ETIOLOGY OF GLUCOSE INTOLERANCE OF AGING

增龄的特点是出现葡萄糖耐量异常， 导致死亡率增加，即使在没有明显糖尿病的情况下。 随着年龄的增长，空腹血糖稳步上升，持续 血糖环境的升高可能有助于糖化蛋白的形成 与年龄相关的并发症有关，如动脉粥样硬化。这个 这笔SERCA赠款的主要目标是确定以下因素 有助于老年性代谢功能障碍的发展，并 了解细胞和组织特定的过程涉及 糖耐量减退。葡萄糖耐量不仅取决于 胰岛素分泌和敏感性，但也与葡萄糖本身的作用有关， 不依赖于胰岛素(“葡萄糖有效性”)，以促进葡萄糖 通过刺激葡萄糖在组织中的运输和吸收来实现正常化 并通过抑制内生生产。我们建议对葡萄糖进行量化 在年轻和老年大鼠身上的有效性，并确定哪些组织是 单独负责高血糖时的葡萄糖摄取，动态 胰岛素反应被抑制。给定的年龄相关的身体变化 成分，我们将研究饮食和肥胖对血糖的影响 并确定胰岛素非依赖性组织部位的有效性 葡萄糖处置会随着瘦体重的变化而改变。我们将研究 卡路里限制是否可以提高血糖的有效性和延缓 发生葡萄糖耐量异常，因为它有能力延长寿命 在啮齿动物身上。我们还将探索葡萄糖在多大程度上能够 使自身浓度正常化是由于刺激了葡萄糖的运输 和细胞摄取与抑制内源性生产的对比，并将 检查相对贡献是否受年龄的影响。最后， 我们将研究葡萄糖自身刺激的程度 不依赖于胰岛素的转运是由胰岛素敏感的葡萄糖介导的 转运蛋白亚型(例如GLUT-4)与相对 对胰岛素刺激不敏感(如GLUT-1、GLUT-2)。葡萄糖 有效性也将在II型糖尿病的动物模型中进行量化， 鉴于有报道称Glut-2蛋白在糖尿病中存在缺陷。这位候选人 广泛研究了非疾病衰老的生物学研究，并 近年来致力于糖耐量的研究。她现在 寻求将这两个领域结合起来，在本次SERCA的支持下，探索 年龄相关性糖耐量异常的病因学。她在南加州大学的环境 提供她的赞助商提供的代谢研究的力量(Dr。 Richard Bergman)和在老年学方面的大力支持和资源， Andrus老年学中心和Caleb Finch博士。因此，这位候选人 处于一个很好的位置来探索葡萄糖 不耐受随着年龄的增长而发展，希望年龄的发病机制- 相关的代谢并发症可能会被避免。

Advancing age is characterized by the development of glucose intolerance, leading to increased mortality rates even in the absence of overt diabetes. Along with steady increments in fasting glycemia with age, prolonged elevation in glycemic environment may aid formation of glycated proteins implicated in age-associated complications such as atherosclerosis. The primary objective of this SERCA grant is to identify the factors which contribute to the development of metabolic dysfunction of aging, and to understand the cellular and tissue-specific processes involved in the glucose intolerance of aging. Glucose tolerance is not only determined by insulin secretion and sensitivity, but also by actions of glucose per se, independent of insulin ("glucose effectiveness"), to promote glucose normalization by stimulating transport and uptake of glucose into tissues and by suppressing endogenous production. We propose to quantify glucose effectiveness in young and old rats, and to determine which tissues are responsible for glucose uptake during hyperglycemia alone, with dynamic insulin response suppressed. Given age-associated changes in body composition, we will examine the effect of diet and obesity on glucose effectiveness and determine whether tissue sites of insulin-independent glucose disposal shift with changes in lean body mass. We will examine whether caloric restriction may improve glucose effectiveness and slow development of glucose intolerance, given its ability to extend life span in rodents. We will also explore the extent to which glucose's ability to normalize its own concentration is due to stimulation of glucose transport and cellular uptake versus suppression of endogenous production, and will examine whether the relative contributions are influenced by age. Finally, we will examine the extent to which glucose's stimulation of its own transport, independent of insulin, is mediated by insulin-sensitive glucose transporter isoforms (e.g. GLUT-4) verses transporters which are relatively insensitive to insulin stimulation (e.g. GLUT-1, GLUT-2). Glucose effectiveness will also be quantified in animal models of Type II diabetes, given reports that GLUT-2 protein is defective in diabetes. This candidate has extensively studied the study of biology of non-diseased aging, and has devoted recent years to the investigation of glucose tolerance. She now seeks to combine these two areas, with support of this SERCA, to explore the etiology of age-related glucose intolerance. Her environment at USC provides the strength of metabolic research offered by her sponsor (Dr. Richard Bergman) and strong support and resources in gerontology, in the Andrus Gerontology Center and Dr. Caleb Finch. This candidate is therefore in an excellent position to explore the mechanisms by which glucose intolerance develops with advancing age, in hopes that pathogenesis of age- associated metabolic complications may be averted.