title: Effect of receptor up-regulation on insulin pharmacokinetics in streptozotocin-treated diabetic rats.
abstract: 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 (QH) 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 (CLon), which represents the binding of A14-125I-insulin to surface receptors in the liver, is significantly elevated in diabetic rats, suggesting an increase in the surface receptor number (RT), i.e., up-regulation in the liver. In both control and diabetic rats, the total-body clearance (CLtot) and steady-state volume of distribution (Vdss) 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 CLtot and Vdss increased significantly in diabetic rats, while nonspecific portions of these parameters were not changed. From the increases in CLtot (80%) and QH (67%) in diabetic rats, a pharmacokinetic analysis has revealed a 40% increase in the hepatic intrinsic clearance (CLint,sp) of A14-125I-insulin via a specific mechanism in diabetic rats. In conclusion, we have provided in vivo evidence for a small increase in CLint,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.
authors.affiliation: Faculty of Pharmaceutical Sciences, Kanazawa University, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Sato
authors.forename: T
authors.initials: T
authors.lastname: Terasaki
authors.forename: K
authors.initials: K
authors.lastname: Okumura
authors.forename: A
authors.initials: A
authors.lastname: Tsuji
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000378:metabolism* / Q000503:physiopathology; D007328:Insulin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008102:Liver Circulation; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011972:Receptor, Insulin / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D007328:Insulin; D011972:Receptor, Insulin