Kinetic models for plasma disappearance of insulin in normal subjects

Three theoretical kinetic models for plasma disappearance of insulin were examined in six normal men. The models allowed for the existence of non-saturable and/or saturable mechanisms. Constant infusion of porcine insulin at different rates was used to achieve different levels of steady state plasma insulin concentrations, while normoglycaemia was secured by a glucose clamp technique. Appropriate validation procedures demonstrated that one of the three models was superior to the others in describing the relationship between the exogenous insulin infusion rate Iex and the steady state plasma insulin concentration C: Iex = -Iend + k2 X C/(k3 + C), where Iend is the endogenous post-hepatic insulin delivery rate. Thus, only saturable mechanism(s) could be demonstrated. The median value of k2 (the maximal insulin disappearance rate) and k3 (the plasma insulin concentration at which the insulin disappearance rate is half maximal) were 7.31 nmol X min.-1 and 3.89 nmol X 1-1. The median value of k2/k3 (the clearance rate of insulin for infinitesimal plasma insulin concentrations) was 25.0 ml X kg-1 X min.-1. Thus, at physiological levels of plasma insulin concentrations the metabolic clearance rate of insulin is higher than insulin clearance estimates previously reported in studies based on the assumption of first order kinetics.