The Influence of Maternal Diet and Metformin Intake on Beta-Cell Physiology in Non-Human Primate Offspring

Abstract

As incidence of maternal obesity increases, the effects of maternal overnutrition and the therapeutics prescribed to prevent or treat peri-gestational glucose intolerance on offspring health should be considered. My work and others in our group found that pancreatic islets from non-human primate offspring exposed to maternal Western style diet exhibit inappropriate hyper-secretion of insulin in response to glucose at 1- and 3-years of age. I hypothesize that developmental exposure to overnutrition induces a compensatory increase in beta-cell metabolism resulting in an increase in insulin secretion from offspring islets that is unnecessary after the offspring have been born. I assessed mitochondrial respiration in 1-year-old offspring islets and found that spare respiratory capacity is increased in the islets of male offspring of western style diet-fed dams, suggesting an increased capacity to adapt to increased metabolic demand. Transcripts for genes associated with beta-cell membrane polarization are increased in islets from maternal western style diet exposed offspring, suggesting that insulin hyper-secretion results from changes in stimulus-secretion coupling. To determine if therapeutics for maternal metabolic dysfunction improve or worsen the effects of maternal overnutrition on offspring health, my work evaluates the effect that metformin, a common type 2 diabetes therapeutic, has on fetal islet function. Metformin is not metabolized by the liver and crosses the placenta, though the implications of exposure to metformin during fetal development on offspring metabolic outcomes are unknown. I found that metformin perturbs nucleotide biosynthetic processes in endocrine cell types and inhibits cellular growth in fetal offspring islets. Given that hyperinsulinemia can lead to insulin resistance, elucidation of the mechanisms mediating developmental adaptation to maternal diet and metformin intake may provide insight on interventions to avoid beta-cell failure and Type 2 Diabetes in the offspring as they age.