Novel Regulators of Glucose Homeostasis in Aging

描述（由申请人提供）：与衰老相关的生物学变化是许多年龄相关疾病发生率增加的主要风险，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。我们研究的重点是确定随年龄变化的生物因素，并可能参与年龄相关疾病的病因或发病机制。Humanin（HN）是一种新型的线粒体肽，由于其在许多组织中具有抗凋亡作用，尤其是在AD相关损伤中具有细胞保护作用。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认可。在我们的初步数据中，我们表明组织和分泌物中的HN水平随着年龄的增长而下降。我们还表明，HN显着提高整体胰岛素敏感性在肝脏和骨骼肌在年轻的大鼠。此外，HN的分子操作产生了有效的humanin类似物（与IGF-1系统相互作用），可以重现天然内源性HN的作用。基于我们的初步数据，我们假设HN水平的降低会增加老年啮齿动物胰岛素抵抗和糖尿病的风险，这种作用是通过下丘脑介导的。此外，我们假设，给老年啮齿动物施用HN将大大改变糖尿病的风险。使用现有技术，我们建议评估HN在导致衰老中葡萄糖代谢受损的整体特征中的作用：a）胰岛素抑制肝脏葡萄糖产生（或肝脏葡萄糖产生）和/或促进外周组织中葡萄糖处置的能力降低，部分通过中枢机制，和B）脂肪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，不仅可以提供机制解释，还可以在影响数百万人的这种常见临床星座中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）等疾病的发病率会增加。这两种疾病相互关联，因为胰岛素抵抗有助于AD的发病机制和进展。Humanin（HN）是一种新的抗AD多肽。我们的初步结果表明，HN，除了其在AD中的作用，也提高胰岛素的作用。在这里，在这个提议中，我们探讨了HN在胰岛素抵抗和衰老代谢下降中的作用。

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.