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Islet Endothelial Dysfunction in Diabetes

糖尿病中的胰岛内皮功能障碍

基本信息

批准号：
8469853
负责人：
REBECCA LUCY HULL-MEICHLE
金额：
$ 28.2万
依托单位：
SEATTLE INST FOR BIOMEDICAL/CLINICAL RES
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-20 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8469853
关键词：
3-nitrotyrosine Address Affect Age Blood Blood Circulation Blood Vessels Blood capillaries Breeding Cell physiology Cells Characteristics Complex Crossbreeding Data Development Diabetes Mellitus Diabetic Angiopathies Diabetic mouse Disease Endothelial Cells Etiology Eye Fibrosis Functional disorder Glucose Hormones Hyperglycemia In Situ In Vitro Insulin Islet Cell Islets of Langerhans Kidney Lead Modeling Mus Nitric Oxide Non-Insulin-Dependent Diabetes Mellitus Organ Pancreas Perfusion Phlorhizin Play Population Prevalence Regional Perfusion Rodent Model Role Signal Transduction Stress Testing Time Tissues Transgenic Mice Vasodilator Agents capillary cell type db/db mouse density diabetic endocrine pancreas development glucose tolerance human NOS3 protein immunoreactivity improved in vivo insulin secretion intravenous glucose tolerance test islet novel overexpression prevent public health relevance relating to nervous system

项目摘要

DESCRIPTION (provided by applicant): Type 2 diabetes is a common, debilitating disease affecting approximately 7% of the US population. A progressive decline in pancreatic islet 2-cell function, manifest as decreased insulin release, is a fundamental cause of type 2 diabetes, but the reasons for this decrease are not well understood. In addition to insulin secreting 2-cells, pancreatic islets contain an extensive capillary network to facilitate the release of insulin and other islet hormones into the blood. In diabetes, endothelial dysfunction affects several tissues and underlies the development of microvascular complications in organs such as the kidney and eye. In this proposal we will test the hypothesis that diabetic hyperglycemia-induced endothelial dysfunction in the islet contributes to impaired insulin release. We have demonstrated in our preliminary data that endothelial dysfunction, in the absence of hyperglycemia, is sufficient to cause impaired insulin release in transgenic mice that lack endothelial nitric oxide synthase (eNOS) and develop endothelial dysfunction. Additionally, we have shown that markers of endothelial dysfunction (decreased eNOS levels and increased oxidative/nitrative stress in endothelial cells) is present in islets of diabetic db/db mice as early as around one week after the onset of hyperglycemia. These data support our hypothesis and led us to proposed the following specific aims: Specific Aim 1. To determine whether endothelial dysfunction is sufficient to impair insulin release. eNOS-/- mice that develop endothelial dysfunction and C57BL/6J control mice that do not will be studied for up to 12 weeks. We will determine insulin secretion in vivo and in vitro and will determine the time course of the development of impaired insulin release. Specific Aim 2. To determine the time course of diabetes-induced endothelial dysfunction in the islet and the role of hyperglycemia in its development. We will first determine the time course of development of islet endothelial dysfunction by studying db/db mice prior to the onset of diabetes, after ~1 week of diabetes and after 8 weeks of diabetes. We will then prevent the development of hyperglycemia with phlorizin treatment to determine whether this can prevent islet endothelial dysfunction. Specific Aim 3. To determine whether preventing endothelial dysfunction can improve insulin release in db/db diabetic mice. We will prevent the development of endothelial dysfunction in db/db mice by breeding db/+ mice with transgenic mice that overexpress eNOS. We will then determine insulin release in vivo.