Glucose Regulation of Pancreatic Islet Gene Experession

胰岛基因表达的葡萄糖调节

基本信息

批准号：
8006994
负责人：
Roderick PAUL ROBERTSON
金额：
$ 8.21万
依托单位：
PACIFIC NORTHWEST RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-12-31 至 2010-11-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Many lines of evidence suggest that chronic exposure to hyperglycemia contributes importantly to the relentless decline in pancreatic islet ¿-cell function characteristic of type 2 diabetes. The mechanisms of this phenomenon, termed glucose toxicity of the ¿-cell, has been shown by us and by others in laboratory models of type 2 diabetes (animals, isolated islets, b-cell lines) to involve decreased levels of two proteins, PDX-1 and MafA, which are critical regulators of insulin promoter activity and thereby insulin gene expression. Our new studies are organized into 3 specific aims: Specific Aim #1. To determine whether beta cell-specific overexpression of glutathione peroxidase (GPx-1) will protect against worsening of insulin secretion and glucose tolerance characteristically observed in streptozotocin-induced hyperglycemia in C57BLKS mice, in high fat diet- induced hyperglycemia in C57BU6 mice, and spontaneously in db/db and NOD mice. Specific Aim #2. To determine whether islets isolated from pancreases of the transgenic mice studied in vivo in Specific Aim #1 are protected against abnormalities that are characteristically found with chronic exposure to hyperglycemia. These include (1) decreased expression of the insulin and PDX-1 genes and MafA protein; (2) decrements in insulin content and insulin secretion; and (3) increased apoptosis and decreased beta cell mass. Specific Aim #3. To determine whether stable reconstitution of MafA, PDX-1, or both in combination are sufficient to restore normal levels of endogenous insulin gene expression in glucotoxic beta cells. Experiments will involve physiologic studies in vivo and molecular biologic studies with isolated islets in vitro, as well as studies using retroviral overexpression of MafA and PDX-1. At the conclusion of these experiments we will ascertain whether enhancing endogenous antioxidant enzyme activity specifically in ¿- cells of db/db and NOD mice will provide protective effects against the beta cell dysfunction and death that are characteristic of these animal models of spontaneous diabetes. We also will determine to what degree MafA, PDX-1, or both in combination play mechanistic roles in defective insulin gene expression in glucotoxic beta cells. Lay language: After onset of type 2 diabetes, high glucose levels over many years cause continuing damage to the cells that make insulin. This is thought to be due to oxidative stress because high glucose levels increase oxygen radical levels in these cells. At the time of onset of type 1 diabetes, cytokines, which cause oxidative stress, cause beta cell death. We will study whether increasing antioxidant protection protects these cells and prevents deterioration of glucose control in diabetes.

描述（通过应用程序提供）：许多证据表明，长期暴露于高血糖的持续暴露对2型糖尿病的胰岛功能特征不断下降至关重要。 The mechanisms of this phenomenon, termed glucose toxicity of the ¿ -cell, has been shown by us and by others in laboratory models of type 2 diabetes (animals, isolated islets, b-cell lines) to involve improved levels of two proteins, PDX-1 and MafA, which are critical regulators of insulin promoter activity and thereby insulin gene expression.我们的新研究分为3个特定目标：特定目标＃1。为了确定谷胱甘肽过氧化物酶（GPX-1）的β细胞特异性过表达是否会保护特定的目标＃2。为了确定从特定目标1中研究的转基因小鼠的胰腺中分离出的胰岛是否受到保护，免受特征性的异常，这些异常是在长期暴露于高血糖的情况下发现的。这些包括（1）胰岛素和PDX-1基因和MAFA蛋白的表达降低；（2）减少胰岛素含量和胰岛素分泌；（3）凋亡增加并减少β细胞量。特定目标＃3。为了确定MAFA，PDX-1的稳定重构是否足以恢复葡萄毒性β细胞中内源性胰岛素基因表达的正常水平。实验将涉及体内和分子生物学研究的生理研究，并在体外进行了分离的胰岛，以及使用MAFA和PDX-1的逆转录病毒过表达的研究。在这些实验的结论中，我们将确定在DB/DB和NOD小鼠中专门提高内源性抗氧化酶活性是否会提供对β细胞功能障碍和死亡的受保护作用，这些作用是这些海报糖尿病动物模型的特征。我们还将确定MAFA，PDX-1的程度，或在组合发挥机械作用中在有缺陷的胰岛素基因表达中在糖毒性β细胞中的作用。外行语言：2型糖尿病发作后，多年来高葡萄糖水平造成胰岛素持续损害。人们认为这是由于氧化应激所致，因为高葡萄糖水平会增加这些细胞中的氧气自由基水平。在1型糖尿病发作时，会导致氧化应激的细胞因子会导致β细胞死亡。我们将研究增加抗氧化剂保护是否可以保护这些细胞并防止糖尿病中的葡萄糖控制恶化。