Unraveling the Athlete’s Paradox—Higher Insulin Sensitivity and Lower PKC? Activation Despite Higher Bioactive Lipids in Endurance-Trained Athletes

High intramyocellular lipid (IMCL) content associates negatively with insulin sensitivity (IS) in insulin resistant, but not in endurance-trained humans. It has been hypothesized that different cellular distribution of bioactive lipids such as diacylglycerols (DAG) and ceramides (CER) could interfere with insulin action and underlie this “athlete’s paradox.” We examined endurance-trained athletes (ATH; n=9) and sedentary individuals (SED; n=12) with comparable total IMCL, as measured by 1 H-magnetic resonance spectroscopy, who underwent spiroergometry and hyperinsulinemic-euglycemic clamps to assess maximal oxidative capacity and IS, respectively. In skeletal muscle biopsies, translocation of protein kinase C (PKC) θ and e were determined by Western blotting and concentrations of DAG and CER were measured using targeted LC-tandem mass spectrometry upon separating fractions of cellular membranes, lipid droplets and cytosol by ultracentrifugation. Maximal oxidative capacity and IS were 46% and 47% higher in ATH than in SED (both p In conclusion, higher IS in endurance-trained ATH can be explained by lower muscle PKCθ activation, which may be due to differences in the stereoselectivity and/or subcompartmentation of cellular DAG between ATH and insulin resistant SED. Disclosure D. Pesta: None. E. Anadol-Schmitz: None. S. Gancheva: None. D.F. Markgraf: None. O.P. Zaharia: None. H. Katsuyama: None. Y. Kupriyanova: None. J. Hwang: None. D. Zhang: None. G.I. Shulman: Advisory Panel; Self; AstraZeneca, Janssen Research & Development, Merck & Co., Inc., Novo Nordisk Inc.. Research Support; Self; Gilead Sciences, Inc. M. Roden: Speaker9s Bureau; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH. Consultant; Self; Poxel SA. Research Support; Self; Danone Nutricia Early Life Nutrition, GlaxoSmithKline plc., Nutricia Advanced Medical Nutrition, Sanofi.