Pancreatic beta-cell endothelial cell function and signaling in intrauterine grow

宫内生长受限（IUGR）影响发达国家所有妊娠的4-8%;最常见的是 病因是胎盘功能不全和胎儿营养供应减少。为了生存，胎儿会适应 促进有限能量供应的最有效利用的方法。胰腺（3-细胞是其中的关键 适应β细胞分泌胰岛素，以营养调节的方式刺激胎儿生长。因此，我们认为， 胰腺β-细胞是使生长速率与营养供应相匹配的最重要的胎儿细胞类型之一。 关于严重IUGR中胰岛素分泌减少的机制，最好的证据是 实验证据表明，这些适应性不能被克服， simply简单by providing提供increased增加nutrients营养to the growth生长restricted限制fetus胎儿.因此，任何治疗IUGR的希望， 改善胎儿生长率必须联合收割机策略以增加胎儿营养输送和β-细胞胰岛素 分泌物此外，如果这些限制胎儿p细胞数量和胰岛素分泌的适应持续存在， 成年后，他们可能会导致先前生长受限的2型糖尿病患者患2型糖尿病的风险更高。 成年人了这个项目的长期目标是确定限制胎儿P细胞的机制 IUGR的人群和胰岛素分泌，目的是最终开发干预措施来扭转这些情况 适应和允许治疗IUGR和预防2型糖尿病。新的证据正在出现， 显示了p细胞对内皮细胞信号传导对于维持正常p细胞群的重要性， 胰岛素分泌因此，该建议将专门研究减少的p-细胞到内皮细胞的信号传导， 作为胎盘功能不全的胎羊模型中p细胞质量和胰岛素分泌减少的原因， IUGR。我们将使用体外试验来测量急性p细胞和胰岛素刺激的内皮细胞功能， 显示IUGR胰岛内皮细胞反应性降低。然后，我们将演示 通过测量胰岛血管分布对胰岛内皮细胞功能降低的影响 和IUGR胎儿中的血管生成。最后，我们将确定是否慢性增加胰岛素浓度， IUGR胎儿可以改善胰岛血管分布、血管生成和P细胞质量。 相关性（参见说明）： 这项研究与公共卫生有关，因为它将证明导致减少的机制。 胎儿P细胞质量和胰岛素分泌在宫内生长受限（IUGR）。这将允许 开发旨在改善IUGR胎儿生长并降低这些风险的产前治疗。 2型糖尿病患者的饮食习惯

Intrauterine growth restriction (IUGR) affects 4-8% of all pregnancies in developed countries; the most common etiology being placental insufficiency and decreased fetal nutrient supply. In order to survive, the fetus adapts in ways which promote the most efficient use of a limited energy supply.Pancreatic (3-cells are key in this adaptation. The p-cell secretes insulin, which stimulates fetal growth, in a nutrient regulated fashion. Therefore, the pancreatic (3-cell is one of the most important fetal cell types for matchinggrowth rates to nutrient supply. The best evidence regarding the mechanism of decreased insulin secretion in severe human IUGR is a decrease in the pancreatic p-cell population.Experimentalevidence suggests that these adaptations cannot be overcome simply by providingincreased nutrients to the growth restricted fetus. Therefore, any hope of treating IUGR to improve fetal growth rates will have to combine strategies to increase fetal nutrient delivery and p-cellinsulin secretion. Additionally, ifthese adaptations which limitthe fetal p-cell populationand insulin secretion persist into adulthood they can contribute to the higher risk of type 2 diabetes mellitus in previously growth restricted adults. The longterm goal of this project is to determine the responsible mechanisms for limitingthe fetal p-cell population and insulin secretion in IUGR with the aim of eventually developing interventions to reverse these adaptations and allow for treatment of IUGR and prevention of type 2 diabetes. New evidence is emerging which shows the importance of p-cellto endothelial cell signalingfor maintenance of the normal p-cell populationand insulin secretion. Therefore, this proposal will specifically examine decreased p-cell to endothelial cellsignaling as the cause of decresaed p-cell mass and insulinsecretion in a fetal sheep model of placental insufficincy and IUGR. We will use in vitro assays to measure acute p-cell and insulin stimulated endothelial cell function and show that the response of IUGR pancreatic islet endothelialcells is decreased. We will then demonstrate the consequences of decreased pancreatic islet endothelialcell function by measuringpancreatic isletvascularity and angiogenesis in IUGR fetuses. Finally, we will determine if chronicallyincreasing insulin concentrations in the IUGR fetus can improve pancreatic islet vascularity,angiogenesis, and P-cell mass. RELEVANCE (See instructions): This research is relevant to public health as it will demonstrate the mechanisms responsible for decreased fetal p-cell mass and insulin secretion in intrauterine growth restriction (IUGR). This will allow the development of prenatal therapies designed to improve fetal growth in IUGR and decrease the risk of these individuals developing type 2 diabetes mellitus as adults.