Recent studies from this laboratory implicate roles of placental lactogen (PL) and prolactin in the control of fetal and neonatal insulin production and in the emergence of glucose-dependent insulin secretion in the perinatal period. To clarify the roles of lactogenic hormones in perinatal insulin production, we propose two specific aims: The first objective is to examine the effects of lactogen resistance on pancreatic islet cell development and insulin production in fetal, neonatal and postnatal mice. Lactogen resistant mice that are deficient in lactogenic (prolactin) receptors have been obtained from Dr. Paul Kelly. We hypothesize that the absence of pancreatic prolactin receptors (PRLRs) will abolish the biological activity of mouse PL and prolactin in the pancreas and thereby reduce beta cell mass, insulin production and glucose-dependent insulin secretion in the perinatal period. The second objective is to explore cellular mechanisms by which lactogens regulate insulin production and secretion in fetal and postnatal mice. Studies will focus on the roles of glucose transport, glucose metabolism, and cellular calcium influx in the insulinotropic effects of lactogenic hormones. The ontogeny of expression of beta cell Glut2, glucokinase and voltage-dependent calcium channels and the rates of glucose transport, glucose oxidation and calcium influx in PRLR-deficient mice will be compared with those in normal control mice at various stages of development. Then the effects of PL and prolactin on glucose transport, glucose utilization, calcium uptake and the expression of Glut2, glucokinase and voltage-dependent calcium channels will be examined in isolated islets from fetal, neonatal and postnatal mice. Finally, we will examine the effects of inhibitors of glucose transport, glucose metabolism and calcium influx on the insulinotropic effects of lactogenic hormones in fetal and postnatal islets. We hypothesize that lactogens exert acute and chronic insulinotropic effects through both glucose-dependent and glucose-independent mechanisms that lead to beta cell calcium influx. The results of these studies should clarify the roles of lactogens in the control of perinatal and postnatal insulin production and may provide new insight into the pathogenesis of fetal macrosomia in the infant of the diabetic mother.

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Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Human Embryology and Development Subcommittee 1 (HED)
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Ilekis, John V
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Duke University
Schools of Medicine
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Arumugam, Ramamani; Fleenor, Don; Freemark, Michael (2014) Knockdown of prolactin receptors in a pancreatic beta cell line: effects on DNA synthesis, apoptosis, and gene expression. Endocrine 46:568-76
Brooks, Elizabeth Drake; Little, Dianne; Arumugam, Ramamani et al. (2013) Pathogenesis of growth failure and partial reversal with gene therapy in murine and canine Glycogen Storage Disease type Ia. Mol Genet Metab 109:161-70
Arumugam, Ramamani; Fleenor, Donald; Lu, Danhong et al. (2011) Differential and complementary effects of glucose and prolactin on islet DNA synthesis and gene expression. Endocrinology 152:856-68
Arumugam, Ramamani; Horowitz, Eric; Noland, Robert C et al. (2010) Regulation of islet beta-cell pyruvate metabolism: interactions of prolactin, glucose, and dexamethasone. Endocrinology 151:3074-83
Arumugam, Ramamani; Horowitz, Eric; Lu, Danhong et al. (2008) The interplay of prolactin and the glucocorticoids in the regulation of beta-cell gene expression, fatty acid oxidation, and glucose-stimulated insulin secretion: implications for carbohydrate metabolism in pregnancy. Endocrinology 149:5401-14
Viengchareun, Say; Servel, Nathalie; Feve, Bruno et al. (2008) Prolactin receptor signaling is essential for perinatal brown adipocyte function: a role for insulin-like growth factor-2. PLoS One 3:e1535
Arumugam, Ramamani; Fleenor, Don; Freemark, Michael (2007) Lactogenic and somatogenic hormones regulate the expression of neuropeptide Y and cocaine- and amphetamine-regulated transcript in rat insulinoma (INS-1) cells: interactions with glucose and glucocorticoids. Endocrinology 148:258-67
Arumugam, Ramamani; Fleenor, Don; Freemark, Michael (2007) Effects of lactogen resistance and GH deficiency on mouse metabolism: pancreatic hormones, adipocytokines, and expression of adiponectin and insulin receptors. Endocrine 32:182-91
Freemark, M (2006) Regulation of maternal metabolism by pituitary and placental hormones: roles in fetal development and metabolic programming. Horm Res 65 Suppl 3:41-9
Fleenor, Don; Arumugam, Ramamani; Freemark, Michael (2006) Growth hormone and prolactin receptors in adipogenesis: STAT-5 activation, suppressors of cytokine signaling, and regulation of insulin-like growth factor I. Horm Res 66:101-10

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