EFFECT OF INSULIN DOSE ON THE MEASUREMENT OF INSULIN SENSITIVITY BY THE MINIMAL MODEL TECHNIQUE - EVIDENCE FOR SATURABLE INSULIN TRANSPORT IN HUMANS

Administration of exogenous insulin during an intravenous glucose tole rance test allows the use of the minimal model technique to determine the insulin sensitivity index in subjects with reduced endogenous insu lin responses. To study the effect of different insulin administration protocols, we performed three intravenous glucose tolerance tests in each of seven obese subjects (age, 20-41 yr; body mass index, 30-43 kg /m(2)), Three different insulin administration protocols were used: a low-dose (0.025 U/kg) infusion given over 10 min, a low-dose (0.025 U/ kg) bolus injection, and a high-dose (0.050 U/kg) bolus injection, res ulting in peak insulin concentrations of 1,167+/-156, 3,014+/-384, and 6,596+/-547 pM, respectively. The mean insulin sensitivity index was 4.80+/-0.95 x 10(-5), 3.56+/-0.53 x 10(-5), and 2.42+/-0.40 x 10(-5) m in(-1)/pM respectively (x+/-SEM; P = 0.01). The association of higher peak insulin concentrations with lower measured insulin sensitivity va lues suggested the presence of a saturable process. Because results we re not consistent with the known saturation characteristics of insulin action on tissue, a second saturable site involving the transport of insulin from plasma to interstitium was introduced, leading to a calcu lated K-m of 807+/-165 pM for this site, a value near the 1/K-d of the insulin receptor. Thus, the kinetics of insulin action in humans in t hese studies is consistent with two saturable sites, and supports the hypothesis for transport of insulin to the interstitial space. Saturat ion may have an impact on minimal model results when high doses of exo genous insulin are given as a bolus, but can be minimized by infusing insulin at a low dose.