Introduction and Objective: Type 2 diabetes (T2D) onset occurs at young ages in Indigenous Americans (IA); thus, IA women often have T2D prior to becoming pregnant. Prenatal exposure to maternal diabetes significantly increases risk of T2D in the offspring, but how early exposure to excess glucose affects islet development/function is unclear. Methods: To mimic intrauterine glucose exposure during islet development, we generated pancreatic progenitors from two IA iPSC lines and exposed the differentiating islets to 5mM or 25 mM glucose during endocrine progenitor (EP) and/or maturation (M) stages, yielding four conditions: 5EP/5M, 5EP/25M, 25EP/5M, 25EP/25M. Results: Islet generation from all conditions were confirmed by flow cytometry assessment of islet makers. Dynamic GSIS assay (11 and 20mM glucose stimulations) showed no difference in basal insulin secretion; however, compared to 5EP/5M islets, 1st phase insulin secretion was lower from 5EP/25M and 25EP/25M islets while 2nd phase insulin secretion was lower from 25EP/5M and 25EP/25M islets. This suggests that excess glucose exposure during islet development (EP) affects 2nd phase while during islet maturation affects 1st phase insulin secretion. Bulk-RNA seq of these islets identified dysregulated expression of known glucose responsive genes (TXNIP, RGS16 and G6PC2) and, consistent with differences in insulin secretion, identified overexpression of G0S2 in 5EP/25M and 25EP/25M islets and downregulation of KCNIP1 in 25EP/5M and 25EP/25M islets. Although not previously studied in islets, G0S2 inhibits ATGL, which plays an important role in 1st phase insulin secretion while KCNIP1 is a binding partner and modulator of voltage-gated potassium channels (Kv4.1 and Kv4.3) and play a role in 2nd phase insulin secretion. Conclusion: This study revealed that the timing of glucose exposure during human islet development differentially impairs insulin secretion phases and identified candidate pathways for T2D intervention in offsprings of diabetic pregnancy. Disclosure A. Nair: None. D. Anup: None. K. Cheranda: None. L. Baier: None. Funding NIDDK Intramural
NAIR et al. (Fri,) studied this question.