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

描述（由申请人提供）：在发达国家，子宫内生长受限（IUGR）影响了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，胎儿会以最有效地利用有限能量供应的方式进行适应。胰腺细胞是这种适应的关键。p细胞分泌胰岛素，以营养调节的方式刺激胎儿生长。因此，胰腺3细胞是最重要的胎儿细胞类型之一，以匹配生长速度和营养供应。关于严重IUGR患者胰岛素分泌减少的机制的最佳证据是胰腺p细胞群的减少。实验证据表明，这些适应不能简单地通过向生长受限的胎儿提供更多的营养来克服。因此，任何治疗IUGR以提高胎儿生长速度的希望都必须结合增加胎儿营养输送和p细胞胰岛素分泌的策略。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到成年，它们可能会导致先前生长受限的成年人患2型糖尿病的风险更高。该项目的长期目标是确定IUGR中限制胎儿p细胞数量和胰岛素分泌的负责机制，目的是最终开发干预措施来逆转这些适应，并允许IUGR的治疗和2型糖尿病的预防。新的证据显示p细胞在内皮细胞信号传导中对维持正常p细胞群和胰岛素分泌的重要性。因此，本研究将在胎盘功能不全和IUGR的胎羊模型中专门研究p细胞到内皮细胞信号传导减少作为p细胞质量和胰岛素分泌减少的原因。我们将使用体外实验来测量急性p细胞和胰岛素刺激的内皮细胞功能，并显示IUGR胰岛内皮细胞的反应降低。然后，我们将通过测量IUGR胎儿胰岛血管和血管生成来证明胰岛内皮细胞功能下降的后果。最后，我们将确定IUGR胎儿长期增加胰岛素浓度是否可以改善胰岛血管，血管生成和p细胞质量。

DESCRIPTION (provided by applicant): 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 matching growth 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. Experimental evidence suggests that these adaptations cannot be overcome simply by providing increased 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-cell insulin secretion. Additionally, if these adaptations which limit the fetal p-cell population and insulin secretion persist into adulthood they can contribute to the higher risk of type 2 diabetes mellitus in previously growth restricted adults. The long-term goal of this project is to determine the responsible mechanisms for limiting the 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-cell to endothelial cell signaling for maintenance of the normal p-cell population and insulin secretion. Therefore, this proposal will specifically examine decreased p-cell to endothelial cell signaling as the cause of decreased p-cell mass and insulin secretion in a fetal sheep model of placental insufficiency 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 endothelial cells is decreased. We will then demonstrate the consequences of decreased pancreatic islet endothelial cell function by measuring pancreatic islet vascularity and angiogenesis in IUGR fetuses. Finally, we will determine if chronically increasing insulin concentrations in the IUGR fetus can improve pancreatic islet vascularity, angiogenesis, and P-cell mass. PUBLIC HEALTH RELEVANCE: 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.