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.
More than 25% of the U.S. population greater than 65 years old has Type II diabetes mellitus, representing the highest prevalence of diabetes of any age-group. Most research aimed at understanding the consequences of obesity in aging have focused on insulin and downstream signaling cascades. However, this research has overlooked a potential role for glucagon. Given that many prominent diabetes treatments target glucagon or glucagon signaling pathways, it is essential to understand the role of glucagon in aging. The work proposed in this grant would close a significant gap in our understanding of how glucagon alters aging, while allowing us to assess the potential risks associated with inhibition of glucagon signaling.
