Investigating Branched Chain Amino Acid Oxidation in Skeletal Muscle and its Contribution to Insulin Resistance

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Project Summary Branched chain amino acids (BCAAs) are essential amino acids, and their catabolism is controlled by the rate- limiting BCAA dehydrogenase complex (BCKDH) and its inhibitory kinase BCKDK. Elevated plasma levels of BCAAs have been associated with type 2 diabetes since the 1960s. Recent studies have suggested that elevated BCAAs contribute to insulin resistance and the development of type 2 diabetes. However, the mechanisms through which BCAAs drive insulin resistance remain unknown. We have previously shown through steady-state in vivo heavy isotopic tracing that the db/db mouse model of insulin resistance and type 2 diabetes has increased BCAA oxidation in skeletal muscle and decreased oxidation in liver and adipose tissue. High BCAA oxidation in skeletal muscle may lead to insulin resistance by a few potential mechanisms including the promotion of fat uptake into muscle cells, as well as the inhibition of fat catabolism. Both of these mechanisms would be predicted to cause an accumulation of lipids in skeletal muscle, leading to insulin resistance. Based on these observations, I hypothesize that elevated BCAA oxidation in skeletal muscle promotes the development of insulin resistance. To test this hypothesis, we have developed skeletal muscle- specific BCKDH gain-of-function and loss-of-function mouse models. I will use a variety of techniques including steady-state in vivo infusions of 13C-labeled nutrients and hyperinsulinemic-euglycemic clamps to determine if increased BCAA oxidation in muscle suppresses fat oxidation and promotes systemic insulin resistance. With these techniques and mouse models at my disposal, I will delineate specific mechanisms by which BCAAs contribute to the development of insulin resistance and type 2 diabetes, which could lead to better, more targeted treatment of patients with this disease.