, for NAMPT results vary greatly depending on which commercial assay is used.104 Other uncertainties include insufficient matching of controls and patients with gestational diabetes for BMI, gestational age, and smoking, and differences in ethnicity of recruited patients. Concerning basic research studies, absence of suitable animal models of gestational diabetes has led to a paucity of studies assessing the role of adipokines in the pathophysiology of gestational diabetes in vivo. Despite these limitations, consistent evidence for a role in gestational diabetes is available for some adipokines and first suggestions for their mode of action have emerged (table 3). Although all adipokines discussed in this Review affect key pathways crucial for the pathophysiology of gestational diabetes—ie, insulin resistance, β-cell dysfunction, and bodyweight gain—some might directly contribute to the pathogenesis of gestational diabetes. Among these, the insulin-sensitising and vasoprotective adiponectin is an important adipokine and might directly affect maternal, fetal, and placental processes. Mechanistically, absence of insulin-sensitising and β cellprotective adiponectin in gestational diabetes might exacerbate insulin resistance and impair β-cell function, which are hallmarks of the disease. Additionally, maternal adiponectin decreases fetal growth and decreased concentrations of the adipokine in gestational diabetes might contribute to gestational diabetes-associated macrosomia. Leptin is another adipokine that is likely to play a part in the pathophysiology of gestational diabetes, although data are less consistent than for adiponectin. In terms of mechanics, leptin might contribute to gestational diabetes pathophysiology by suppressing insulin secretion from pancreatic β cells and by amplifying low-grade inflammation, which is a feature of both gestational diabetes and the metabolic syndrome.105 Furthermore, it is probable that other central and peripheral effects of the adipokine affecting appetite control, bodyweight and composition,

Gestation

Placental origin Leptin↑ Adiponectin↓ TNFα↑ AFABP↑

Non-placental origin: adipocytes, immune cells, hepatocytes Leptin↑ TNFα↑ Adiponectin↓ AFABP↑

Inflammation Inadequate stress response Gluco-/Lipotoxicity

Insulin resistance, β-cell dysfunction, or both

Diabetes

Figure 2: Model of adipokine involvement in the pathogenesis of gestational diabetes The adipokines adiponectin, leptin, TNFα, and AFABP are prime candidate adipokines for direct involvement in the pathophysiology of gestational diabetes. Placental and non-placental origins of these adipokines are likely to contribute to dysregulated levels in gestational diabetes. By induction of insulin resistance, β-cell dysfunction, or both, they might directly induce the disease. Additionally, adipokines might indirectly cause gestational diabetes by enhancing a proinflammatory state, decreasing stress response mechanisms, and increasing glucose and lipid toxicity. TNFα=tumour necrosis factor α. AFABP=adipocyte fatty acid-binding protein.

Search strategy and selection criteria We searched Medline, Embase, and Cochrane databases from January 1, 1960, to May 29, 2013, with the search terms ‘‘adipokine’’, OR ‘‘adipocytokine’’, OR ‘‘leptin’’, OR ‘‘adiponectin’’, OR ‘‘tumour necrosis factor’’, OR ‘‘afabp’’, OR ‘‘fabp4’’, OR ‘‘ap2’’, OR ‘‘rbp4’’, OR ‘‘resistin’’, OR ‘‘visfatin’’, OR ‘‘vaspin’’, OR ‘‘chemerin’’, OR ‘‘progranulin’’, OR ‘‘fgf21’’, OR ‘‘timp1’’, OR ‘‘lipocalin2’’, OR ‘‘ngal’’, OR ‘‘zag’’, OR ‘‘apelin’’, OR ‘‘omentin’’, AND ‘‘gestational diabetes’’ OR ‘‘gdm’’ OR ‘‘pregnancy’’. We reviewed articles resulting from these searches and relevant references cited in those articles. Before examining the full text, we selected articles on the basis of the abstracts. We included articles published in English, French, and German, and articles that reported the results of original basic research on the effect of at least one adipokine on gestational diabetes or if they described original cross-sectional or longitudinal studies on the association of at least one adipokine with gestational diabetes. MF did the data extraction from the full texts. Data were divided by type of study into basic research and clinical studies, with studies further divided into cross-sectional and prospective studies.

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and energy expenditure are also involved in the pathogenesis of gestational diabetes. Consistent with lowgrade inflammation being present in gestational diabetes, circulating concentrations of the proinflammatory adipokine TNFα are increased in gestational diabetes, as shown in several independent cross-sectional studies. Because TNFα potently induces insulin resistance and impairs β-cell function, increased circulating concentrations could directly contribute to the disease. However, the role of first trimester TNFα in the prediction of the disease has only been determined in a small nested case-control study. Clearly, evidence from larger prospective studies is needed to better elucidate the role of this adipokine in the pathogenesis of gestational diabetes. Of the more recently discovered adipokines, insulin resistance-inducing AFABP is an interesting candidate, which could be involved in the pathophysiology of gestational diabetes. Unfortunately, prospective studies and data for expression of AFABP in the placenta and adipose tissue of patients with gestational diabetes have not been published and are needed to better elucidate the role in the pathogenesis of gestational diabetes. Increased first trimester concentrations of LCN2 independently predict the risk of developing gestational diabetes. Additional results from cross-sectional and prospective studies, and from expression analysis in the placenta, are needed to determine the role of this adipokine in gestational diabetes in more detail. Data for regulation of RBP4 and resistin in gestational diabetes are conflicting in cross-sectional studies; however, in independent prospective cohorts both adipokines do not predict risk of gestational diabetes. The regulation of NAMPT in gestational diabetes is far from clear: data in cross-sectional studies are conflicting and one prospective study showed that first trimester NAMPT predicts the risk of gestational diabetes. For other adipokines—including vaspin, chemerin, progranulin, FGF21, TIMP1, AZGP1, APLN, and omentin—cross-sectional evidence consistently suggests that they are not significantly dysregulated in women with gestational diabetes. Data from prospective studies, and for expression in placenta and adipose tissue in gestational diabetes, are not available for most of these adipokines, which could enable firmer conclusions. Based on the restricted evidence available, it is unlikely that RBP4, resistin, NAMPT, SERPINA12, chemerin, progranulin, FGF21, TIMP1, AZGP1, APLN, and omentin contribute to the pathophysiology of gestational diabetes. Together, the adipokines adiponectin, leptin, TNFα, and AFABP are prime candidates for direct involvement in the pathophysiology of gestational diabetes (figure 2). Placental and non-placental origins of these adipokines are likely to contribute to dysregulated concentrations in gestational diabetes. By induction of insulin resistance or β-cell dysfunction, these adipokines might directly induce the disease. To investigate pathophysiological mechanisms in more detail, generation of suitable animal models of gestational diabetes should be a major goal of future work. www.thelancet.com/diabetes-endocrinology Vol 2 June 2014

In addition, additional high quality and adequately powered clinical studies are needed to better elucidate the role of these and other adipokines in the pathogenesis of gestational diabetes. Contributors MF searched the published work. MF, MB, and MS wrote and approved the Review. Conflicts of interest We declare that we have no conflicts of interest. Acknowledgments This study was supported by grants to MF from the Deutsche Forschungsgemeinschaft (DFG, SFB 1052/1, C06), the Federal Ministry of Education and Research (BMBF), Germany, FKZ: 01EO1001 (IFB AdiposityDiseases, project K7–9), and the Deutsche Hochdruckliga e.V., and by grants to MB and MS from the ICEMED alliance (Helmholtz Gemeinschaft). References 1 Landon MB, Gabbe SG. Gestational diabetes mellitus. Obstet Gynecol 2011; 118: 1379–93. 2 Vrachnis N, Augoulea A, Iliodromiti Z, Lambrinoudaki I, Sifakis S, Creatsas G. Previous gestational diabetes mellitus and markers of cardiovascular risk. Int J Endocrinol 2012; 2012: 458610. 3 Lambrinoudaki I, Vlachou SA, Creatsas G. Genetics in gestational diabetes mellitus: association with incidence, severity, pregnancy outcome and response to treatment. Curr Diabetes Rev 2010; 6: 393–99. 4 Kralisch S, Bluher M, Paschke R, Stumvoll M, Fasshauer M. Adipokines and adipocyte targets in the future management of obesity and the metabolic syndrome. Mini Rev Med Chem 2007; 7: 39–45. 5 Festa A, Shnawa N, Krugluger W, Hopmeier P, Schernthaner G, Haffner SM. Relative hypoleptinaemia in women with mild gestational diabetes mellitus. Diabet Med 1999; 16: 656–62. 6 Mokhtari M, Hashemi M, Yaghmaei M, Naderi M, Shikhzadeh A, Ghavami S. Evaluation of the serum leptin in normal pregnancy and gestational diabetes mellitus in Zahedan, southeast Iran. Arch Gynecol Obstet 2011; 284: 539–42. 7 Horosz E, Bomba-Opon DA, Szymanska M, Wielgos M. Third trimester plasma adiponectin and leptin in gestational diabetes and normal pregnancies. Diabetes Res Clin Pract 2011; 93: 350–56. 8 Saucedo R, Zarate A, Basurto L, et al. Relationship between circulating adipokines and insulin resistance during pregnancy and postpartum in women with gestational diabetes. Arch Med Res 2011; 42: 318–23. 9 Skvarca A, Tomazic M, Krhin B, Blagus R, Janez A. Adipocytokines and insulin resistance across various degrees of glucose tolerance in pregnancy. J Int Med Res 2012; 40: 583–89. 10 Maple-Brown L, Ye C, Hanley AJ, et al. Maternal pregravid weight is the primary determinant of serum leptin and its metabolic associations in pregnancy, irrespective of gestational glucose tolerance status. J Clin Endocrinol Metab 2012; 97: 4148–55. 11 Ranheim T, Haugen F, Staff AC, Braekke K, Harsem NK, Drevon CA. Adiponectin is reduced in gestational diabetes mellitus in normal weight women. Acta Obstet Gynecol Scand 2004; 83: 341–47. 12 Thyfault JP, Hedberg EM, Anchan RM, et al. Gestational diabetes is associated with depressed adiponectin levels. J Soc Gynecol Investig 2005; 12: 41–45. 13 Retnakaran R, Qi Y, Connelly PW, Sermer M, Hanley AJ, Zinman B. Low adiponectin concentration during pregnancy predicts postpartum insulin resistance, beta cell dysfunction and fasting glycaemia. Diabetologia 2010; 53: 268–76. 14 Ortega-Senovilla H, Schaefer-Graf U, Meitzner K, et al. Gestational diabetes mellitus causes changes in the concentrations of adipocyte fatty acid-binding protein and other adipocytokines in cord blood. Diabetes Care 2011; 34: 2061–66. 15 Lappas M, Yee K, Permezel M, Rice GE. Release and regulation of leptin, resistin and adiponectin from human placenta, fetal membranes, and maternal adipose tissue and skeletal muscle from normal and gestational diabetes mellitus-complicated pregnancies. J Endocrinol 2005; 186: 457–65.

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