Islet Endothelial Dysfunction in Diabetes

糖尿病中的胰岛内皮功能障碍

• 批准号: 7855210
• 负责人: REBECCA LUCY HULL-MEICHLE
• 金额: $ 28.94万
• 依托单位: SEATTLE INST FOR BIOMEDICAL/CLINICAL RES
• 依托单位国家: 美国
• 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/7855210
• 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

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. PUBLIC HEALTH RELEVANCE: Type 2 diabetes is a devastating disease that affects 7% of the US population and whose prevalence is rapidly increasing. Decreased release of the hormone insulin from the pancreatic islet is required for the development of type 2 diabetes. The focus of this proposal is the novel hypothesis that endothelial dysfunction occurs in the pancreatic islet in diabetes and contributes to decreased insulin release.

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%的美国人口。胰岛2细胞功能的进行性下降，表现为胰岛素释放减少，是2型糖尿病的根本原因，但这种下降的原因尚不清楚。除了分泌胰岛素的2细胞外，胰岛还包含一个广泛的毛细血管网络，以促进胰岛素和其他胰岛激素释放到血液中。在糖尿病中，内皮功能障碍影响多个组织，是肾脏和眼睛等器官微血管并发症发生的基础。在这一提议中，我们将验证糖尿病高血糖诱导的胰岛内皮功能障碍导致胰岛素释放受损的假设。我们已经在我们的初步数据中证明，在没有高血糖的情况下，内皮功能障碍足以导致缺乏内皮型一氧化氮合酶（eNOS）的转基因小鼠胰岛素释放受损并发生内皮功能障碍。此外，我们已经证明，早在高血糖发作后一周左右，糖尿病db/db小鼠的胰岛中就存在内皮功能障碍标志物（内皮细胞eNOS水平降低和氧化/硝化应激增加）。这些数据支持我们的假设，并使我们提出以下具体目标：确定内皮功能障碍是否足以影响胰岛素释放。发生内皮功能障碍的eNOS-/-小鼠和未发生内皮功能障碍的C57BL/6J对照小鼠将进行长达12周的研究。我们将测定体内和体外的胰岛素分泌，并测定胰岛素释放受损发展的时间进程。具体目标2。目的：探讨糖尿病诱导胰岛内皮功能障碍的时间进程及高血糖在胰岛内皮功能障碍发生中的作用。我们将首先通过研究db/db小鼠在糖尿病发病前、1周后和8周后胰岛内皮功能障碍的发展时间进程。然后，我们将用苯丙素治疗预防高血糖的发展，以确定这是否可以预防胰岛内皮功能障碍。具体目标3。探讨预防内皮功能障碍是否能改善db/db糖尿病小鼠胰岛素释放。我们将通过将db/+小鼠与过表达eNOS的转基因小鼠杂交来预防db/db小鼠内皮功能障碍的发展。然后我们将测定体内胰岛素的释放。