Investigations to Assess the Role of Glucagon Signaling in Healthspan and Aging

评估胰高血糖素信号在健康寿命和衰老中的作用的研究

• 批准号: 9384942
• 负责人: JENNIFER HELENE STERN
• 金额: $ 10.75万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9384942
• 关键词: Address; Adipocytes; Adipose tissue; Advocate; Age; Aging; Antidiabetic Drugs; Behavioral Assay; Biology of Aging; Caloric Restriction; Characteristics; Closure by clamp; Cognitive; Data; Depressed mood; Development; Diabetes Mellitus; Disease; Doctor of Philosophy; Energy Metabolism; Foundations; Functional disorder; Genetic Models; Glucagon; Glucagon Receptor; Grant; Hepatic; Hepatocyte; High Prevalence; Homeostasis; Hyperglycemia; Hyperinsulinism; Impairment; Incidence; Insulin; Insulin Resistance; Intervention; Investigation; Knowledge; Laboratories; Longevity; Mentors; Metabolic; Metabolic Control; Metabolism; Metformin; Modeling; Monitor; Motor; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Pathway interactions; Phase; Play; Population; Receptor Signaling; Research; Risk; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Thinness; Tissues; Training; Weight; Work; adenylate kinase; age group; age related; blood glucose regulation; glucose output; glucose production; healthy aging; human old age (65+); hyperglucagonemia; improved; insulin signaling; novel therapeutics; response

As our population ages, the incidence of Type II diabetes mellitus (T2DM) continues to rise, nearly doubling from the age of 45 to 65. T2DM is characterized by both hyperinsulinemia and hyperglucagonemia. The majority of research in the metabolic field has focused on the hyperinsulinemia that is characteristic of this disease. However, inhibition of glucagon action is highly effective in treating T2DM. In fact, metformin, the most prescribed anti-diabetic drug, activates AMP Kinase (AMPK) to inhibit hepatic glucagon signaling and limit hepatic glucose production in T2DM. Similar to the metabolic field, research focused on the accelerated aging in T2DM has primarily examined the role of hyperinsulinemia. Interventions and genetic models which decrease insulin signaling enhance lifespan, alter energy metabolism, and decrease age-related diseases in the mouse. Despite the hyperglycemia of T2DM and essential role of glucagon receptor signaling in the long-term survival of the lean aging mouse, we lack knowledge of the role glucagon plays in the accelerated aging of obesity or the slowed aging resulting from calorie restriction (CR). The widespread use and development of new therapeutics that inhibit glucagon signaling to treat T2DM demand studies focused on the role of glucagon signaling in healthy aging. I propose 3 aims focused on the role of global, hepatocyte, and adipocyte glucagon signaling in metabolic control and progression of aging in lean, obese, and calorie restricted mice. The studies proposed in this grant will be the first that investigate the role of glucagon signaling in healthspan, assess the response to elimination of glucagon signaling in either the adipocyte or hepatocyte, and address the potential for alternative responses to glucagon signaling inhibition in obesity, normal weight, and calorie restriction.

随着人口老龄化，II 型糖尿病 (T2DM) 的发病率持续上升，几乎翻倍 45至65岁。T2DM的特征是高胰岛素血症和高胰高血糖素血症。大部分 代谢领域的研究集中在该疾病的特征性高胰岛素血症上。 然而，抑制胰高血糖素作用对于治疗 T2DM 非常有效。事实上，二甲双胍是最常用的药物 抗糖尿病药物，激活 AMP 激酶 (AMPK) 抑制肝胰高血糖素信号传导并限制肝葡萄糖 T2DM 中的生产。与代谢领域类似，针对 T2DM 加速衰老的研究已经 主要检查高胰岛素血症的作用。降低胰岛素水平的干预措施和遗传模型 信号传导可以延长小鼠的寿命，改变能量代谢，并减少与年龄相关的疾病。尽管 T2DM 的高血糖以及胰高血糖素受体信号传导在瘦人长期生存中的重要作用 对于衰老的小鼠，我们缺乏对胰高血糖素在肥胖加速衰老或减慢衰老中的作用的了解。 热量限制（CR）导致的衰老。新疗法的广泛使用和开发 抑制胰高血糖素信号传导治疗 T2DM 需求研究重点关注胰高血糖素信号传导在健康中的作用 老化。我提出了 3 个目标，重点关注整体、肝细胞和脂肪细胞胰高血糖素信号传导在代谢中的作用 瘦、肥胖和热量限制小鼠的衰老控制和进展。本次资助中提出的研究 将是第一个研究胰高血糖素信号传导在健康寿命中的作用，评估对消除的反应 脂肪细胞或肝细胞中的胰高血糖素信号传导，并解决替代反应的可能性 肥胖、正常体重和热量限制中的胰高血糖素信号传导抑制。