Postpartum defects in inflammatory response after gestational diabetes precede progression to type 2 diabetes: a nested case-control study within the SWIFT

Background: Gestational diabetes (GDM) is a distinctive form of diabetes that first presents in pregnancy. While most women return to normoglycemia after delivery, they are nearly ten times more likely to develop type 2 diabetes than women with uncomplicated pregnancies. Current prevention strategies remain limited due to our incomplete understanding of the early underpinnings of progression. Aim: To comprehensively characterize the postpartum profiles of women shortly after a GDM pregnancy and identify key mechanisms responsible for the progression to overt type 2 diabetes using multi-dimensional approaches.Methods: We conducted a nested case-control study of 200 women from the Study of Women, Infant Feeding and Type 2 Diabetes After GDM Pregnancy (SWIFT) to examine biochemical, proteomic, metabolomic, and lipidomic profiles at 6-9 weeks postpartum (baseline) after a GDM pregnancy. At baseline and annually up to two years, SWIFT administered research 2-hour 75-gram oral glucose tolerance tests. Women who developed incident type 2 diabetes within four years of delivery (incident case group, n = 100) were pair-matched by age, race, and pre -pregnancy body mass index to those who remained free of diabetes for at least 8 years (control group, n = 100). Correlation analyses were used to assess and integrate relationships across profiling platforms.Results: At baseline, all 200 women were free of diabetes. The case group was more likely to present with dys-glycemia (e.g., impaired fasting glucose levels, glucose tolerance, or both). We also detected differences between groups across all omic platforms. Notably, protein profiles revealed an underlying inflammatory response with perturbations in protease inhibitors, coagulation components, extracellular matrix components, and lipoproteins, whereas metabolite and lipid profiles implicated disturbances in amino acids and triglycerides at individual and class levels with future progression. We identified significant correlations between profile features and fasting plasma insulin levels, but not with fasting glucose levels. Additionally, specific crossomic relationships, particularly among proteins and lipids, were accentuated or activated in the case group but not the control group.Conclusions: Overall, we applied orthogonal, complementary profiling techniques to uncover an inflammatory response linked to elevated triglyceride levels shortly after a GDM pregnancy, which is more pronounced in women who progress to overt diabetes.