Effects of Diet/Exercise and Pioglitazone on the Association between Fitness and Intramyocellular FFA Trafficking

Background: Intramyocellular (im) triglycerides (TG) are increased in athletes, but also insulin resistant (IR) adults. To elucidate this discrepancy, we studied FFA storage in imTG and im oleyl-carnitine (OC) concentrations in IR humans pre and post 2 methods of insulin sensitization (IS) in the context of fitness (VO2max). Methods: 39 adults (BMI 28-36 kg/m2) were given a diet/exercise program (DE; 11.7 ± 3.2 kg weight loss) or 30 mg/day pioglitazone (PI) for ∼19 weeks. Blood and muscle samples were taken before and after a 6 hour [U-13C]oleate infusion with either a euglycemic, hyperinsulinemic clamp (n=20) or saline infusion. Plasma oleate storage in imTG (nmol FFA/g muscle/hr) was calculated. Results: Quantative IS was similar in DE and PI groups. VO2max increased post DE (44 ± 1 to 46 ± 2 ml/kgFFM/min†), but not PI (45 ± 1 ml/kgFFM/min pre and post PI). At baseline, oleate storage in imTG during clamps correlated with VO2max (r=0.51*), but the δVO2max with treatment did not correlate with the δoleate storage in imTG. Following IS, VO2max correlated with imOC (r=0.46*); the latter was true for men (m) (r=0.89*), but not women (r=0.32), and for DE (m: r=0.97*) but not PI (m: r=0.70, p=0.18). δ VO2max correlated with δimOC (m: r=0.92*, f: r=0.57†), both post WL (r=0.91*) and PI (r=0.96*).Summary: In IR adults, IS influences the associations between fitness and markers of imFFA oxidation and storage in imTG during hyperinsulinemia. These relationships are more apparent in men and exaggerated post-IS. Conclusion: Fitness in men regulates imFFA trafficking towards storage and oxidation. *p