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

在发达国家，宫内生长受限(IUGR)影响到4%-8%的妊娠；最常见的 病因是胎盘功能不全和胎儿营养供应减少。为了生存，胎儿适应了 促进最有效地利用有限的能源的方法。胰腺(3-细胞在这方面是关键 适应。P细胞以一种营养调节的方式分泌胰岛素，刺激胎儿生长。因此， 胰腺(3-细胞)是将生长速度与营养供应相匹配的最重要的胎儿细胞类型之一。 关于重度胎儿宫内发育迟缓患者胰岛素分泌减少的最好证据是 实验证据表明，这些适应是无法克服的。 仅仅通过为生长受限的胎儿提供更多的营养就可以了。因此，治疗宫内发育迟缓的希望 要提高胎儿生长速度，必须结合增加胎儿营养和p-细胞胰岛素的策略。 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，他们可能会导致以前生长受限的2型糖尿病的高风险 成年人。这个项目的长期目标是确定限制胎儿p细胞的负责机制。 IUGR的人口和胰岛素分泌，目的是最终开发干预措施来逆转这些 适应并允许治疗宫内发育迟缓和预防2型糖尿病。新的证据正在浮现， 显示p-细胞对内皮细胞信号的重要性，以维持正常p-细胞数量和 胰岛素分泌。因此，这项建议将专门研究减少的p细胞到内皮细胞的信号。 作为胎盘不足胎羊模型中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和 提示IUGR胰岛内皮细胞反应性降低。然后，我们将演示 测量胰岛血管对胰岛内皮细胞功能降低的影响 以及IUGR胎儿的血管生成。最后，我们将确定慢性升高的胰岛素浓度是否 IUGR胎儿可以改善胰岛血管、血管生成和P细胞质量。 相关性(请参阅说明)： 这项研究与公共卫生有关，因为它将证明导致减少的机制 宫内生长受限(IUGR)胎儿P细胞质量与胰岛素分泌的关系这将允许 旨在改善IUGR胎儿生长并降低其风险的产前治疗的发展 成年后罹患2型糖尿病的个人。

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.