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

随着我们的人口老龄化，II型糖尿病（T2DM）的发病率持续上升，从2010年的2011年几乎翻了一番。 年龄在45到65岁之间T2DM的特征是高胰岛素血症和高胰高血糖素血症。大多数 代谢领域的研究集中在作为这种疾病特征的高胰岛素血症上。 然而，胰高血糖素作用的抑制在治疗T2DM中非常有效。事实上，二甲双胍， 抗糖尿病药物，激活AMP激酶（AMPK）以抑制肝胰高血糖素信号传导并限制肝葡萄糖 生产T2DM。与代谢领域类似，针对T2DM加速老化的研究 主要研究高胰岛素血症的作用。降低胰岛素的干预措施和遗传模型 信号传导增强寿命，改变能量代谢，并减少小鼠的年龄相关疾病。尽管 T2DM的高血糖和胰高血糖素受体信号传导在瘦猪长期存活中的重要作用 在衰老小鼠中，我们缺乏胰高血糖素在加速肥胖衰老或减缓肥胖衰老中的作用的知识。 卡路里限制（CR）导致的衰老。新疗法的广泛使用和发展， 抑制胰高血糖素信号传导以治疗T2DM需求研究集中于胰高血糖素信号传导在健康 衰老我提出了3个目标，重点是全球，肝细胞和脂肪细胞胰高血糖素信号转导在代谢中的作用， 在瘦的、肥胖的和卡路里限制的小鼠中控制和进展衰老。本补助金中提出的研究 将是第一个研究胰高血糖素信号传导在健康中的作用，评估对消除的反应， 胰高血糖素信号在脂肪细胞或肝细胞，并解决替代反应的潜力 在肥胖、正常体重和热量限制中胰高血糖素信号传导抑制。

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.