Biomarker of Pancreatic B-cell Loss Predicting Progression to Type 2 Diabetes After Gestational Diabetes

ABSTRACT/PROJECT SUMMARY In this project, we prospectively examine the associations and predictive ability of unmethylated insulin gene (INS) DNA from 6-12 weeks postpartum and their subsequent changes several years later preceding the onset of type 2 diabetes (T2D) among two cohorts of women with prior gestational diabetes mellitus (GDM). We will leverage the extant resources from two large prospective studies of 1410 women diagnosed with GDM: the Study of Women, Infant Feeding, and Type 2 Diabetes After Gestational Diabetes (SWIFT) in the U.S. funded by NIH, and the Tianjin GDM Observational study (TGDM-O) in China funded by the European Foundation for the Study of Diabetes (EFSD). The SWIFT study is an ongoing, prospective, longitudinal cohort of 990 women (75% minority; Asian, Hispanic, Black) diagnosed with GDM (2008-2011) who underwent three research 2-h 75 g oral glucose tolerance tests (OGTT) from 6-9 weeks postpartum (baseline), follow up Year 1 and Year 2 post- baseline, and additional testing for diabetes up to 12 years (10/2020) via the Kaiser Permanente electronic health records system. The TGDM-O study is a 4-year, prospective, longitudinal study of 420 Chinese women with GDM who underwent 5 research 2-hr 75 g OGTTs from 6-12 weeks or ~1 year postpartum (baseline) to up to 4- 7 years after baseline (2020). All study participants have fasting glucose, 2-h glucose during serial 2-h OGTTs, in addition to other laboratory (e.g., HbA1c, insulin, lipids), clinical (e.g., adiposity) and behavioral (e.g., diet, exercise, lactation) measures at baseline and follow-up research visits. From the stored fasting serum samples collected from multiple OGTTs, we will measure unmethylated INS DNA and methylated DNA at baseline, Year 1 and Year 2. In Aim 1, we will identify unmethylated INS DNA levels at 6-9 weeks postpartum and longitudinal changes after baseline, and their associations with incident T2D up to ~12 years after GDM pregnancy in the SWIFT. In Aim 2, we will determine the generalizability of Aim 1.a-d in the TGDM-O cohort by assessing heterogeneity in effect estimates and computing pooled associations using a meta-analysis technique. In exploratory Aim 3, we will identify whether unmethylated INS DNA levels at baseline and their temporal changes are associated with baseline measures of IR and β-cell secretory function and their changes in Aims 1-2. If successful, our study will provide novel methodology to assess β-cell death and help transfer this assay into clinical practice for early prevention and potential treatment for inhibiting β-cell apoptosis.