1731-P: Determining the Mechanistic Relationship between Maternal Diet and Postnatal Beta-Cell Function

Abstract

Previous studies have shown that intrauterine nutrient levels impact the risk of diabetes in offspring postnatally, but the molecular mechanisms underpinning this phenomenon remain poorly characterized. We hypothesize that maternal malnutrition during gestation may disrupt the fetus’ epigenetic program during development, leading to insufficient functional beta-cell mass postnatally. To this end, we show that: 1) endocrine progenitor cells with different DNA methylation signatures give rise to beta-cell subsets with different functional and proliferative capacity; 2) de novo DNA methyltransferases Dnmt3a and Dnmt3b are downregulated in embryonic endocrine progenitors exposed to a low-protein or high-fat diet in utero, while DNA demethyltransferases Tet1 and Tet2 are upregulated; 3) beta cells in offspring of dams fed a low-protein or high-fat diet during gestation demonstrate reduced expression of genes associated with beta cell maturation and function both during development and postnatally (e.g. Pdx1, MafA); 4) islets from adult mice exposed to maternal high-fat diet in utero have compromised insulin secretion when treated with sustained high glucose or free fatty acids in vitro. These findings are consistent with a model in which abnormal DNA methylation in islet progenitors is a key mechanism by which maternal nutrients mediate postnatal functional beta-cell mass and diabetes risk. Disclosure S.Nevills: None. G.Gu: None. Funding National Institutes of Health (5R01DK125696-03, 5T32HD007502-25)