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、阿尔茨海默氏病（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，这些因素可能与年龄相关疾病的病因或发病机制有关。护脑素 (HN) 是一种新型线粒体肽，因其在许多组织（尤其是 AD 相关损伤）中的抗凋亡功能而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受到认可。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 的分子操作产生了有效的护脑素类似物（与 IGF-1 系统相互作用），可以重现天然内源性 HN 的作用。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胰岛素抵抗和糖尿病的风险，并且这种效应是通过下丘脑介导的。此外，我们假设对老年啮齿动物施用 HN 将大大改变患糖尿病的风险。利用最先进的技术，我们建议评估 HN 在导致衰老过程中葡萄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（或肝葡萄糖产生）和/或部分通过中枢机制促进外周组织中葡萄糖的处理的能力减弱，b）脂肪尤其是内脏脂肪的增加。 HN 代表了碳水化合物代谢受损、糖尿病和神经变性之间的一种新型分子联系，不仅可以提供机制解释，还可以为影响数百万人的这一常见临床群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，因为胰岛素抵抗导致 AD 的发病机制和进展。护脑素 (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，HN 除了在 AD 中发挥作用外，还可以改善胰岛素的作用。在这里，在本提案中，我们探讨了 HN 在胰岛素抵抗和衰老过程中代谢下降中的作用。