Keeping fat out of muscle - Role of Branched Amino AcidsAmino Acids in Insulin Resistance

SUMMARY Type 2 Diabetes and its precursor insulin resistance (IR) continue to rise and drive cardiovascular complications worldwide. The mechanisms underlying IR remain incompletely understood. Epidemiological studies have consistently revealed a signature of elevated plasma branched chain amino acids (BCAAs) in patients with diabetes or IR, as well as subjects who will go on to develop IR. Mouse studies in laboratories worldwide have shown that systemic suppression of BCAA catabolism worsens IR, while systemic activation of BCAA catabolism (most often with BT2, a specific inhibitor of BCKDK, which in turn inhibits BCKDH, the rate-limiting step of BCAA catabolism) improves IR. There is thus strong interest in targeting this pathway, and multiple pharmaceutical companies are developing novel BT2-based molecule series. Despite these efforts, how systemic activation of BCAA catabolism improves IR remains surprisingly unknown. In our search for potential mechanisms, we discovered that BT2 promotes vasodilation and lowers blood pressure, and that it does so independently of nitric oxide (NO) production by endothelial cells, suggesting that BT2 acts on smooth muscle cells (SMCs) instead. Substantial literature indicates that insulin-stimulated vasodilation contributes to glucose uptake, although how insulin promotes vasodilation remains incompletely understood. These observations and additional preliminary data have led us to the hypothesis that insulin promotes BCAA catabolism in SMCs, in turn promoting vasodilation and glucose tolerance, thereby explaining the metabolic benefits of systemic activation of BCAA catabolism. We will test this hypothesis with novel genetic murine models; with state-of-the-art vascular physiology assays; with hyperinsulinemic euglycemic clamps; and with human studies to test the impact of this pathway on human vascular tone and reactivity. These highly focused studies will elucidate the role of BCAA catabolism in regulating vascular reactivity and glucose tolerance, including human studies.