Based on previous steady-state measures of the biologic activity of insulin, it was thought that postprandial hyperinsulinemia in obesity compensated for insulin resistance. However, we recently demonstrated kinetic defects in insulin action in insulin-resistant nondiabetic obese subjects: activation of insulin-stimulated glucose disposal was slower and deactivation was faster in obese than in normal subjects. In view of these kinetic defects in peripheral insulin action and of the fact that insulin is normally secreted in a phasic manner after meals, we postulated that the hyperinsulinemia of obesity does not compensate for insulin resistance and that the abnormal kinetics of insulin action in obesity are functionally important. To test this hypothesis, oral glucose tolerance tests (OGTTs) were performed in five control (mean age, 33 ± 2 yr) and five obese (mean age, 41 ± 5 yr) subjects. All controls had normal glucose tolerance; two obese subjects had normal and three had impaired glucose tolerance. After the results of the OGTTs were available, euglycemic clamp studies were performed in which insulin was infused in a phasic stepped fashion to mimic the rise and fall of mean peripheral insulin levels during the OGTTs. Each subject was clamped at both the “normal” and “obese” OGTT insulin profiles.

During the OGTT, glucose and insulin levels were significantly elevated in the obese subjects compared with controls. Insulin-stimulated glucose disposal rates and total incremental glucose disposal (IGD) over 4 h were markedly reduced in obese compared with control subjects at the lower (normal) insulin-infusion profile (3 ± 1 vs. 41 ± 5 g, P < .001) and at the higher (obese) insulin-infusion profile (15 ± 4 vs. 72 ± 6 g, P < .001). Furthermore, during the normal insulin profile in controls compared with the obese insulin profile in obese subjects, IGD was still significantly reduced in the obese subjects (41 ± 5 vs. 15 ± 4 g, P < .001). At the lower as well as the higher insulin infusion, suppression of hepatic glucose output was not significantly different between obese and control subjects, as assessd by analysis of variance.

In conclusion, our data demonstrate three important points. 1) Kinetic defects in the onset and decay of peripheral insulin action are functionally important in obesity when insulin is infused to match the physiological rise and fall of OGTT insulin levels. 2) Postprandial hyperinsulinemia in obesity only partially compensates for the peripheral insulin resistance. 3) The relative postprandial hyperglycemia in obesity may promote glucose disposal via the mass action of glucose and may be an important compensatory factor serving to normalize peripheral glucose disposal in insulin-resistant obese subjects.

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