Adaptations to maternal WSD-feeding and metformin use on fetal islets from non-human primate offspring

Abstract

Given the current increased prevalence of diabetes in pregnancy, the potential relative risks and benefits of oral glycemic agents on the developing offspring should be evaluated and considered. Metformin (Met) is a common oral glycemic agent prescribed in pregnancy that is not metabolized, but is renally excreted and actively transported across the placenta. Thus, the developing fetus is exposed to near equivalent maternal adult doses with subsequent risk of adverse consequences. Using a non-human primate model of maternal overnutrition, our group previously demonstrated that developmental exposure to a Western-style diet (WSD) results in an inappropriate increase in glucose-stimulated insulin secretion and changes in expression of several ion channels involved in insulin secretion in islets from juvenile offspring. Given that maternal overnutrition results in an excess energy supply to the developing fetus while Met inhibits mitochondrial respiration, we hypothesize that maternal WSD-feeding and Met will result in maladaptive beta-cell function in the fetus. Static insulin secretion assays on islets from chow (CD) and WSD +/- Met-exposed offspring show no differences in glucose-stimulated insulin secretion. Nevertheless, islets from a mWSD+Met-exposed fetus showed lower oxygen consumption and extracellular acidification rate relative to mWSD+placebo fetal islets, suggesting that maternal diet influences fetal programming and adaptation to Met in fetal islets. Therefore, we predict that the metabolic response to intrauterine Met exposure differs depending on the maternal diet. Elucidation of the mechanisms mediating adaptations to maternal diet and Met exposure during development may provide insight on interventions to avoid beta-cell failure in the offspring as they age. All nonhuman primate studies were supported in part by the Oregon National Primate Research Center grant P51 OD011092 from the National Institutes of Health/Offce of the Director. D.T.C. was supported by the Vanderbilt University Training Program in Molecular Endocrinology (5T32 DK563-30) and a predoctoral fellowship from the NIH/NIDDK (1F31 DK135164).T.A.D., C.E.M., K.M.A., J.E.F., P.K., and M.G. were supported by NIH/NIDDK Grants R24 DK090964 and R01 DK128187. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.