Physical exercise to preserve beta-cell function and mass. - Project Summary/Abstract A sedentary lifestyle is a primary cause of many chronic diseases, including diabetes. Type 1 and 2 diabetes are two life-threatening diseases with individual and socioeconomic burdens. Physical exercise is a prevention tool and a non-pharmacological treatment for metabolic disorders such as obesity, insulin resistance, prediabetes, and diabetes. Exercise has both direct and indirect effects on pancreatic beta cells. Indirectly, exercise improves peripheral glucose uptake and insulin sensitivity, reducing the metabolic load on human and rodent beta cells. Evidence from rodent studies and our preliminary data show that exercise also directly affects beta cells, promoting proliferation, survival, glucose sensing, insulin signaling, and insulin content. In vitro, soluble factors secreted by human and rodent myotubes acutely and directly potentiate beta cell insulin secretion, proliferation, and survival. Importantly, the serum of acutely and chronically exercised human subjects protects beta cells from cytokine-mediated death. However, the precise effects of exercise on human islet structure and function have not been determined in vivo because islets in human subjects are not accessible. Therefore, there is a need to move current in vitro studies addressing the effects of exercise on human islet biology into a more physiological setting. We propose to use high-resolution microscopy, single-cell transcriptional/epigenetic profiling tools, living tissue physiological assessment, and human islet transplantation models to define the impact of physical exercise on beta cell molecular and functional properties. We hypothesize that physical exercise promotes islet function by activating transcriptional pathways involved in cell proliferation and survival, enhancing vascular function and resilience to diet-induced stress, and optimizing islet transplantation. We will test the hypothesis with three aims. Aim 1 will determine how different physical exercise intensities impact mouse beta cell function and structure, Aim 2 will investigate the role of physical exercise on human beta cell function, structure, and resilience to diabetogenic conditions, and Aim 3 will establish physical exercise as an adjuvant therapy for islet transplantation. At their successful completion, our studies will provide mechanistic insights into how exercise impacts mouse and human beta cell structure and function. These results will serve as the basis for exercise prescription to preserve islet function and mass in diabetes.
