ETIOLOGY OF GLUCOSE INTOLERANCE OF AGING

年龄增长的特征是葡萄糖耐受不良的发展， 甚至在没有明显糖尿病的情况下导致死亡率增加。 随着年龄的增长，空腹血糖沿着稳定增加， 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如动脉粥样硬化有关。 的 这项SERCA补助金的主要目标是确定 有助于衰老代谢功能障碍的发展， 了解参与的细胞和组织特异性过程， 葡萄糖不耐症 葡萄糖耐量不仅取决于 胰岛素分泌和敏感性，而且还通过葡萄糖本身的作用， 独立于胰岛素（“葡萄糖有效性”），以促进葡萄糖 通过刺激葡萄糖转运和摄取进入组织实现正常化 和抑制内源性生产。 我们建议量化葡萄糖 有效性在年轻和老年大鼠，并确定哪些组织是 在高血糖期间单独负责葡萄糖摄取， 胰岛素反应受到抑制。 考虑到年龄相关的身体变化 我们将研究饮食和肥胖对葡萄糖的影响， 有效性和确定组织部位是否胰岛素非依赖性 葡萄糖处置随瘦体重的变化而改变。 我们将研究 热量限制是否可以改善葡萄糖的有效性， 葡萄糖耐受不良的发展，鉴于其延长寿命的能力 在啮齿类动物中。 我们还将探讨葡萄糖在多大程度上能够 使其自身浓度正常化是由于刺激葡萄糖转运 和细胞摄取与内源性产生的抑制，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的刺激作用 转运不依赖于胰岛素，由胰岛素敏感葡萄糖介导 转运蛋白同种型（例如GLUT-4）与相对 对胰岛素刺激不敏感（例如GLUT-1、GLUT-2）。 葡萄糖 还将在II型糖尿病的动物模型中量化有效性， GLUT-2蛋白在糖尿病中有缺陷。 这位候选人 广泛研究了非疾病衰老的生物学研究， 近年来致力于葡萄糖耐量的研究。 她现在 寻求联合收割机这两个领域，与支持本SERCA，探索 年龄相关性葡萄糖耐受不良的病因学。 她在南加州大学的环境 提供了她的赞助商提供的代谢研究的力量（博士。 理查德伯格曼）和强大的支持和资源，在老年学， 安德罗斯老年学中心和凯莱布·芬奇医生 因此，这位候选人 能够很好地探索葡萄糖 不耐受随着年龄的增长而发展，希望年龄的发病机制- 可以避免相关的代谢并发症。

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.