Novel Regulators of Glucose Homeostasis in Aging

衰老过程中血糖稳态的新型调节剂

• 批准号: 8277249
• 负责人: Radhika Hiren Muzumdar
• 金额: $ 32.51万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8277249
• 关键词: Acute; Affect; Age; Aged, 80 and over; Aging; Alzheimer' s Disease; Apoptosis; Apoptotic; Attenuated; Biological; Biological Factors; Blood Glucose; Body Composition; Body fat; Brain; Cardiovascular Diseases; Cells; Chronic; Clinical; Complex; Cytokine Receptors; Data; Dependovirus; Diabetes Mellitus; Disease; Dose; Energy Metabolism; Etiology; Euglycemic Clamping; Fatty acid glycerol esters; Functional disorder; Glucose Clamp; Goals; Hepatic; Homeostasis; Homologous Gene; Human; Hypothalamic structure; Incidence; Infusion procedures; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Lead; Link; Liver; Mammals; Mediating; Mediator of activation protein; Memory Loss; Metabolic; Mitochondria; Modeling; Molecular; Mus; Muscle; Myocardial Ischemia; Neuraxis; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Pathogenesis; Pathology; Patients; Peptides; Peripheral; Physiological; Plasma; Play; Prevalence; Prevention; Rattus; Research; Risk; Rodent; Rodent Model; Role; Scopolamine; Serum; Signal Pathway; Skeletal Muscle; Stroke; System; Techniques; Technology; Testing; Therapeutic; Tissues; Vascular Smooth Muscle; Visceral; age related; analog; base; blood glucose regulation; carbohydrate metabolism; diabetes risk; diabetic; glucose disposal; glucose metabolism; glucose production; humanin; improved; insulin sensitivity; insulin sensitizing drugs; neuron loss; neurotoxicity; novel; overexpression; public health relevance; receptor; response

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.

描述（由申请人提供）：与衰老相关的生物学变化是许多与年龄相关疾病的发病率增加，包括胰岛素抵抗/2型糖尿病，阿尔茨海默氏病（AD），中风和缺血性心脏病。我们研究的重点是确定随着年龄的变化而变化的生物学因素，并可能参与与年龄相关疾病的病因或发病机理。一种新型的线粒体肽Humanin（HN）因其在许多组织中的抗凋亡功能（尤其是与AD相关的损伤）中的抗凋亡功能而被认可。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降低。我们还表明，HN显着提高了肝脏和幼虫的骨骼肌的总体胰岛素敏感性。此外，HN的分子操作会产生有效的人类类似物（与IGF-1系统相互作用），从而可以再现天然内源性HN的作用。根据我们的初步数据，我们假设HN水平的降低会增加衰老啮齿动物中胰岛素抵抗和糖尿病的风险，并且通过下丘脑介导这种作用。此外，我们假设给予HN对衰老啮齿动物的施用将大大改变糖尿病的风险。我们建议使用最先进的技术来评估HN在衰老中导致葡萄糖代谢受损的积分特征中的作用： HN代表了碳水化合物代谢，糖尿病和神经降级的受损分子联系，并且不仅可以提供机械解释，而且还提供了影响数百万人的常见临床星座中的潜在治疗选择。 公共卫生相关性：随着年龄的增长，诸如2型糖尿病和阿尔茨海默氏病（AD）等疾病的发生率有所增加。这两种疾病彼此相关，因为胰岛素抵抗有助于AD的发病机理和进展。 Humanin（HN）是一种新型肽，已被证明可以预防AD。我们的初步结果表明，除了其在AD中的作用外，HN还改善了胰岛素作用。在这里，在此提案中，我们探讨了HN在胰岛素抵抗和代谢下降中在衰老中的作用。