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 (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.
Sato
H
H
Faculty of Pharmaceutical Sciences, Kanazawa University, Japan.
Terasaki
T
T
Okumura
K
K
Tsuji
A
A
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
D007328:Insulin; D011972:Receptor, Insulin