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 ß-cell secretory function and their changes in Aims 1-2. If
successful, our study will provide novel methodology to assess ß-cell death and help transfer this assay into
clinical practice for early prevention and potential treatment for inhibiting ß-cell apoptosis.
