Metabolomic profiles are reflective of hypoxia-induced insulin resistance during exercise in healthy young adult males

Hypoxia-induced insulin resistance appears to suppress exogenous glucose oxidation during metabolically-matched aerobic exercise during acute (<8-h) high-altitude (HA) exposure. However, a better understanding of this metabolic dysregulation is needed to identify interventions to mitigate these effects. The objective of this study was to determine if differences in metabolomic profiles during exercise at sea level (SL) and HA are reflective of hypoxia-induced insulin resistance. Native lowlanders (n=8 males) consumed 145g (1.8g/min) of glucose while performing 80-min of metabolically-matched treadmill exercise at SL (757 mmHg) and HA (460 mmHg) after 5-h exposure. Exogenous glucose oxidation and glucose turnover were determined using indirect calorimetry and dual tracer technique (13C-glucose and [6,6-2H2]-glucose). Metabolite profiles were analyzed in serum as change (Δ), calculated by subtracting postprandial/exercised state SL (ΔSL) and HA (ΔHA) from fasted, rested conditions at SL. Compared to SL, exogenous glucose oxidation, glucose rate of disappearance , and glucose metabolic clearance rate (MCR) were lower (P<0.05) during exercise at HA. 118 metabolites differed between ΔSL and ΔHA (P<0.05, Q<0.10). Differences in metabolites indicated increased glycolysis, TCA cycle, amino acid catabolism, oxidative stress, and fatty acid storage, and decreased fatty acid mobilization for ΔHA. BCAA and oxidative stress metabolites, Δ3-methyl-2-oxobutyrate (r=-0.738) and Δgamma-glutamylalanine (r=-0.810), were inversely associated (P<0.05) with Δexogenous glucose oxidation. Δ3-hydroxyisobutyrate (r=-0.762) and Δ2-hydroxybutyrate/2-hydroxyisobutyrate (r=-0.738) were inversely associated (P