Validation of a practical in vivo insulin dose-response curve in man

To adequately investigate the state of insulin resistance, an insulin dose-response curve should be constructed so that insulin sensitivity (right shift of dose-response curve) and insulin responsiveness (maximal response) can be determined. This paper describes and validates in man a practical in vivo insulin dose-response curve technique, using a modification of the euglycaemic clamp described by De Fronzo et al. Insulin action at steady state was expressed as metabolic clearance rate of glucose (MCRG) rather than overall rate of glucose disappearance (M or Rd). MCRG was chosen because at plasma insulin concentrations greater than 25 microunits/ml it was shown (n = 5) not to be altered by changes in blood glucose concentration (MCRG 379 +/- 23 and 408 +/- 19 ml/m2/min; at plasma glucose concentrations 5.4 +/- 0.3 and 10.2 +/- 0.7 respectively), whereas Rd was critically dependent on the prevailing blood glucose concentration (Rd 2007 +/- 128 and 4124 +/- 219 mumol m2/min respectively). MCRG was demonstrated to be stable over a 6 hr period (n = 8) and to be reproducible (n = 4). Insulin dose-response curves (MCRG Versus insulin concentration) were performed on two obese and seven normal weight individuals. The insulin dose-response curves were linearized, allowing accurate prediction of the maximal MCRG, as compared to the experimentally determined maximal response (r = 0.953 p less than 0.01). The use of this transformation obviates the need to employ very high insulin infusion rates to determine the maximal insulin response. In conclusion, the technique permits, in a single 6 hr study, a precise insulin dose-response curve to be constructed for accurately determining insulin sensitivity and responsiveness.