Measurement using tracers of steady-state turnover and metabolic clearance of insulin in dogs.

In nine conscious dogs, the steady-state metabolic clearance rate (MCR) and the systemic appearance rate (Ra) of insulin were determined by the tracer dilution method. [3H-PheB1]insulin ([3H]insulin) was infused as a tracer from time 0 at a constant rate. After tracer equilibration was attained, unlabeled porcine insulin was infused at variable constant rates (10.6-279 mU/min) with somatostatin (0.3 microgram . kg-1 . min-1) to suppress endogenous insulin secretion. Glucose was infused to prevent hypoglycemia. Tritiated and immunoreactive insulin (IRI) concentrations were determined in plasma samples after extraction on a C-18 reverse-phase column. Tracer-determined basal Ra of insulin was 2.39 +/- (SE) 0.61 mU/min. The calculated steady-state Ra of insulin for plasma IRI from 20 to 2,300 microU/ml showed good agreement with insulin infusion rates. The mean ratio of these rates was 0.973 +/- 0.018. The MCR of insulin under basal conditions was 29.9 +/- 3.4 ml . kg-1 . min-1, and it decreased with increasing insulin concentrations. It is concluded that 1) insulin turnover rates can be measured accurately using [3H]insulin as a tracer and 2) insulin kinetics are nonlinear.