Modeling of plasma disappearance of unlabeled insulin in man

Fifty-two portal and 68 peripheral, brief infusions of unlabeled insulin were given to ambulant, nondiabetic patients. After intraportal insulin infusion (5--50 mU/kg), plasma clearance rate (PCR, dose/area of the incremental plasma insulin concentrations) decreased with increasing dose, varying from 32 to 14 ml-min-1-kg-1 at normoglycemia. After peripheral insulin infusion (5--30 mU/kg), PCR (mean value 15 ml-min-1-kg-1) showed no certain dose-dependence, but transfer rate constants and distribution volumes did. Despite a detectable reentry of insulin from one or more extravascular pools to the plasma pool, transfer rate constants or distribution volumes could not be accurately determined. The shortcomings of conventional noncompartmental and compartmental models did not appear to be due to the dose-dependence demonstrated. Instead, the limitations of these models were caused mainly by the difficulty of defining a proper base-line concentration and, in particular, by the imprecision of the experimental data, indicating that it will be difficult to find more appropriate models from data obtained with unlabeled insulin.