Introduction and Objective: Use of the oral glycemic agent metformin (Met) in pregnancy has expanded beyond treatment of maternal diabetes, but effects on offspring metabolic health are understudied. Met is not metabolized by the maternal liver and is transported across the placenta, and in humans is associated with small for gestational age, increased postnatal catch-up growth, and increased adiposity. We hypothesize that Met exposure in utero decreases nutrient utilization and growth-metabolic processes, impairing postnatal offspring beta-cell maturity and function. Methods: Adult female Rhesus macaques were fed control (CD) or Western-style diet (WD) plus vehicle (Veh) or Met (10 mg/kg BID) starting at gestational day 30 until 3 months postpartum, yielding 4 groups: CD/Veh (n=8), CD/Met (n=6), WD/Veh (n=10), WD/Met (n=8). At weaning, offspring were maintained on the maternal diet, with a study endpoint of 2-years-old. Isolated islets were subjected to perifusion studies to assess insulin secretion and Seahorse to determine oxygen consumption rate. Results: Offspring body weight did not differ between groups, but HbA1c was significantly elevated by WD (p=0.0001), with WD/Met exhibiting the highest values. Perifused CD/Met islets showed diminished area under the curve for both basal (p≤0.0141) and glucose-stimulated (p≤0.0077) insulin secretion compared with all other groups. Compared with islets from CD/Veh or WD/Veh, developmental Met exposure led to reduced maximal oxygen consumption from isolated islets exposed to 20 mM glucose regardless of diet. Conclusion: Met exposure throughout pregnancy and lactation leads to impaired mitochondrial function and potential alterations in mitochondrial capacity, regardless of diet. In offspring from CD fed dams, Met exposure also impairs basal and glucose-stimulated insulin secretion. Thus, developmental Met exposure may diminish offspring beta-cell adaptability under metabolic stress, and this may differ depending on the maternal metabolic milieu. Disclosure A. DelBene: None. J. Fuhr: None. S.R. Lindsley: None. M. Kirigiti: None. T. Dean: None. S.R. Wesolowski: None. C.E. McCurdy: None. J. Friedman: None. K. Aagaard-Tillery: None. P. Kievit: Consultant; Current; Crinetics Pharmaceuticals, Inc. Research Support; Ended; Flagship Pioneering. Research Support; Current; Eli Lilly and Company, Novo Nordisk A/S. Consultant; Current; Merck & Co., Inc. M. Gannon: None. Funding National Institutes of Health (1R01DK128187-01A1), National Institutes of Health (T32 DK7563-30)
DELBENE et al. (Fri,) studied this question.