Effect of Receptor Up-Regulation on Insulin Pharmacokinetics in Streptozotocin-Treated Diabetic Rats

The present study investigated the mechanism by which the disposition of insulin is altered in streptozotocin (STZ)-treated diabetic rats as compared with 48-hr-fasted normal (control) rats. It was shown by an indocyanine green infusion method that the hepatic plasma flow rate (Q_H) in diabetic rats (1.64 ml/min/g liver) is significantly higher than that in control rats (0.982 ml/min/g liver). The portal injection technique revealed that the unidirectional clearance (CL_on), which represents the binding of A₁₄-¹²⁵ I-insulin to surface receptors in the liver, is significantly elevated in diabetic rats, suggesting an increase in the surface receptor number R_T), i.e., up-regulation in the liver. In both control and diabetic rats, the total-body clearance (CL_tot) and steady-state volume of distribution (Vd_ss) of labeled insulin decreased significantly with a simultaneous injection of unlabeled insulin (8 U/kg), confirming that the disposition of insulin is affected largely by specific, saturable receptor-mediated processes. The CL_tot and Vd_ss increased significantly in diabetic rats, while nonspecific portions of these parameters were not changed. From the increases in CL_tot (80%) and Q_H (67%) in diabetic rats, a pharmacokinetic analysis has revealed a 40% increase in the hepatic intrinsic clearance (CL_{int sp}) of A₁₄-¹²⁵ I-insulin via a specific mechanism in diabetic rats. In conclusion, we have provided in vivo evidence for a small increase in CL_{int sp} of insulin in STZ-diabetic rats compared with control rats, which may be caused by an increase in the surface receptor number in the livers of diabetic rats.