ASSESSMENT OF INSULIN ACTION ON GLUCOSE-UPTAKE AND PRODUCTION DURING A EUGLYCEMIC-HYPERINSULINEMIC CLAMP IN DOG - A NEW KINETIC-ANALYSIS

We evaluated the validity of the traditional method of assessment of t he speed of insulin action during a euglycemichyperinsulinemic clamp. We first estimated the error of Steele's model on glucose uptake in th ese experimental conditions. We tested the appropriateness of estimati ng the half-time of insulin action by expressing the glucose flux chan ges as a percent of the maximal change (normalization on a 0% to 100% scale). For this purpose, we performed a 390-minute euglycemichyperins ulinemic (2 mU.min(-1).kg(-1)) clamp in five chronically catheterized conscious dogs. We used [3-H-3]glucose to assess glucose kinetics. We used a novel analysis based on a circulatory model, which allowed us t o overcome the limitations of compartmental analysis. We found that th e primary effect of insulin (increased from 12.3 +/- 1.6 to 104 +/- 15 mu U/mL) was to increase the whole-body fractional extraction of gluc ose (3.0% +/- 0.3% to 18% +/- 2%). Insulin did not alter the mean whol e-body artery-vein transit time (3.1 +/- 0.2 v 2.9 +/- 0.4 minutes). i n contrast to the assumptions of the Steele model, which assumes that glucose uptake and rate of appearance (Ra) are equal during the clamp, during the initial 30 minutes of the clamp the increase in glucose up take preceded (by similar to 4 minutes) the increase in Ra. Thus, duri ng this period uptake exceeded Ra by about 15%. The maximal difference between Ra and uptake (1 to 1.5 mg.min(-1).kg(-1)) occurred approxima tely 15 minutes after insulin infusion. Finally, to estimate the half- time of the insulin si gnat that controls glucose uptake and productio n, we accounted for the nonlinear relationship between insulin concent ration and glucose uptake and production. We found that the traditiona l normalization of the glucose flux changes on a 0% to 100% scale unde restimated the half-time of onset of the insulin signal that controls glucose uptake (half-time, 20 v 54 minutes) and glucose production (ha lf-time, 25 v 39 minutes). Accounting for the nonlinearity of the dose -response curves may thus be of crucial importance in the evaluation o f the onset and offset of insulin action. Copyright (C) 1997 by W.B. S aunders Company.