Use of a variable insulin infusion to assess insulin action in obesity: defects in both the kinetics and amplitude of response.

To determine whether the severity of insulin resistance in obesity, as assessed by the traditional hyperinsulinemic glucose clamp, reflects the severity of resistance present during changing insulin concentrations, such as occur after meal ingestion, 9 moderately obese and 12 lean subjects were studied on 2 occasions: once during a primed continuous insulin infusion and once during a variable 8-step insulin infusion. Identical amounts of insulin were given on each occasion, and euglycemia was maintained by a glucose infusion. Stimulation of isotopically determined glucose utilization above the basal value was lower in the obese than in the lean subjects during the variable [2.4 +/- 0.5 (+/- SEM) vs. 5.4 +/- 0.7 g/m2; P = 0.004] and the constant (2.9 +/- 0.7 vs 4.2 +/- 0.9 g/m2; P = 0.32) insulin infusions; however, the differences were only significant with the variable insulin infusion. The variable insulin infusion also was associated with lower rates of activation of glucose utilization (slope, 0-90 min, 0.27 +/- 0.05 vs. 0.55 +/- 0.09 mg/m2 X min 2; P = 0.01) in obese compared to lean subjects. In contrast, rates of activation during the low constant infusion (0.24 +/- 0.05 vs. 0.29 +/- 0.06 mg/m2 X min 2; P = 0.51) did not differ in the lean and obese subjects. Despite identical amounts of insulin, stimulation of glucose utilization was greater (P less than 0.03) during the variable than during the constant insulin infusion in the lean subjects. In contrast, stimulation during the variable and constant insulin infusions was equal in the obese subjects. These observations indicate that insulin resistance in obesity is due to a defect in the rate as well as absolute response achieved and suggest that under conditions of daily living the contribution of insulin resistance to impaired carbohydrate tolerance is greater than that previously estimated by a constant insulin infusion.