Metabolomic Signatures of Insulin Resistance in Human Skeletal Muscle Are Exacerbated with Insulin Stimulation

Metabolomic profiling has identified signatures of insulin resistance in skeletal muscle; however, the direct effect of insulin stimulation on these metabolite signatures in humans remains largely unresolved. To address this, we investigated the effect of insulin stimulation on skeletal muscle metabolites in a well characterized cohort of humans spanning the spectrum of insulin sensitivity. Vastus lateralis muscle samples were obtained from endurance athletes, sedentary lean and obese adults, and individuals with type 2 diabetes (n=16,15,15,12, respectively) under basal conditions and 1-hour into a hyperinsulinemic-euglycemic clamp. Metabolomic analysis was performed using UPLC-MS/MS. Basal concentrations of TCA cycle intermediates, including citrate, alpha-ketoglutarate, succinate, fumarate, malate and oxaloacetate, were positively related to insulin sensitivity (steady-state clamp R d glucose in mg/kg/min; all P 2 = 0.453, P 2 = 0.501, P P P Disclosure S.A. Newsom: None. L. Perreault: Advisory Panel; Self; Novo Nordisk A/S. Speaker9s Bureau; Self; Novo Nordisk A/S. Advisory Panel; Self; Merck & Co., Inc.. Speaker9s Bureau; Self; Merck & Co., Inc., AstraZeneca, Janssen Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Advisory Panel; Self; Sanofi. Speaker9s Bureau; Self; Sanofi. A. Kerege: None. K.A. Harrison: None. D.E. Kahn: None. T. Nemkov: None. A. D’Alessandro: None. B. Bergman: Research Support; Self; Eli Lilly and Company. Advisory Panel; Spouse/Partner; Novo Nordisk Inc., Merck & Co., Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company.