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

随着人口老龄化，II型糖尿病(T2 DM)的发病率继续上升，从 年龄在45岁到65岁之间。T2 DM的特点是既有高胰岛素血症，又有高血糖素血症。大多数人 代谢领域的研究主要集中在这种疾病所特有的高胰岛素血症上。 然而，抑制胰高血糖素的作用在治疗T2 DM方面是非常有效的。事实上，二甲双胍是处方最多的 抗糖尿病药物，激活AMP激酶(AMPK)，抑制肝脏胰高血糖素信号转导，限制肝脏葡萄糖 在T2 DM中生产。与代谢领域类似，对T2 DM加速衰老的研究也有 初步检测了高胰岛素血症的作用。降低胰岛素的干预措施和遗传模型 信号可延长小鼠的寿命，改变能量代谢，减少与年龄相关的疾病。尽管 2型糖尿病患者的高血糖及胰升糖素受体信号在瘦肉者长期生存中的重要作用 衰老的小鼠，我们对胰高血糖素在肥胖或减慢的衰老中所起的作用缺乏了解 卡路里限制(CR)引起的衰老。新疗法的广泛使用和发展 抑制胰高血糖素信号转导治疗2型糖尿病需求研究侧重于胰升糖素信号在健康人群中的作用 衰老。我提出了三个目标，集中在全局、肝细胞和脂肪细胞的胰升糖素信号在代谢中的作用。 瘦身、肥胖和卡路里限制小鼠衰老的控制和进展。在这项拨款中提议的研究 将是第一个调查胰高血糖素信号在健康寿命中的作用，评估消除反应的人 脂肪细胞或肝细胞中的胰高血糖素信号，并解决替代反应的可能性 对于肥胖、正常体重和卡路里限制中的胰高血糖素信号抑制。

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.