Abstract
There is a need for well characterized and economical type 2 diabetic model that mimics the human disease. We have developed a type 2 diabetes rat model that closely resembles the diabetic patients and takes only 24 days to develop robust diabetes. Nonlethal doses of allyl alcohol (35 mg/kg i.p.), CCl4 (2 ml/kg i.p.), or thioacetamide (300 mg/kg i.p.) yielded 80 to 100% mortality in diabetic rats. The objective of the present study was to investigate two hypotheses: higher CCl4 bioactivation and/or inhibited compensatory tissue repair were the underlying mechanisms for increased CCl4 hepatotoxicity in diabetic rats. Diabetes was induced by feeding high fat diet followed by a single dose of streptozotocin on day 14 (45 mg/kg i.p.) and was confirmed on day 24 by hyperglycemia, normoinsulinemia, and oral glucose intolerance. Time course studies (0–96 h) of CCl4 (2 ml/kg i.p.) indicated that although initial liver injury was the same in nondiabetic and diabetic rats, it progressed only in the latter, culminating in hepatic failure, and death. Hepatomicrosomal CYP2E1 protein and activity, lipid peroxidation, glutathione, and 14CCl4 covalent binding to liver tissue were the same in both groups, suggesting that higher bioactivation-based injury is not the mechanism. Inhibited tissue repair resulted in progression of injury and death in diabetic rats, whereas in the nondiabetic rats robust tissue repair resulted in regression of injury and survival after CCl4 administration. These studies show high sensitivity of type 2 diabetes to model hepatotoxicants and suggest that CCl4 hepatotoxicity is potentiated due to inhibited tissue repair.
Footnotes
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This study was supported by The Louisiana Board of Reagents Fund through The University of Louisiana at Monroe, Kitty DeGree Chair in Pharmacy (Toxicology). The studies reported in this article are part of graduate dissertation of S.P.S. and were presented at the 42nd Annual Meeting of the Society of Toxicology [The Toxicologist (2003) 72:956] and received First Place Best Paper Award from Comparative Veterinary Specialty Section of the Society of Toxicology. S.P.S. is a recipient of predoctoral fellowship award from American Heart Association.
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DOI: 10.1124/jpet.103.058834.
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ABBREVIATIONS: STZ, streptozotocin; DB, diabetic; NDB, nondiabetic; ND + STZ, normal diet-fed rats injected streptozotocin; TA, thioacetamide; AA, allyl alcohol; SD, Sprague-Dawley; 3H-T, tritiated thymidine; HFD, high fat diet-fed rats injected citrate buffer; HFD + STZ, high fat diet-fed rats injected streptozotocin; ND, normal diet fed rats injected citrate buffer; ALT, alanine aminotransferase; AST, aspartate aminotransferase; PCNA, proliferating cell nuclear antigen; MES, 2-(N-morpholino)ethanesulfonic acid.
- Received August 19, 2003.
- Accepted October 29, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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