The Diabetes Risk Phenotype of Young Women With Recent Gestational Diabetes

Context: The pathogenesis of type 2 diabetes (T2D) is still incompletely understood. In-depth phenotyping of young individuals at risk for T2D can contribute to the understanding of this process. Objective: The purpose of this study was to metabolically characterize women with recent gestational diabetes (GDM), an at-risk cohort for T2D. Study Participants: Participants were 147 women consecutively recruited 3 to 16 months after pregnancy: women who had GDM and women after a normoglycemic pregnancy (control subjects) in a 2: 1 ratio. Design: This was a monocenter cross-sectional analysis (Prediction, Prevention and Subclassification of Type 2 Diabetes Study [PPS-Diab]). Methods: A 5-point oral glucose tolerance test with calculation of the insulin sensitivity index and disposition index (validation by euglycemic clamp and intravenous glucose tolerance test) was performed. In addition, anthropometrics, medical and family history, clinical chemistry and biomarkers, statistical modeling, and a magnetic resonance imaging/magnetic resonance spectroscopy substudy (body fat distribution and liver and muscle fat; n = 66) were obtained. Results: Compared with control subjects, women after GDM had a reduced disposition index, higher levels of plasma fetuin-A, and a lower insulin sensitivity index. A low insulin sensitivity index was also the major determinant of pathological glucose tolerance after GDM. The factors most strongly predictive of low insulin sensitivity were high plasma plasma leptin, body mass index, triglycerides, and waist circumference. Ectopic lipids showed no body mass index-independent associations with having had GDM or low insulin sensitivity in a magnetic resonance imaging substudy. Conclusions: We found that beta-cell function is already impaired in women with recent GDM, a young at-risk cohort for T2D. In addition, our data suggest that fetuin-A and leptin signaling may be important early contributors to the pathogenesis of T2D, at this disease stage equally or more relevant than ectopic lipids and low-grade inflammation.