Ravi Retnakaran1
(1)
Leadership Sinai Centre for Diabetes, Toronto, ON, Canada
Ravi Retnakaran
Email: rretnakaran@mtsinai.on.ca
Abstract
Chronic subclinical inflammation and dysregulation of adipocyte-derived proteins (adipokines) have emerged as novel, non-traditional risk factors for both type 2 diabetes and cardiovascular disease. Since GDM is associated with future risk of both of these conditions, study of these novel risk factors in women with GDM has grown. Indeed, these factors may potentially contribute to (i) the development of GDM in affected women, and (ii) their future risk of type 2 diabetes and vascular disease. This chapter reviews current evidence linking inflammation and adipokine dysregulation to GDM, both during and after pregnancy.
10.1 Introduction
In the past decade, advances in our understanding of the pathophysiology of type 2 diabetes (T2DM) have identified chronic subclinical inflammation and dysregulation of adipocyte-derived proteins (adipokines) as pathologic processes that may contribute to the development of metabolic and vascular disease. Characterized by abnormal circulating concentrations of inflammatory proteins and adipokines, these processes have been linked to both the underlying pathophysiology and development of incident T2DM. As such, they may be relevant to populations at high-risk of developing T2DM, such as women with GDM. In this chapter, we address the relationships between these factors and GDM, both during and after pregnancy. We begin by reviewing current concepts regarding inflammation and adipokines in relation to T2DM and the central role of obesity in this context. We then examine the growing body of evidence linking these factors to GDM and the associated implications for insulin resistance and pancreatic beta-cell function in pregnancy. Finally, we consider the limited data currently available from the postpartum period, which suggest that previous GDM may be associated with chronic subclinical inflammation and adipokine dysregulation. It emerges that inflammatory proteins and adipokines clearly warrant further study both during, and particularly after pregnancy complicated by GDM, as these factors may provide (1) insight into the pathophysiology of GDM and T2DM, (2) risk stratification of a patient population at high risk of developing future diabetes, and (3) potential therapeutic targets for the amelioration of this risk.
10.2 Pathophysiologic Similarity Between GDM and Type 2 Diabetes
As discussed in the preceding chapters, GDM and T2DM share considerable pathophysiologic similarity. In particular, both conditions are characterized by two main metabolic defects: (1) target cell resistance to the activity of insulin (insulin resistance) and (2) insufficient secretion of insulin by the pancreatic beta cells to compensate for this peripheral tissue resistance (beta-cell dysfunction).1– 3 Insight regarding the pathophysiology of T2DM may be relevant to GDM and vice versa.4
Consistent with its being a high-risk state for later T2DM, GDM is characterized by chronic insulin resistance and beta-cell dysfunction.4 Normal pregnancy is characterized by progressive insulin resistance from mid-gestation onwards, with overall reductions in insulin sensitivity of 50–60%.5 Women with GDM, however, have greater reductions in insulin sensitivity than do pregnant women with NGT.6 This finding reflects these patients’ chronic insulin resistance that likely exists prior to pregnancy and is known to persist postpartum.4, 7–10
Against this background of insulin resistance, women with GDM have a chronic defect in beta-cell function.4,11 In normal physiology, insulin secretion is linked to insulin sensitivity through a postulated negative feedback loop that allows the beta cells to compensate for any change in whole-body insulin sensitivity through a proportionate and reciprocal change in insulin secretion.12–14 Accordingly, in pregnancy, the beta cells must increase their secretion of insulin in order to overcome declining insulin sensitivity and maintain normoglycemia. Women with GDM, however, have a chronic underlying beta-cell defect such that their compensatory increase in insulin secretion is not sufficient to fully offset the insulin resistance of pregnancy, resulting in the hyperglycemia that defines GDM.4,11 Importantly, for women with a history of GDM, even in the postpartum when their glucose tolerance may appear to be normal, beta-cell function remains abnormal. This becomes apparent when insulin secretion is appropriately adjusted for ambient insulin resistance.11
10.2.1 Role of Obesity
Recognizing (1) that GDM is associated with subsequent T2DM and (2) that these two conditions share pathophysiologic similarity, research interest has focussed on risk factors linking GDM and T2DM, as these factors may provide insight relating to the development of both conditions.4 Clinical factors that have been reported to predict the development of T2DM in women with a history of GDM include high prepregnancy body mass index (BMI), elevated fasting glucose and degree of hyperglycemia in pregnancy, earlier gestational age at diagnosis, recurrent GDM, nonwhite ethnicity, dysglycemia at 1–4 months postpartum, and additional pregnancies.15–25 Of note, prepregnancy BMI is a particularly important risk factor, having emerged as the factor accounting for the highest attributable risk fraction in multivariate analysis.25 As such, considerable attention has been focused on the pathologic effects of obesity and how they may relate to insulin resistance, beta-cell dysfunction, and the clinical development of GDM and T2DM. In this context, two pathologic sequelae of obesity have emerged as processes that may potentially link adiposity with the development of GDM and T2DM: (1) chronic subclinical inflammation and (2) dysregulation of adipokines.26,27 These processes are characterized by abnormal serum concentrations of (1) inflammatory biomarkers, such as C-reactive protein (CRP) and (2) adipokines, such as adiponectin and leptin, respectively. These proteins have thus emerged as novel, nontraditional risk factors for T2DM (discussed in the next section) and GDM (discussed in Sects. 10.4 and 10.5).
10.3 Inflammatory Proteins and Adipokines as Nontraditional Risk Factors for T2DM
The emergence of inflammatory proteins and adipokines as novel risk factors for metabolic disease originated with recognition of their associations with T2DM. As such, before considering their relevance to GDM, it is informative to first review these associations with T2DM.
10.3.1 Inflammatory Proteins and T2DM
In the past decade, evidence has emerged indicating that obesity is a state of subclinical inflammation, as reflected by chronic, low-grade activation of the acute-phase response.26,28 The acute-phase response, as manifested by the dramatic change in serum concentration of certain proteins (acute-phase proteins) in the setting of stressors, such as inflammation and infection, is part of the innate immune system. In the short term, the acute-phase response has survival value in restoring homeostasis after environmental stress. Long-term activation of this system, however, has been proposed as an etiologic factor in disease, including T2DM and cardiovascular disease (CVD).26
It is now recognized that the expansion of visceral fat mass is associated with the infiltration of adipose tissue by macrophages, which may be recruited by adipocyte necrosis, hypoxia, or specific chemokines, such as monocyte chemo-attractant protein-1.29 These macrophages release proinflammatory cytokines that act upon adipose tissue, ultimately resulting in the increased secretion of several inflammatory proteins, including interleukin-6 (the main upstream regulator of the hepatic acute-phase response) and CRP (the prototypical acute-phase protein). This adiposity-related inflammation may then be a factor that links obesity with increased risk of T2DM.
The suggestion that inflammation may play a role in the pathogenesis of T2DM is based on experimental, cross-sectional, and prospective evidence linking increased serum concentrations of acute-phase proteins, such as CRP, IL-6, and plasminogen activator inhibitor-1 (PAI-1), with the metabolic defects of hyperglycemia, insulin resistance, and overt T2DM.26,30–32 Indeed, several prospective studies have shown that elevated serum levels of CRP, IL-6, and PAI-1 can independently predict the development of incident T2DM in a variety of populations, including healthy middle-aged women (Women’s Health Study), middle-aged men (West of Scotland Coronary Prevention Study), elderly subjects (Cardiovascular Health Study) and a large, multiethnic cohort (Insulin Resistance Atherosclerosis Study (IRAS)).33–36 These associations linking CRP and incident T2DM have been robust to adjustment for typical diabetes risk factors, although it should be noted that in all but IRAS, the adjustment for obesity was made by accounting for BMI (which reflects total body adiposity), rather than waist circumference (i.e., which may better reflect visceral adiposity). In this context, it is noteworthy that, in IRAS, after adjustment for waist circumference and insulin sensitivity, the significant association between CRP and risk of diabetes was markedly attenuated, while PAI-1 remained an independent predictor of incident T2DM.36 In general, these data are consistent with a model in which increased visceral fat is associated with subclinical inflammation that may then contribute to insulin resistance and the development of T2DM.
10.3.2 Adipokines and T2DM
Once considered a passive storage depot for triglycerides, adipose tissue is now recognized as an active endocrine organ, responsible for the secretion of several metabolically important proteins called adipokines. The growing list of adipokines includes adiponectin, leptin, tumor necrosis factor alpha (TNFα), retinol-binding protein-4 (RBP-4), resistin, and visfatin. In general, obesity is associated with dysregulation of the secretion of these proteins by adipose tissue, leading to their over-abundance in the circulation (with the notable exception of adiponectin, as discussed below) and potential pathologic effects.
One of the best-studied adipokines related to T2DM is adiponectin, a collagen-like plasma protein with putative insulin-sensitizing, antiatherogenic and anti-inflammatory properties.37 Secreted exclusively by adipocytes, adiponectin circulates at relatively high concentration in oligomeric complexes, consisting of trimers, hexamers, and high-molecular-weight (HMW) multimers of 12–18 subunits.38,39 Unlike other adipokines, total serum adiponectin concentration (i.e., consisting of all multimeric forms) decreases as visceral fat mass expands.40 Accordingly, central obesity, insulin resistance, and T2DM are all characterized by hypoadiponectinemia.40–42 In a longitudinal investigation of adiponectin and the deterioration of glucose tolerance in rhesus monkeys, Hotta et al found that adiponectin levels begin to decline at an early stage in the pathogenesis of diabetes, in parallel with increases in adiposity and reductions in insulin sensitivity, and prior to the appearance of frank hyperglycemia.43 Indeed, in human studies, low serum concentration of adiponectin has predicted the future development of insulin resistance in the Pima Indian population44 and has been associated with beta-cell dysfunction in limited studies.45,46 Furthermore, hypoadiponectinemia has been shown to predict the future development of incident T2DM in various populations, including Pima Indians, Caucasians, Japanese, and South Asians.47– 50 Taken together, these data are consistent with a role for adiponectin deficiency early in the pathogenesis of diabetes.
Experimental evidence suggests that hypoadiponectinemia is a pathologic factor in diabetogenesis rather than a marker of risk alone. In animal models of obesity and diabetes, the administration of adiponectin has been shown to ameliorate insulin resistance, enhance hepatic insulin action, and lower glucose levels.38, 51,52 Furthermore, transgenic over-expression of globular adiponectin afforded diabetes-prone ob/ob mice protection from diabetes that was accompanied by enhancement of both insulin sensitivity and secretion, suggestive of improved beta-cell function.53
In contrast to adiponectin, circulating concentrations of other adipokines are increased in the setting of obesity. Leptin is an adipocyte-derived hormone that controls food intake and energy expenditure, with circulating levels that generally parallel fat stores.29 While leptin also affects the reproductive and central nervous systems, the complex physiology of this hormone in relation to insulin sensitivity and beta-cell function remains to be fully elucidated. Similarly, TNFα is a multifunctional circulating cytokine that is upregulated in obesity and may have varying effects on insulin sensitivity in different tissues (e.g., muscle, liver, pancreatic beta-cells).27 Circulating levels of the newer adipokines RBP-4 and resistin have also both been reported to be increased with obesity and linked to insulin resistance, although conflicting evidence exists regarding these associations.29 Finally, the relationships between visfatin and both obesity and T2DM are similarly unclear, although recent evidence implicates a potential proinflammatory role for this adipokine.54
In general, in the setting of obesity, it is apparent that adipokine dysregulation and inflammation are not isolated processes, but rather are closely interrelated. For example, obesity is characterized by low circulating concentrations of adiponectin (which has putative anti-inflammatory activity) and increased levels of adipokines that have been linked to inflammatory effects (e.g. TNFα, resistin and visfatin). While our understanding of the relationships between these processes and T2DM continues to evolve, it should be noted that inflammation and adipokine dysregulation are both relevant to GDM as well, as will be reviewed in the following sections.
10.4 Inflammation During Pregnancy in Women with GDM
10.4.1 C-Reactive Protein and Other Inflammatory Proteins
As with T2DM, the strongest evidence linking inflammation to GDM is derived from studies of CRP. Indeed, prospective nested case-control studies in pregnancy cohorts have shown that increased CRP concentration in the first trimester is associated with a significantly increased risk of subsequent GDM.55,56 Of note, in the Massachusetts General Hospital Obstetric Maternal Study, this association was attenuated by adjustment for BMI.55 Increased serum CRP in women with GDM has also been reported in some,57, 58 although not all cross-sectional studies later in pregnancy.59 These differing results may be due to changes in CRP levels late in gestation.58 It is more likely, however, that these differences reflect the dominant effect of maternal obesity on circulating CRP levels, a consistent finding in previous reports.55, 59,60 Specifically, as may be anticipated based on the pathologic effects of adiposity discussed earlier, maternal obesity has emerged as a principal determinant of CRP concentration in pregnancy.59
Besides CRP, other markers of inflammation have also been linked to GDM. In first trimester, increased leukocyte count, an inflammatory marker previously associated with T2DM, has been shown to independently predict subsequent GDM.61 In cross-sectional studies, upregulation of the proinflammatory cytokine IL-6 has been reported in women with GDM.62, 63 Increased ferritin early in pregnancy has been shown to predict subsequent GDM, although this relationship was again attenuated by adjustment for pregravid BMI.64 In women from Hong Kong, the association between ferritin and GDM has been partly explained by maternal carriage of hepatitis B surface antigen.65 Finally, heterozygosity for the 5G allele of the PAI-1 gene has been related to GDM, potentially consistent with a pathophysiologic role for PAI-1 in this setting.66
10.4.2 Pathophysiologic Implications of Inflammation in GDM
In the nonpregnant state, obesity-mediated subclinical inflammation is believed to contribute to insulin resistance.28 Similarly, in pregnancy, CRP (principally driven by obesity, as noted above) has been linked to insulin resistance.59 Indeed, after adjustment for covariates (including BMI), CRP concentration in pregnancy has been shown to be independently and significantly associated with fasting insulin, a surrogate measure of insulin resistance.59 Overall, these data support a model in which maternal obesity mediates a chronic systemic inflammatory response, with possible downstream metabolic sequelae, including insulin resistance and gestational dysglycemia.59
10.5 Adipokines During Pregnancy in Women with GDM
10.5.1 Adiponectin and Other Adipokines
As with T2DM, low circulating adiponectin has been strongly linked to GDM. First, several clinical studies have demonstrated that serum levels of total adiponectin are decreased in women with GDM compared with pregnant women with normal glucose tolerance.67–73 Furthermore, hypoadiponectinemia in the first trimester independently predicts the subsequent development of GDM later in the pregnancy, after adjustment for known GDM risk factors.74 In addition, the high molecular weight (HMW) form of adiponectin has been specifically implicated in GDM.75 In the nonpregnant state, it is believed that the insulin-sensitizing and antidiabetic activity of adiponectin is mediated by its HMW form. Consistent with this concept, the hypoadiponectinemia of GDM has been characterized by decreased levels of HMW adiponectin.75 Overall, as with T2DM in the nonpregnant state, the relationship between decreased adiponectin and GDM has been consistent across numerous studies.
Interestingly, women of South Asian descent (who have a well-established increased risk of both GDM and T2DM) exhibit markedly decreased circulating levels of both total and HMW adiponectin in pregnancy, compared with Caucasian women.76, 77 It has thus been hypothesized that hypoadiponectinemia may be a factor contributing to the increased metabolic and vascular risk faced by this patient population.78
There have been fewer studies addressing other adipokines in GDM, although their findings have been generally concordant with expectations. Indeed, women with GDM have been shown to exhibit increased circulating levels of TNFα.62,72 Similarly, recent reports have documented increased concentrations of RBP-4 in women with GDM compared with their peers.79, 80 GDM has also been associated with higher levels of visfatin,81 although the implications of this observation are not clear.
In contrast to the generally consistent findings that have been reported for the preceding adipokines, studies of leptin and resistin in GDM have offered some conflicting results. Specifically, whereas two studies noted increased leptin in women with GDM compared to women with normal glucose tolerance in pregnancy,82,83 Festa et al reported relative hypoleptinemia in subjects with GDM compared with peers, after adjustment for BMI and insulin resistance.84 Similarly, there have been conflicting reports of both increased and decreased resistin levels in women with GDM.85,86
10.5.2 Pathophysiologic Implications of Adipokine Dysregulation in GDM
Adipokine dysregulation may hold several pathophysiologic implications in GDM. As in the nonpregnant state, both total and HMW adiponectin are independently and inversely related to insulin resistance in pregnancy.67, 75Indeed, the longitudinal changes in maternal circulating adiponectin during normal pregnancy (levels of which reach a nadir in the third trimester) are strongly associated with the physiologic changes in insulin sensitivity that occur during gestation (i.e., lowest in third trimester).87 Importantly, as shown in Fig. 10.1, hypoadiponectinemia in pregnancy has also been associated with beta-cell dysfunction.46 Furthermore, the relationship between decreased total adiponectin and beta-cell dysfunction in pregnant women has been shown to be independent of covariate adjustment, raising the possibility that it may reflect a pathophysiologic association.46 More recently, a similar independent relationship was demonstrated between decreased circulating levels of HMW adiponectin (as in GDM) and beta-cell dysfunction in pregnancy.75 Overall, these data suggest that, as with T2DM, hypoadiponectinemia (and specifically deficiency of HMW adiponectin) may be a pathophysiologic factor contributing to the development of insulin resistance, beta-cell dysfunction, and ultimately GDM in affected women.
Fig. 10.1
Beta-cell function, measured by insulin secretion-sensitivity index (ISSI) curves, declines with decreasing tertile of adiponectin concentration in pregnancy (tertile 3: dotted line; tertile 2: dashed line; tertile 1: solid line) (trend p < 0.0001). (From: Retnakaran et al46)
Besides adiponectin, other adipokines have also been linked to insulin resistance in GDM. The correlation between TNFα and insulin resistance in pregnancy is particularly noteworthy.57,72, 88,89Interestingly, in contrast to the classical teaching implicating placental hormones, Kirwan et al90 demonstrated that, amongst candidate hormones (including estrogen, progesterone, human placental lactogen, and cortisol), the change in TNFα from pre-gravid to late pregnancy was the most significant independent predictor of the longitudinal change in insulin sensitivity over this period of time (even after adjustment for fat mass) in a study of 15 women (5 with GDM) assessed before pregnancy, at 12–14 weeks gestation, and at 34–36 weeks gestation. It should be noted that adiponectin was not measured in this study. In other studies, leptin has been consistently associated with insulin resistance in pregnancy.82–84 Finally, the effects of RBP-4 and visfatin in GDM remain to be fully elucidated.
10.6 Inflammatory Proteins and Adipokines in the Postpartum Following GDM
By testing the capacity for beta-cell compensation in the context of the significant acquired insulin resistance of pregnancy, a woman’s glucose tolerance in pregnancy can provide unique insight into her future risk of T2DM. It has long been recognized that women who develop GDM have a substantial risk of developing T2DM in the future. In fact, it has recently emerged that any degree of abnormal glucose homeostasis in pregnancy (i.e., not just GDM) predicts an increased risk of prediabetes or diabetes in the postpartum (Fig. 10.2) and that this risk is proportional to the degree of antepartum dysglycemia.91–93Women with GDM thus represent the highest level on this continuum of future diabetic risk. As such, they constitute an important patient population in whom evaluation in the years following the index pregnancy may provide insight into key factors that mediate a woman’s risk of developing T2DM. Given their emerging associations with both GDM and T2DM, inflammatory proteins and adipokines have recently begun to garner interest as factors of particular interest.
Fig. 10.2
Prevalence of glucose intolerance (prediabetes or diabetes) in four groups of women with varying degrees of glucose tolerance in pregnancy: (1) normal glucose challenge test (GCT) with normal glucose tolerance (NGT) on OGTT; (2) abnormal GCT with NGT; (3) gestational impaired glucose tolerance (GIGT); and (4) GDM (trend p < 0.0001). (From: Retnakaran et al91)
Consistent with the evidence of inflammation in women with GDM in pregnancy, several studies have reported increased levels of inflammatory proteins in this patient population following pregnancy. In a study of 96 women (46 with previous GDM and 50 without) evaluated at 7-years postpartum, Sriharan et al demonstrated increased levels of total sialic acid (a measure of the acute-phase response) in women with previous GDM that correlated with the metabolic syndrome and its components.94 Similarly, circulating PAI-1 is also elevated in women with a history of GDM compared with their peers.95 Further, increased CRP levels have been consistently reported in women with previous GDM96–99 and, as with sialic acid, correlated with the metabolic syndrome.99 A recurrent finding in these studies has been the significant association between CRP and central obesity.97,99 Indeed, in the population-based Third National Health and Nutrition Survey Examination (NHANES III), adjustment for waist circumference attenuated differences in CRP levels between women with previous GDM and women without such a history.100 At present, from limited studies to date, it appears that women with a history of GDM exhibit evidence of chronic subclinical inflammation following the index pregnancy, but further study is needed to determine if this relationship is entirely driven by a tendency towards visceral fat accumulation and central obesity in this population.
There has been very little study thus far of adipokines in women with previous GDM. In a study of 89 women with previous GDM, compared with 19 controls, the former exhibited significantly lower levels of adiponectin and higher leptin concentration at 3-months postpartum.96 The observed hypoadiponectinemia in women with previous GDM persisted even after adjustment for body fat mass. Moreover, low adiponectin was independently associated with decreased insulin sensitivity and low HDL. While further study is needed, these data suggest that hypoadiponectinemia may be a factor contributing to the risk of T2DM in women with a history of GDM.
It is readily apparent that the literature on inflammation and adipokines following GDM is limited, with the few reports thus far generally modest in size and cross-sectional in design. Nevertheless, their characterization of the post-GDM postpartum as a state of subclinical inflammation and hypoadiponectinemia is intriguing when considering that (1) these features are associated with incident T2DM,33–36, 47–50 (2) treatment with a thiazolidinedione significantly reduced the risk of T2DM following GDM in the TRoglitazone In the Prevention Of Diabetes (TRIPOD) study,101 and (3) TZD therapy decreases concentrations of inflammatory proteins and increases adiponectin levels.102,103 These findings, in conjunction with the pathophysiologic effects of inflammation and adipokine dysregulation discussed earlier, suggest that inflammatory proteins and adipokines may play an important role in the development of T2DM in women with previous GDM by contributing to the progressive worsening of insulin resistance, beta-cell dysfunction, and dysglycemia, in the years following the index pregnancy. Given the substantial risk of T2DM in women with a history of GDM, the results of large-scale prospective longitudinal studies evaluating the potential contributions of inflammatory proteins and adipokines will be welcomed. These ongoing studies91 may also provide insight into the relevance of these factors to cardiovascular risk, as GDM is also associated with an increased risk of CVD.104
10.7 Conclusions and Future Research
As reviewed in this chapter, chronic subclinical inflammation and adipokine dysregulation are pathologic effects of central obesity that may relate to insulin resistance and beta-cell dysfunction and thereby contribute to the development of GDM and T2DM in at-risk individuals. At present, these processes have been linked to both GDM and T2DM. However, their potential contribution to the risk of progression to T2DM in women with a history of GDM has not yet been studied.
The importance of further clarifying their role in this patient population is underscored by the potential implications that such insight may hold for basic science, public health, and clinical practice. First, such study could help to elucidate key mechanisms underlying the pathophysiology of both GDM and T2DM. Second, if inflammatory proteins or adipokines are indeed important to the development of T2DM in women with a history of GDM, then these factors may provide a simple means of stratifying patients who are at the highest risk of progression to T2DM. Further, this insight may inform the identification of relevant therapeutic targets and effective interventions prior to the onset of clinical disease. Notably, both lifestyle modification targeting weight loss and certain medications can decrease levels of inflammatory proteins and increase adiponectin levels.102,103,105
In conclusion, evidence to date suggests that, in women at risk of GDM, subclinical inflammation and adipokine dysregulation may be relevant in both pregnancy and in the postpartum. As women with a history of GDM face a high risk of both T2DM and vascular disease, further study is needed to clarify the effects of inflammatory proteins and adipokines in this context. Ultimately, such study may help to elucidate the shared pathophysiology of GDM and T2DM and may inform the clinical care of this high-risk patient population.
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