Novel Regulators of Glucose Homeostasis in Aging

衰老过程中血糖稳态的新型调节剂

基本信息

批准号：
8817892
负责人：
Radhika Hiren Muzumdar
金额：
$ 30.26万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8817892
关键词：
Acute Affect Age Aged, 80 and over Aging Alzheimer&apos 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 receptor response

项目摘要

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.

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。使用最先进的技术，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）的能力减弱和/或部分地通过中枢机制促进外周组织中葡萄糖的处理，以及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。