Beta Cell Adaptation in HF Diet-Induced Obesity

高频饮食引起的肥胖中的β细胞适应

• 批准号: 7089241
• 负责人: DAVID A. D'ALESSIO
• 金额: $ 19.78万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7089241
• 关键词: diabetes risk; dietary lipid; fatty acid metabolism; glucose metabolism; glucose tolerance; histology; insulin; insulin sensitivity /resistance; laboratory rat; morphometry; noninsulin dependent diabetes mellitus; nutrition related tag; obesity; pancreatic islet function; saturated fatty acids; tissue /cell culture; triglycerides; unsaturated fatty acids

Type 2 diabetes mellitus constitutes an enormous health burden in the United States, and despite the increasing prevalence of this disease there are still major gaps in understanding the underlying causes. Increasing evidence indicates that type 2 diabetes ensues when beta-cell secretion is insufficient for insulin needs, and that the development of insulin resistance accelerates this process. Obesity is a common cause of insulin resistance and this connection is mediated in part by increased levels of fatty acids in the circulation of overweight individuals. Recent studies of cultured cells suggest that elevations of fatty acids may also be detrimental to insulin secretion and islet growth. Moreover, these studies suggest a differential effect among fatty acids, with saturated but not monounsaturated fatty acids leading to beta-cell damage. These interesting findings have not been confirmed in vivo. Thus, high circulating levels of fatty acids could contribute to the increased demand for, and decreased supply of, insulin that are the core problems leading to diabetes. In the first cycle of this program project we demonstrated that ad libitum intake of a diet containing 20% of calories as butter fat- a high saturated fat diet- caused rats to get obese, insulin resistant, and hyperinsulinemic. They also developed glucose intolerance indicating that their beta-cell response was inadequate to compensate for their increased insulin requirements. The overall goal of this application is to determine whether increased fat content in the diet leads to beta-cell dysfunction and whether the specific types of fatty acids consumed are important in this process. The central hypothesis guiding this application is that the intake of high amounts of saturated fat in the diet impairs islet function and the ability to compensate for insulin resistance. We will test this hypothesis by completing three specific aims: i) To determine the effects of short- and long-term exposure to diets high in saturated or monounsaturated fatty acids on glucose metabolism; 2) To determine the effects of dietary saturated fatty acids on beta-cell adaptation to increased demand; 3) To determine the effects of varying ambient concentrations of mono- and saturated-fatty acids on islet/p-cell function and lipid content. Completion of this project will extend a body of compelling in vitro work to intact animals and provide important new information regarding the effect of diet on beta-cell function and glucose tolerance. These translational studies are highly relevant to human disease and could form the basis for clinical studies aimed at modifying diabetes risk.

2型糖尿病在美国构成了巨大的健康负担，尽管 这种疾病的患病率的增加，了解基本原因仍然存在重大差距。 越来越多的证据表明，当β细胞分泌不足以胰岛素时，会发生2型糖尿病 需要，胰岛素抵抗的发展加速了这一过程。肥胖是 胰岛素抵抗和这种连接部分是通过循环中脂肪酸水平升高来介导的 超重的人。最近对培养细胞的研究表明，脂肪酸的升高也可能是 不利于胰岛素分泌和胰岛生长。此外，这些研究表明 脂肪酸，带有饱和但不饱和的脂肪酸，导致β细胞损伤。这些很有趣 研究结果尚未在体内确认。因此，高循环水平的脂肪酸可能有助于 对导致糖尿病的核心问题的需求增加和减少胰岛素的供应。在 该计划项目的第一个周期我们证明了饮食中含有20％的饮食的摄入量 卡路里是黄油脂肪 - 高饱和脂肪饮食 - 导致大鼠肥胖，胰岛素耐药性和 高胰岛素。他们还产生了葡萄糖不耐症，表明他们的β细胞反应是 不足以补偿其增加的胰岛素要求。该应用程序的总体目标是 确定饮食中增加的脂肪含量是否会导致β细胞功能障碍以及特定类型是否会导致 在此过程中，消耗的脂肪酸很重要。指导此应用的中心假设是 饮食中大量饱和脂肪的摄入量会损害胰岛功能和补偿能力 胰岛素抵抗。我们将通过完成三个具体目标来检验这一假设：i）确定效果 短期和长期暴露于葡萄糖上饱和或单不饱和脂肪酸高的饮食 代谢; 2）确定饮食饱和脂肪酸对β细胞适应增加的影响 要求; 3）确定不同环境浓度的单酸和饱和脂肪酸的影响 在胰岛/P细胞功能和脂质含量上。该项目的完成将延长体外引人入胜的体系 致力于完整动物，并提供有关饮食对β细胞功能影响的重要新信息 和葡萄糖耐受性。这些转化研究与人类疾病高度相关，可以形成 旨在改变糖尿病风险的临床研究的基础。