MECHANISMS OF THE GLUCOSE INTOLERANCE OF AGING

衰老过程中葡萄糖不耐症的机制

• 批准号: 6328636
• 负责人: MARILYN ADER
• 金额: $ 30.44万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-02 至 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6328636
• 关键词: age difference; animal old age; caloric dietary content; gluconeogenesis; glucose clamp technique; glucose metabolism; glucose tolerance; glucose tolerance test; glucose transporter; hyperglycemia; insulin; insulin sensitivity /resistance; juvenile animal; laboratory rat; liver metabolism; nutrition of aging; nutrition related tag; pancreatic islet function; pathologic process; reducing diet

Impaired glucose tolerance is a hallmark of aging even in the absence of attendant pathology, and is associated with increased mortality due to enhanced risk for development of diabetes and cardiovascular disease. Intolerance of aging is typically attributed to the development of insulin resistance, resulting from changes in adiposity, diet, and/or sedentary lifestyle, and studies to understand the pathogenesis of intolerance have focused on the relative contributions of insulin resistance and pancreatic islet dysfunction. We have demonstrated that insulin-independent mechanisms of glucose regulation are equally important in determining glucose tolerance. These processes, termed "glucose effectiveness", are defined as the actions of glucose to regulate its own utilization (Rd) and hepatic production (HGO) independent of elevated insulin. The purpose of this proposal is to examine the role of glucose effectiveness in the glucose intolerance of normal, non-diseased aging in the rat. We will test the hypothesis that in insulin-resistant states such as aging, efficient disposition of a carbohydrate challenge becomes increasingly dependent on metabolic factors which are independent of insulin action, i.e. glucose effectiveness. These studies will establish the role of glucose effectiveness in the glucose intolerance of normal, non-diseased aging. We will apply newly developed methods to quantify glucose effectiveness directly in young and old rats, and determine how aging alters the relative contributions of Rd vs HGO and the specific tissue sites and glucose transporters involved. We will examine the mechanisms by which glucose effectiveness may compensate in aging-associated insulin resistance. Finally, we propose to examine the ability of caloric restriction to improve tolerance through their actions on glucose effectiveness, and determine the tissue sites, mechanisms, and glucose transporters which may be involved.

葡萄糖耐量受损是衰老的标志， 伴随的病理学，并与死亡率增加， 增加患糖尿病和心血管疾病的风险。 对衰老的不耐受通常归因于以下发展： 胰岛素抵抗，由肥胖、饮食和/或 久坐的生活方式，并研究了解发病机制， 胰岛素不耐受主要集中在胰岛素的相对作用上 抵抗和胰岛功能障碍。 我们已经证明 胰岛素非依赖性葡萄糖调节机制同样 在确定葡萄糖耐量方面很重要。 这些过程被称为 “葡萄糖有效性”定义为葡萄糖对 调节自身利用（Rd）和肝脏产生（HGO） 与胰岛素升高无关。 这项建议的目的是 检查葡萄糖有效性在葡萄糖耐受不良中的作用， 在大鼠中正常的、无疾病的衰老。我们将检验这个假设， 在胰岛素抵抗状态如衰老时， 碳水化合物的挑战越来越依赖于代谢 与胰岛素作用无关的因素，即葡萄糖 有效性 这些研究将确定葡萄糖的作用 在葡萄糖耐受不良的正常，非疾病老化的有效性。 我们将应用新开发的方法来量化葡萄糖的有效性 直接在年轻和老年大鼠，并确定如何老化改变 Rd与HGO和特定组织部位的相对贡献， 葡萄糖转运蛋白参与。 我们将研究 葡萄糖的有效性可能会补偿与衰老相关的胰岛素 阻力 最后，我们建议检查热量的能力， 限制通过其对葡萄糖的作用来改善耐受性 有效性，并确定组织部位，机制和葡萄糖 可能涉及的运输商。