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Molecular Regulation of Muscle Glucose Metabolism in Man

Sponsored by National Institute of Diabetes and Digestive and Kidney Diseases

$3.4M Funding
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Twenty-five years ago we showed that skeletal muscle in type 2 diabetes preferentially oxidizes carbohydrateover fat and exhibits what we termed metabolic inflexibility. This results in accumulation of fat in insulinsensitive tissues and leads to insulin resistance. Genetic activation of the pyruvate oxidation pathway throughdeletion of pyruvate dehydrogenase (PDH) kinase showed that an increase in glucose oxidation is sufficient toinduce insulin resistance by this mechanism. Although many studies have described how the consequences oflipid accumulation lead to insulin resistance little is known of the mechanisms causing metabolic inflexibility tobegin with. In the past project period we developed evidence for two potential mechanisms. The first of thesederives from our findings that acetylation on lysine 23 of the mitochondrial solute carrier adenine nucleotidetranslocase 1 (ANT1) lowers the affinity of the protein for ADP. This is associated with a higher KmADP forrespiration and ATP synthesis. Modeling predicts this leads to higher free ADP and AMP concentrations.Higher [ADP]f would enhance glycolytic rates raise [pyruvate] and activate PDH via inactivation of PDHkinase leading to higher rates of glucose oxidation. Second we used a proteomics screen of livers of high fatfed mice and discovered an uncharacterized mitochondrial protein KIAA0564 (VWA8) that dampens fatoxidation is elevated in skeletal muscle of type 2 diabetic or morbidly obese patients undergoing bariatricsurgery and has genetic variants that are associated with obesity diabetes and abnormal plasma lipid levels.Given this we believe it is timely to return to the question of what mechanisms drive elevated carbohydrateoxidation and metabolic inflexibility in muscle of patients with type 2 diabetes and morbid obesity. The overallgoal of this proposal is to determine how acetylation of ANT1 at lysine 23 and expression of the novelmitochondrial protein VWA8 influence fuel selection in patients with Type 2 diabetes mellitus. Wepropose 1. To determine the mechanisms responsible for metabolic inflexibility in skeletal muscle ofpatients with type 2 diabetes mellitus 2. To determine the mechanisms responsible for impaired controlof respiration and higher resting carbohydrate oxidation in skeletal muscle of patients with type 2diabetes mellitus and 3. To further characterize the mechanisms by which VWA8 regulates fuel selection.!