Exercise, Exosomes, and Metabolic Health in Type-2 Diabetes

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PROJECT SUMMARY/ABSTRACT Native Hawaiians and other Pacific Islanders (NHOPI) are disproportionately affected by type 2 diabetes (T2DM), with a two-fold higher prevalence than Whites in Hawaii. T2DM is characterized by hyperglycemia due to defective insulin action in metabolic tissues, including liver, skeletal muscle, and adipose tissue. Exercise is an effective intervention to improve glycemic control and reduce the risk of developing T2DM, yet even this risk reduction is lower in NHOPI than Whites. One important component of addressing the health disparities of T2DM is to better understand the molecular mechanisms by which exercise increases insulin sensitivity. Almost all cells release a class of nano-sized extracellular vesicles, called exosomes, which circulate widely throughout the body. These exosomes carry cellular proteins, RNAs, and lipids from their cell of origin and signal recipient cells through the release of their cargo. Recent evidence suggests that many exercise-induced signaling molecules released from skeletal muscle (SkM) are transported in exosomes, and acute exercise increases the number of these circulating exosomes. In pre-clinical studies, sedentary mice injected with exosomes isolated from the SkM of exercise-trained mice show improved glucose tolerance and insulin sensitivity. However, there are no reported studies on how exercise stimulates SkM exosome release or affects their cargo contents, and it is poorly understood how exercise-induced SkM exosomes increase insulin sensitivity. The objective of the proposed project is to elucidate the mechanism by which exercise-induced SkM exosomes modulate insulin sensitivity and glucose metabolism of major metabolic tissues. Our preliminary studies have identified the exocyst protein complex as a potential link between SkM metabolism and exosome production. We have found that exocyst activity in SkM cells is highly responsive to insulin and contraction signaling, and in other tissues, the exocyst regulates exosome production. Our central hypothesis is that exercise stimulates the exocyst-dependent release of exosomes in SkM, which deliver muscle-derived factors increasing insulin sensitivity in major metabolic tissues. To test this hypothesis, we propose the following Aims: (1) Determine how exercise stimulates exosome release in SkM cells; (2) Identify the molecular cargo and recipient tissues of exercise-induced SkM exosomes; (3) Determine the signaling mechanism by which SkM-derived exosomes increase post-exercise insulin sensitivity in models of insulin resistance. This project brings together state-of-the-art in vitro and in vivo approaches for the first comprehensive molecular study of SkM-derived exosomes and how they regulate insulin sensitivity and glucose metabolism of major metabolic tissues. These investigations lay the pre-clinical foundation for therapeutic approaches with SkM exosomes, and may lead to the development of improved exercise intervention guidelines, which will benefit NHOPI and others disproportionately afflicted by T2DM.