732-P: Insulin Sensitivity Nonresponders after Long-Term Intensive Exercise Training Are Characterized by Perturbed Amino Acid Metabolism and Mitochondrial Dysfunction

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Exercise may effectively improve insulin sensitivity, although some individuals do not reap this benefit. Yet, mechanisms underlying variations in training-improved insulin sensitivity remain unknown. We investigated men with or without dysglycemia subjected to 12 w of high-intensity endurance and strength exercise, and classified them as nonresponders (n=5) or responders (n=21) based on glucose infusion rate (GIR) from euglycemic hyperinsulinemic clamping. We explored variables related to variation in training-improved GIR. VO2max, muscle strength, fat depots, adipose tissue (AT) and skeletal muscle (SkM) lipidomics, mRNA sequencing, and blood amino acid profiles were evaluated pre- and post-training. By design, nonresponders did not improve their GIR, whereas responders exhibited a pronounced increase (42%). There was no difference in attendance to training sessions between the groups, or any correlation between attendance rate and training-improved GIR. Both groups improved VO2max, leg press, pull down and chest press strength, but responders increased significantly more in VO2max and chest press strength. Nonresponders exhibited higher baseline plasma concentrations of leucine, isoleucine, valine, homocysteine and cysteine, more intraperitoneal AT and impaired insulin signaling, branched-chain amino acids and methionine and cysteine metabolism in AT, and higher SkM triacylglycerol, free fatty acids and cholesterol levels and impaired SkM oxidative phosphorylation, branched-chain amino acids degradation and tricarboxylic acid cycle. Failing to improve insulin sensitivity after long-term intensive training may relate to perturbed amino acids metabolism and mitochondrial dysfunction. Initial plasma levels of branched-chain and sulphur amino acids may determine individuals not obtaining glucometabolic improvements after training. Disclosure S. Lee: None. H.L. Gulseth: Consultant; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; Merck Sharp & Dohme Corp., Sanofi-Aventis. C.A. Drevon: Board Member; Self; Vitas AS. Consultant; Self; Vitas AS. K.I. Birkeland: Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lifecare, Inc., Merck Sharp & Dohme Corp., Roche Diabetes Care. Other Relationship; Self; Norwegian Diabetes Association.