In vivo kinetics of insulin action on peripheral glucose disposal and hepatic glucose output in normal and obese

To determine whether abnormal kinetics of insulin's biologic actions contribute to the overall insulin resistance in obesity, we compared the rate of activation and deactivation of insulin's ef-fects to stimulate glucose disposal rate (Rd) and inhibit hepatic glucose output (HGO) in 12 nonobese and 10 obese subjects using the euglycemic clamp technique at insulin infusion rates of 15,40,120, and 1,200 mU/M2 per min. In both groups, stim-ulation of Rd was faster the higher the insulin infusion rate and the time to reach half maximal stimulation (Aso value) in normals was 52±4, 44±2, 29±3, and 21±2 min at infusion rates of 15, 40, 120, and 1,200 mU/M2 per min, respectively. In the obese subjects, the rate of activation was slower (higher As5 values) with A5. values of 74±6, P < 0.001 (compared to normal), 64±8 min., P < 0.001, and 28±3 mm, P < 0.01, at the 40, 120, and 1,200 mU/M2 per min insulin infusions. Deactivation of the in-sulin effect to stimulate glucose disposal rate (Rd) was faster in the obese group compared with normal individuals after all com-parable insulin infusions. In summary: (a) for both groups, the higher the insulin infusion rate, the higher the steady state Rd value, the faster the rate of activation and the slower the sub-sequent rate of deactivation. (b) In insulin-resistant obese sub-jects, the rate of activation of insulin action was slower and the rate of deactivation faster at comparable insulin infusion rates. (c) The rate of suppression ofHGO was comparable in normal and obese subjects, but the rate of recovery of HGO back to basal values was faster in the obese group. And (d) In view of the phasic manner in which insulin is normally secreted following meals, steady state insulin action is not normally achieved. Therefore, the abnormal kinetics of insulin action in insulin-resistant obese individuals may represent functionally important manifestations of the insulin resistance in this condition