Review
Adipokines in gestational diabetes Mathias Fasshauer, Matthias Blüher, Michael Stumvoll
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
Lancet Diabetes Endocrinol 2013 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
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.
www.thelancet.com/diabetes-endocrinology Published online December 30, 2013 http://dx.doi.org/10.1016/S2213-8587(13)70176-1
1
Review
See Online for appendix
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 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.
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 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
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 2
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
www.thelancet.com/diabetes-endocrinology Published online December 30, 2013 http://dx.doi.org/10.1016/S2213-8587(13)70176-1
Review
Gestational age (weeks) of patients with gestational diabetes/ controls
Multivariate correlation Circulating adipokine concentration in gestational diabetes
55/166
26·0/25·4
↔
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
Number of patients with gestational diabetes/controls Leptin Festa et al (1999)5
Maple-Brown et al (2012)10
198/477
+ BMI, + fasting insulin – Gestational diabetes
Ranheim et al (2004)11
22/29
38·1/38·5
↔
ND
Thyfault et al (2005)12
22/27
39·3/39·2
↔
ND
29/30
↔
+ Post-P β-cell function ND
Retnakaranet al (2010)13
137/259
Ortega-Sanovilla et al (2011)14
98/86
26·4/26·9
↔
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
Stepan et al (2010)18
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
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
Adiponectin
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
Stepan et al (2010)18
40/80
29·3/28·3
↔
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
↓
– 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)
www.thelancet.com/diabetes-endocrinology Published online December 30, 2013 http://dx.doi.org/10.1016/S2213-8587(13)70176-1
3
Review
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
TNFα
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
AFABP 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
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 4
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,
www.thelancet.com/diabetes-endocrinology Published online December 30, 2013 http://dx.doi.org/10.1016/S2213-8587(13)70176-1
Review
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
Adipokines in gestational diabetes Mathias Fasshauer, Matthias Blüher, Michael Stumvoll
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
Lancet Diabetes Endocrinol 2013 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
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.
www.thelancet.com/diabetes-endocrinology Published online December 30, 2013 http://dx.doi.org/10.1016/S2213-8587(13)70176-1
1
Review
See Online for appendix
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 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.
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 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
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 2
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
www.thelancet.com/diabetes-endocrinology Published online December 30, 2013 http://dx.doi.org/10.1016/S2213-8587(13)70176-1
Review
Gestational age (weeks) of patients with gestational diabetes/ controls
Multivariate correlation Circulating adipokine concentration in gestational diabetes
55/166
26·0/25·4
↔
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
Number of patients with gestational diabetes/controls Leptin Festa et al (1999)5
Maple-Brown et al (2012)10
198/477
+ BMI, + fasting insulin – Gestational diabetes
Ranheim et al (2004)11
22/29
38·1/38·5
↔
ND
Thyfault et al (2005)12
22/27
39·3/39·2
↔
ND
29/30
↔
+ Post-P β-cell function ND
Retnakaranet al (2010)13
137/259
Ortega-Sanovilla et al (2011)14
98/86
26·4/26·9
↔
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
Stepan et al (2010)18
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
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
Adiponectin
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
Stepan et al (2010)18
40/80
29·3/28·3
↔
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
↓
– 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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Review
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
TNFα
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
AFABP 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
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 4
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,
www.thelancet.com/diabetes-endocrinology Published online December 30, 2013 http://dx.doi.org/10.1016/S2213-8587(13)70176-1
Review
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
