Impact of Changes Over Time in Adipokines and Inflammatory Proteins on Changes in Insulin Sensitivity, β-Cell Function, and Glycemia in Women With Previous Gestational Dysglycemia

Adipokine dysregulation and subclinical inflammation are putative diabetogenic features of adiposity. However, while alterations in adipokines/inflammatory proteins can predict incident type 2 diabetes in longitudinal studies (1–3), evidence for causality is generally hindered by two limitations. First, there is a relative paucity of human data linking changes in adipokines/inflammatory proteins with changes in insulin sensitivity and β-cell function over time, as might be expected for causal mediators. Second, because obesity-induced changes in circulating proteins do not occur in isolation, the precise elucidation of causal mediators ideally requires consideration of multiple adipokines/inflammatory proteins simultaneously (as opposed to individually, as typically occurs in studies). Thus, to address these limitations, we evaluated changes over 2 years in adipokines (adiponectin, chemerin, retinol-binding protein 4 [RBP-4]) and inflammatory proteins (C-reactive protein [CRP], plasminogen activator inhibitor 1 [PAI-1]) in relation to changes in insulin sensitivity, β-cell function, and glycemia in women with varying degrees of recent gestational dysglycemia and hence a range of future risk of diabetes.

In this study, 339 women underwent a glucose challenge test (GCT) and oral glucose tolerance test (OGTT) in pregnancy, followed by repeat OGTT and measurement of adiponectin (Millipore), chemerin (Millipore), RBP-4 (ALPCO), CRP (Dade Behring), and PAI-1 (Invitrogen) at both 1 year and 3 years postpartum. The study protocol has been previously described in detail (4,5). On each OGTT, insulin sensitivity/resistance was measured by Matsuda index and HOMA of insulin resistance (HOMA-IR), and β-cell function was measured by the Insulin Secretion-Sensitivity Index-2 and insulinogenic index/HOMA-IR (4,5). The antepartum GCT/OGTT identified four gestational glucose tolerance groups (gestational diabetes mellitus, gestational impaired glucose tolerance, abnormal GCT with normal OGTT, normal GCT/OGTT), each of which predicts distinct trajectories of future risk of diabetes (5). On multiple linear regression analyses (Table 1), none of the adipokines/inflammatory proteins or their changes predicted β-cell function at 3 years (models A and B). Adiponectin at 1 year predicted insulin sensitivity (Matsuda index) at 3 years, while PAI-1 at 1 year and its change from 1 to 3 years were negative predictors (model C). The same predictors emerged for HOMA-IR, in addition to CRP at 1 year and its change from 1 to 3 years (model D). For both fasting and 2-h glucose at 3 years (models E and F), significant independent predictors were the respective glucose measurement at baseline, BMI at 1 year, and change in BMI from 1 to 3 years. Of note, although weight gain is associated with both increased CRP and insulin resistance, the change in CRP was itself independently and inversely associated with HOMA-IR and fasting glucose at 3 years, likely reflecting the impact of adjustment for concurrent change in BMI and the other adipokines/inflammatory proteins. Finally, on logistic regression analysis with the same covariates, the only predictors of prediabetes/diabetes at 3 years were glucose intolerance at 1 year (odds ratio 8.12, 95% CI 3.98–16.56), BMI at 1 year (1.09, 1.02–1.16), and change in BMI (1.30, 1.05–1.59).

Thus, in fully adjusted models simultaneously evaluating all of the adipokines/inflammatory proteins and their changes over time, the dominant independent predictors of all of the metabolic outcomes were BMI at 1 year and its change from 1 to 3 years. The impact of adiposity on risk of diabetes in this population does not appear to be mediated by changes in adiponectin, chemerin, RBP-4, CRP, or PAI-1.