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：
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
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/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

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. 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，影响着大约 7% 的美国人口。胰岛 2 细胞功能进行性下降（表现为胰岛素释放减少）是 2 型糖尿病的根本原因，但其原因尚不清楚。除了分泌胰岛素的 2 细胞外，胰岛还含有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，内皮功能障碍会影响多个组织，并成为肾脏和眼睛等器官微血管并发症发生的基础。在本提案中，我们将检验糖尿病高血糖引起的胰岛内皮功能障碍导致胰岛素释放受损的假设。我们在初步数据中证明，在没有高血糖的情况下，内皮功能障碍足以导致缺乏内皮一氧化氮合酶（eNOS）的转基因小鼠胰岛素释放受损并出现内皮功能障碍。此外，我们还发现，早在高血糖发生后一周左右，糖尿病 db/db 小鼠的胰岛中就存在内皮功能障碍的标志物（eNOS 水平降低和内皮细胞氧化/硝化应激增加）。这些数据支持我们的假设，并促使我们提出以下具体目标：具体目标 1. 确定内皮功能障碍是否足以损害胰岛素释放。出现内皮功能障碍的 eNOS-/- 小鼠和未出现内皮功能障碍的 C57BL/6J 对照小鼠将接受长达 12 周的研究。我们将确定体内和体外的胰岛素分泌，并将确定胰岛素释放受损的发展时间过程。具体目标 2. 确定糖尿病引起的胰岛内皮功能障碍的时间进程以及高血糖在其发展中的作用。我们将首先通过研究糖尿病发病前、糖尿病约 1 周后和糖尿病 8 周后的 db/db 小鼠来确定胰岛内皮功能障碍发展的时间过程。然后，我们将通过根皮苷治疗来预防高血糖的发生，以确定这是否可以预防胰岛内皮功能障碍。具体目标 3. 确定预防内皮功能障碍是否可以改善 db/db 糖尿病小鼠的胰岛素释放。我们将通过将 db/+ 小鼠与过度表达 eNOS 的转基因小鼠交配来预防 db/db 小鼠发生内皮功能障碍。然后我们将确定体内胰岛素的释放。公共卫生相关性：2 型糖尿病是一种毁灭性的疾病，影响着 7% 的美国人口，而且其患病率正在迅速增加。 2 型糖尿病的发生需要减少胰岛释放的胰岛素激素。该提案的重点是新的假设，即糖尿病患者的胰岛发生内皮功能障碍，并导致胰岛素释放减少。