High-Intensity Exercise Decreases IP6K1 Muscle Content and Improves Insulin Sensitivity (SI2*) in Glucose-Intolerant Individuals.

Abstract

Insulin resistance (IR) in skeletal muscle contributes to whole body hyperglycemia and the secondary complications associated with type 2 diabetes. Inositol hexakisphosphate kinase-1 (IP6K1) may inhibit insulin-stimulated glucose transport in this tissue type. Muscle and plasma IP6K1 were correlated with two-compartment models of glucose control in insulin-resistant hyperinsulinemic individuals. Muscle IP6K1 was also compared after two different exercise trials. Nine prediabetic [hemoglobin A1c; 6.1% (0.2%)] patients were recruited to take part in a resting control, a continuous exercise (90% of lactate threshold), and a high-intensity exercise trial (6 30-second sprints). Muscle biopsies were drawn before and after each 60-minute trial. A labeled ([6,62H2]glucose) intravenous glucose tolerance test was performed immediately after the second muscle sample. Fasting muscle IP6K1 content did not correlate with insulin sensitivity (SI2*) (P = 0.961). High-intensity exercise reduced IP6K1 muscle protein and messenger RNA expression (P = 0.001). There was no effect on protein IP6K1 content after continuous exercise. Akt308 phosphorylation of was significantly greater after high-intensity exercise. Intermittent exercise reduced hepatic glucose production after the same trial. The same intervention also increased SI2*, and this effect was significantly greater compared with the effect of continuous exercise improvements. Our in vitro experiment demonstrated that the chemical inhibition of IP6K1 increased insulin signaling in C2C12 myotubes. The in vivo and in vitro approaches used in the current study suggest that a decrease in muscle IP6K1 may be linked to whole body increases in SI2*. In addition, high-intensity exercise reduces hepatic glucose production in insulin-resistant individuals.