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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on December 1, 2005; DOI: 10.1124/jpet.105.092122

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Received for publication July 7, 2005.
Revised November 23, 2005.
Accepted for publication November 30, 2005.

Metformin prevents endotoxin-induced liver injury after partial hepatectomy

Ina Bergheim 1, James P. Luyendyk 2, Chad Steele 3, Gilandra K. Russell 1, Luping Guo 1, Robert A. Roth 2, Gavin E. Arteel 1*

1 University of Louisville Health Sciences Center 2 Michigan State University 3 University of Pittsburgh School of Medicine

* Address correspondence to: E-mail: gavin.arteel{at}louisville.edu

Abstract

Metformin [2-(N,N-dimethylcarbamimidoyl)guanidine] is a drug used in the treatment of type 2 diabetes. Recent studies have suggested that metformin may have effects in addition to lowering serum glucose concentrations (e.g., anti-inflammatory). The aim of the present study was to determine whether metformin prevents the inflammatory reaction and liver damage in a model of post-surgical sepsis. Accordingly, rats underwent 2/3 partial hepatectomy (PH; or sham surgery); 48h after surgery, animals were administered endotoxin (LPS; 1.5 mg/kg i.v.). Both PH and LPS alone caused some minor liver damage. However, their combined effect (PH/LPS) was synergistic, leading to robust hepatic damage, as indicated by plasma enzymes and histological assessment. Although metformin treatment did not alter changes caused by PH alone, it almost completely blunted the effects of LPS in the PH/LPS group. Increases in biomarkers of inflammation (e.g. IL-6, INF{gamma}, and neutrophil number) were also blunted by metformin treatment. Furthermore, PH/LPS caused a >200x increase in hepatic PAI-1 mRNA expression and plasma PAI-1 protein. These increases were associated with inhibition of hepatic uPA activity and an increase in fibrin deposition, indicative of local thrombosis. These effects were markedly reduced by metformin treatment. In conclusion, these data demonstrate that metformin prevents liver damage in a model of post-surgical sepsis in rats by decreasing proinflammatory and hemostatic responses.


Key words: Plasminogen activator inhibitor-1, hemostasis, inflammation, insulin resistance, sepsis, urokinase plasminogen activator


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