Adipokines in gestational diabetes

Summary

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, 2, 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 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.