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：
8680230
负责人：
REBECCA LUCY HULL-MEICHLE
金额：
$ 29.22万
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 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8680230
关键词：
3-nitrotyrosine Address Affect Age Blood Blood Circulation Blood capillaries Breeding Cell physiology Cells Characteristics Complex Crossbreeding Data Development Diabetes Mellitus Diabetic mouse Disease Endothelial Cells Etiology Eye Fibrosis Glucose Hormones Hyperglycemia In Situ In Vitro Insulin Islet Cell Islets of Langerhans Kidney Lead Microvascular Dysfunction 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 endothelial dysfunction glucose tolerance human NOS3 protein immunoreactivity improved in vivo insulin secretion intravenous glucose tolerance test islet novel overexpression prevent relating to nervous system vascular contributions

3-nitrotyrosine Address Affect Age Blood Blood Circulation Blood capillaries Breeding Cell physiology Cells Characteristics Complex Crossbreeding Data Development Diabetes Mellitus Diabetic mouse Disease Endothelial Cells Etiology Eye Fibrosis Glucose Hormones Hyperglycemia In Situ In Vitro Insulin Islet Cell Islets of Langerhans Kidney Lead Microvascular Dysfunction 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 endothelial dysfunction glucose tolerance human NOS3 protein immunoreactivity improved in vivo insulin secretion intravenous glucose tolerance test islet novel overexpression prevent relating to nervous system vascular contributions

展开

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.

描述（由申请人提供）：2型糖尿病是一种常见的，使人衰弱的疾病，影响了大约7％的美国人群。胰岛2细胞功能的逐渐下降，表现为胰岛素释放减少，是2型糖尿病的基本原因，但尚不清楚这种降低的原因。除了分泌2细胞的胰岛素外，胰岛还具有广泛的毛细血管网络，可促进胰岛素和其他胰岛激素释放到血液中。在糖尿病中，内皮功能障碍会影响几个组织，并构成器官（例如肾脏和眼睛）微血管并发症的发展。在此提案中，我们将检验以下假设：胰岛中糖尿病高血糖引起的内皮功能障碍有助于胰岛素释放受损。我们在初步数据中证明了内皮功能障碍在没有高血糖的情况下足以引起缺乏内皮氧化物合酶（ENOS）的转基因小鼠的胰岛素释放受损，并产生内皮功能障碍。此外，我们已经表明，内皮功能障碍的标志物（eNOS水平降低和内皮细胞中氧化/硝化应激的增加）在高血糖症发作后一周左右就存在于糖尿病DB/dB小鼠的胰岛中。这些数据支持我们的假设，并使我们提出了以下特定目的：具体目的1。确定内皮功能障碍是否足以损害胰岛素释放。 eNOS - / - 鼠标会出现内皮功能障碍和C57BL/6J控制小鼠的eNOS - 最多可研究12周。我们将在体内和体外确定胰岛素分泌，并确定胰岛素释放受损的时间过程。具体目的2。确定胰岛诱导的内皮功能障碍的时间过程和高血糖在其发育中的作用。我们将首先通过在糖尿病发作之前研究DB/DB小鼠，糖尿病和糖尿病8周后研究胰岛内皮功能障碍的时间过程。然后，我们将防止通过硫素治疗的高血糖发展，以确定这是否可以预防胰岛内皮功能障碍。特定目的3。确定防止内皮功能障碍是否可以改善DB/DB糖尿病小鼠中的胰岛素释放。我们将通过用过表达eNOS的转基因小鼠繁殖DB/+小鼠，以防止DB/DB小鼠中内皮功能障碍的发展。然后，我们将在体内确定胰岛素释放。