The Developmental Origins of Health and Disease hypothesis states that the intrauterine environment influences postnatal health and adult disease susceptibility. In the United States, over 30% of women of childbearing age are obese, in part due to Western Style Diet (WSD) consumption. Previous data from our group using a Japanese macaque model, revealed that maternal overnutrition increases the β:α cell ratio in the islets of offspring. WSD-exposed offspring islets also exhibit inappropriate hypersecretion of insulin in response to glucose at 1 and 3 years of age. We hypothesize that fetal exposure to WSD induces a compensatory increase in β-cell fuel metabolism resulting in an inappropriate increase in insulin secretion by offspring islets. When we assessed the effect of maternal diet on mitochondrial respiration in offspring islets, we found that spare respiratory capacity is increased in islets of one year old WSD-exposed male offspring, suggesting an increased capacity to adapt to increased metabolic demand. This could be due to increased mitochondrial abundance; however, maternal overnutrition does not appear to increase β cell mitochondrial density when analyzed via transmission electron microscopy (TEM) . Insulin granule density is increased in male offspring islets in TEM micrographs, implying that insulin production is increased in response to intrauterine WSD exposure. Transcripts for CACNA1C (voltage gated calcium channel subunit) , ABCC8 (ATP-sensitive potassium channel subunit) , and VAMP2 (vesicle fusion) are increased in response to maternal WSD exposure in offspring islets. Thus, our data suggest that increases in insulin secretion in offspring exposed to maternal overnutrition result from changes in metabolic and secretion pathways. Importantly, these mechanisms could potentiate hyperinsulinism which may predispose offspring to insulin resistance and beta cell failure in adulthood.
D.T. Carroll: None. V.F. Ricciardi: None. J.C. Dunn: None. S.R. Lindsley: None. T. Dean: None. M. Kirigiti: None. S.R. Wesolowski: None. C.E. McCurdy: None. P. Kievit: Research Support; Novo Nordisk A/S. J.E. Friedman: None. M. Gannon: None.
NIH-NIDDK (5T32 DK7563-30, R24DK090964-06, 1R01DK128187)