Dose-response characteristics of insulin action on glucose metabolism: a non-steady-state approach

The traditional methods for the assessment of insulin sensitivity yield onl y a single index, not the whole dose-response curve information. This curve is typically characterized by a maximally insulin-stimulated glucose clear ance (Cl-max) and an insulin concentration at half-maximal response (EC50) We developed an approach for estimating the whole dose-response curve with a single in vivo test, based on the use of tracer glucose and exogenous ins ulin administration (two steps of 20 and 200 mU.min(-1).m(-2), 100 min each ). The effect of insulin on plasma glucose clearance was calculated from no n-steady-state data by use of a circulatory model of glucose kinetics and a model of insulin action in which glucose clearance is represented as a Mic haelis-Menten function of insulin concentration with a delay (t(1/2)). In s even nondiabetic subjects, the model predicted adequately the tracer concen tration: the model residuals were unbiased, and their coefficient of variat ion was similar to the expected measurement error (similar to 3%), indicati ng that the model did not introduce significant systematic errors. Lean (n = 4) and obese (n. = 3) subjects had similar half-times for insulin action (t(1/2) = 25 +/- 9 vs. 25 +/- 8 min) and maximal responses (Cl-max = 705 +/ - 46 vs. 668 +/- 259 ml.min(-1).m(-2), respectively), whereas EC50 was 240 +/- 84 mu U/ml in the lean vs. 364 +/- 229 mu U/ml in the obese (P < 0.04). EC50 and the insulin sensitivity index (ISI, initial slope of the dose-res ponse curve), but not Cl-max, were related to body adiposity and fat distri bution with r of 0.6-0.8 (P < 0.05). Thus, despite the small number of stud y subjects, we were able to reproduce information consistent with the liter ature. In addition, among the lean individuals, t(1/2) was positively relat ed to the ISI (r = 0.72, P < 0.02). We conclude that the test here presente d, based on a more elaborate representation of glucose kinetics and insulin action, allows a reliable quantitation of the insulin dose-response curve for whole body glucose utilization in a single session of relatively short duration.