Maternal Hyperinsulinemia and Fetal Programming

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DESCRIPTION (provided by applicant): Fetal/neonatal insults can lead to adult-onset diseases (obesity, diabetes, etc.) but little is known about the mechanisms involved. We have demonstrated that newborn rats artificially reared on a high carbohydrate (HC) milk formula during their suckling period immediately develop hyperinsulinemia, which persists into adulthood and is accompanied by obesity. This proposal is based on our observation that HC female rats spontaneously transmit maternal traits (chronic hyperinsulinemia and adult-onset obesity) to the progeny due to the fetal experience of a hyperinsulinemic/obese HG pregnancy. To elucidate the mechanisms involved in this maternal-fetal transfer of phenotype three specific aims are proposed: (1) Investigate the maternal environmental factor(s) responsible for programming fetal B cells to develop hyperinsulinemia after weaning. It is hypothesized that hormonal and metabolic adaptations associate with such a pregnancy are responsible for programming of hyperinsulinemia in the progeny. (2) Investigate the biochemical and molecular mechanisms responsible for chronic hyperinsulinemia an adult-onset obesity in the progeny born to HG females. The hypothesis is that the intrauterine environment of the HG female programs molecular and biochemical changes in islets of the progeny facilitating the onset of hyperinsulinemia on weaning and its persistence into adulthood. (iii) Investigate the effects of maternal hyperinsulinemia on fetal and neonatal pancreatic ontogeny as influenced by alterations in the levels of specific growth factors (IGFs, FGFs, etc.) and transcription factors. Our hypothesis is that the H( intrauterine environment alters pancreatic cellular development in the progeny in response to the change in levels of specific growth factors and transcription factors. Experimental procedures include: artificial rearing of newborn rats, reciprocal embryo transfer, insulin secretion by isolated islets radioimmunoassays, semiquantitative RT-PCR assay, immunohistochemistry and in situ hybridization.