Novel Regulators of Glucose Homeostasis in Aging

描述(申请人提供)：与衰老相关的生物变化是许多与年龄相关的疾病发病率增加的主要风险，包括胰岛素抵抗/2型糖尿病、阿尔茨海默病(AD)、中风和缺血性心脏病。我们研究的重点一直是确定随年龄变化的生物学因素，这些因素可能与年龄相关疾病的病因或发病机制有关。人蛋白(HN)是一种新型的线粒体多肽，在许多组织，特别是AD相关损伤中具有抗细胞凋亡的功能，因此被认为具有细胞保护作用。此外，HN与IGF系统密切相关，IGF系统因其在衰老中的作用而被公认。在我们的初步数据中，我们显示组织和分泌物中的HN水平随着年龄的增长而下降。我们还表明，HN显著改善了年轻大鼠肝脏和骨骼肌的整体胰岛素敏感性。此外，HN的分子操作产生了强大的人蛋白类似物(与IGF-1系统相互作用)，可以复制天然内源性HN的效果。根据我们的初步数据，我们假设HN水平的降低会增加老年啮齿动物患胰岛素抵抗和糖尿病的风险，这种影响是通过下丘脑介导的。此外，我们假设，给老年啮齿动物服用HN将显著改变糖尿病的风险。利用最先进的技术，我们建议评估HN在导致衰老过程中糖代谢受损的整体特征中的作用：a)胰岛素抑制肝脏产生葡萄糖的能力减弱(或肝脏葡萄糖产生)和/或部分通过中枢机制促进外周组织中葡萄糖的处置，以及b)脂肪增加，特别是内脏脂肪增加。HN代表了碳水化合物代谢受损、糖尿病和神经退行性变之间的一种新的分子联系，并可能不仅提供机制上的解释，而且可能在这个影响数百万人的常见临床星座上提供潜在的治疗选择。 公共卫生相关性：随着年龄的增长，2型糖尿病和阿尔茨海默病(AD)等疾病的发病率有所增加。这两种疾病是相互关联的，因为胰岛素抵抗导致了AD的发生和发展。人蛋白(Human in，HN)是一种新型多肽，具有抗AD作用。我们的初步结果表明，HN除了在AD中的作用外，还可以改善胰岛素的作用。在这项研究中，我们将探讨HN在胰岛素抵抗和衰老过程中代谢下降中的作用。

DESCRIPTION (provided by applicant): Biological changes associated with aging are a major risk for increased incidence of many age-related diseases including insulin resistance/type 2 diabetes mellitus, Alzheimer's disease (AD), stroke and ischemic heart disease. The focus of our research has been to identify biological factors that change with age and may be involved in the etiology or pathogenesis of age-related diseases. A novel mitochondrial peptide, Humanin (HN), has been recognized for its cyto-protective role due to its anti-apoptotic function in many tissues, especially AD related insults. In addition, HN is closely linked to the IGF system, which is recognized for its role in aging. In our preliminary data we show that that HN levels in tissues and secretions decrease with age. We also show that HN significantly improves overall insulin sensitivity both at the liver and skeletal muscle in young rats. Furthermore, molecular manipulations of HN create potent humanin analogs (that interact with IGF-1 system) that can reproduce the effects of native endogenous HN. Based on our preliminary data, we hypothesize that the decrease in HN levels increase risk of insulin resistance and diabetes in aging rodents, and this effect is mediated through the hypothalamus. Furthermore, we hypothesize that administration of HN to aging rodents will substantially alter the risk of diabetes. Using state of the art technology, we propose to evaluate the role of HN in the integral features that leads to the impaired glucose metabolism in aging: a) diminished ability of insulin to restrain the production of glucose from the liver (or hepatic glucose production) and/or to promote the disposal of glucose in peripheral tissues, in part by a central mechanism, and b) increase in fat especially visceral fat. HN represents a novel molecular link between impaired carbohydrate metabolism, diabetes and neuro-degeneration, and may provide not only mechanistic explanations but also potential therapeutic options in this common clinical constellation affecting millions of people. PUBLIC HEALTH RELEVANCE: With age, there is an increase in the incidence of disease such as type 2 diabetes and Alzheimer's disease (AD). These two diseases are linked to each other in that insulin resistance contributes to the pathogenesis and progression of AD. Humanin (HN) is a novel peptide that has been shown to protect against AD. Our preliminary results suggest that HN, in addition to its role in AD also improves insulin action. Here, in this proposal we explore the role of HN in insulin resistance and metabolic decline in aging.