Increased Clearance and Degradation of [3H]Insulin in Streptozotocin Diabetic Rats: ROLE OF THE INSULIN-RECEPTOR COMPARTMENT

The role of the insulin-receptor compartment in the pharmacokinetics of intravenously injected insulin in rats was studied. Since streptozotocin-diabetes in rats results in increased insulin binding to tissues in vitro, insulin pharmacokinetics in streptozotocin-diabetic rats were compared to controls, using semisynthetic [ 3 H]insulin as the tracer. The initial distribution volume for [ 3 H]insulin was elevated by 60% in diabetic rats. By contrast, no difference in initial distribution volume for [ 14 C]inulin was observed, and the absolute values were lower than those found for [ 3 H]insulin. The metabolic clearance rate of [ 3 H]insulin was elevated by 44% in diabetic rats. That these differences were the result of increased binding of insulin to a specific receptor compartment in diabetic rats was shown by three additional experiments. The first involved receptor saturation by injection of 10 U native insulin 2 min before the tracer injection, resulting in identical [ 3 H]insulin disappearance rates in the two groups of rats. The second consisted of displacing [ 3 H]insulin from receptors by injecting 10 U unlabeled insulin 6 min after the tracer injection. Displacement of intact [ 3 H]insulin from receptors and subsequent reappearance in the circulation occurred in both control and diabetic animals; however, such displacement was 25% greater in the diabetic rats. Finally, treatment of diabetic rats with insulin for 8 d normalized [ 3 H]insulin clearance even though the tracer was injected at a time when the animals were again hyperglycemic and hypoinsulinemic. This suggests that down-regulation of insulin receptors had occurred during insulin therapy. These results confirm that a specific compartment for insulin exists (the insulin-receptor compartment) and that this compartment plays an important role in insulin clearance.