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

Hitoshi Sato, Tetsuya Terasaki, Kiminori Okumura, Akira Tsuji

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34 Citations (Scopus)


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 A14-125 I-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 A14-125 I-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.

Original languageEnglish
Pages (from-to)563-569
Number of pages7
JournalPharmaceutical Research: An Official Journal of the American Association of Pharmaceutical Scientists
Issue number5
Publication statusPublished - 1991 May
Externally publishedYes


  • diabetic rats
  • hepatic clearance
  • insulin pharmacokinetics
  • insulin receptor
  • streptozotocin
  • up-regulation

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)


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