In vivo effects of physical exercise on human islet structure and function

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Project Summary/Abstract Physical inactivity is a primary cause of many chronic diseases. Chronic 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 impacting pancreatic islets. Indirectly, exercise improves peripheral glucose uptake and insulin sensitivity, reducing the metabolic load on human and rodent beta cells. Evidence from rodent studies appreciate that exercise directly improves beta cell 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, serum of acute and chronic exercised human subjects protects beta cells from cytokine-mediated death. In humans, exercise improves beta cell function despite greater insulin sensitivity. 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. The long-term goal of my research is to understand how physical exercise impacts human pancreatic islet structure and function in the living organism. I hypothesize that regular physical exercise preserves human islet function by activating transcriptional pathways involved in cell proliferation and survival and by promoting islet vascular function. This hypothesis will be tested in two specific aims. Specific Aim 1 is to determine the impact of physical exercise on human islet biology and Specific Aim 2 will establish physical exercise as an adjuvant therapy for islet transplantation. I will use the human islet transplantation into the mouse eye model which offers a technological solution to overcome major roadblocks that prevent identifying the direct effects of exercise on human islet biology. A great advantage is that I can monitor longitudinally human islet structure and vasculature as well as assess islet and vascular functions. I will compare exercise- and sedentary-treated recipients transplanted with the same human islet preparation, thus circumventing the variability associated with human islet preparations from different donors. Human islet transcriptome and function will be assessed after exercise for the first time. At their successful completion, my studies will serve as the basis of exercise prescription for preservation of islet function and mass as well as an adjuvant therapy to human islet transplantation.