MECHANISMS OF THE GLUCOSE INTOLERANCE OF AGING

即使在没有糖耐量的情况下，糖耐量受损也是衰老的标志 与随之而来的病理有关，并与因 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 胰岛素抵抗，由肥胖、饮食和/或改变引起 久坐不动的生活方式，以及了解糖尿病发病机制的研究 不耐受主要集中在胰岛素的相对贡献上。 抵抗和胰岛功能障碍。我们已经证明了 不依赖于胰岛素的血糖调节机制同样 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”，被定义为葡萄糖对 调节自身利用(RD)和肝脏生产(HGO) 不受胰岛素升高的影响。这项建议的目的是 研究葡萄糖有效性在糖耐量低减中的作用 正常的、非疾病的大鼠衰老。我们将检验这一假设 在胰岛素抵抗状态，如衰老，有效地处置 碳水化合物挑战越来越依赖于新陈代谢 独立于胰岛素作用的因素，即葡萄糖 有效性。这些研究将确定葡萄糖的作用 对正常、非疾病衰老的葡萄糖耐量的有效性。 我们将应用新开发的方法来量化葡萄糖的有效性。 直接在幼年和老年大鼠身上进行研究，并确定衰老如何改变 RD与HGO的相对贡献以及特定的组织部位和 牵涉到葡萄糖转运蛋白。我们将研究通过哪些机制 葡萄糖效应可能对衰老相关的胰岛素起到补偿作用 抵抗。最后，我们建议检查热量的能力 限制通过对葡萄糖的作用来提高耐受性 有效性，并确定组织部位、机制和葡萄糖 可能涉及的运输商。

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.