PLACENTAL LACTOGEN AND FETAL DEVELOPMENT

该实验室最近的研究表明胎盘催乳素的作用 (PL)和催乳素在控制胎儿和新生儿胰岛素产生中的作用 以及在糖尿病患者中出现葡萄糖依赖性胰岛素分泌， 围产期目的：探讨催乳激素在围生儿中的作用， 胰岛素生产，我们提出了两个具体目标：第一个目标是 研究催乳素抵抗对胰岛细胞的影响， 胎儿、新生儿和出生后小鼠的发育和胰岛素产生。 催乳素（催乳素）缺乏的催乳素抵抗小鼠 从保罗·凯利博士那里获得了受体。我们假设 胰腺催乳素受体（PRLR）的缺乏将消除 小鼠PL和催乳素在胰腺中的生物活性， 减少β细胞质量、胰岛素产生和葡萄糖依赖性胰岛素 围产期的分泌物。第二个目标是探索 催乳素调节胰岛素产生的细胞机制， 胎儿和出生后小鼠的分泌物。研究将侧重于以下方面的作用： 葡萄糖转运、葡萄糖代谢和细胞钙内流 催乳激素的促胰岛素作用。表达的个体发生 β细胞Glut2、葡萄糖激酶和电压依赖性钙通道， 葡萄糖转运、葡萄糖氧化和钙内流的速率 将PRLR缺陷小鼠与正常对照小鼠进行比较， 不同的发展阶段。然后观察PL和催乳素对 葡萄糖转运、葡萄糖利用、钙摄取和表达 Glut2、葡萄糖激酶和电压依赖性钙通道的功能将被 在来自胎儿、新生儿和出生后小鼠的分离的胰岛中检查。 最后，我们将研究葡萄糖转运抑制剂的作用， 葡萄糖代谢和钙内流对促胰岛素作用的影响 胎儿和出生后胰岛中的催乳激素。我们假设 催乳素通过两种途径发挥急性和慢性促胰岛素作用 葡萄糖依赖性和葡萄糖非依赖性机制导致β-葡萄糖依赖性和葡萄糖非依赖性机制导致β-葡萄糖依赖性和葡萄糖非依赖性机制 细胞钙内流这些研究的结果应阐明 在控制围产期和出生后胰岛素产生中的作用 并可能提供新的见解，巨大胎儿的发病机制， 糖尿病母亲的婴儿。

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.