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Am J Physiol Endocrinol Metab 295: E692-E697, 2008. First published July 29, 2008; doi:10.1152/ajpendo.90370.2008
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Effects of hyperinsulinemia on hepatic metalloproteinases and their tissue inhibitors

Guenther Boden ,* Weiwei Song,* Karen Kresge, Maria Mozzoli, and Peter Cheung

Division of Endocrinology/Diabetes/Metabolism, Temple University School of Medicine, Philadelphia, Pennsylvania

Submitted 16 April 2008 ; accepted in final form 23 July 2008

To gain insight into the pathogenesis of hepatic fibrosis related to insulin resistance, we have examined the effects of euglycemic hyperinsulinemia on three matrix metalloproteinases (MMP-2, MMP-9, and MT1-MMP) and on two major tissue inhibitors of MMPs (TIMP-1 and TIMP-2) in liver of insulin-sensitive and insulin-resistant rats. Four hours of insulin infusion (4.8 mU·kg–1·min–1) without or with lipid-heparin infusion (to produce insulin resistance) decreased hepatic MMP-2 mRNA (by RT-PCR), pro-MMP-2, MMP-2, MMP-9, and MT1-MMP (all by Western blots) and the gelatinolytic activity of MMP-2 (by gelatin zymography) by ~60–80%. Hyperinsulinemia (~1.6 mmol/l) increased TIMP-1 and TIMP-2 concentrations (by ELISA) in insulin-sensitive and insulin-resistant rats. Phosphoinositide 3-kinase was activated by insulin in insulin-sensitive rats and inhibited in insulin-resistant rats. Extracellular signal-regulated kinases 1/2 (ERK1/2) were activated by insulin in insulin-sensitive rats and partially inhibited in insulin-resistant rats; c-jun NH2-terminal kinase-1 (JNK1), JNK2/3, or p38 MAPK were only activated by lipid but not by insulin. We conclude that hyperinsulinemia, whether or not associated with insulin resistance, shifts the MMP/TIMP balance toward reduction of extracellular matrix degradation and thus may promote the development of hepatic fibrosis.

insulin resistance; lipid infusion; fibrosis; phosphoinositide 3-kinase; extracellular signal-regulated kinases 1/2; matrix metalloproteinases; tissue inhibitors of matrix metalloproteinases


Address for reprint requests and other correspondence: G. Boden, Temple University Hospital, 3401 North Broad St., 4 West, Philadelphia, PA 19140 (E-mail: bodengh{at}tuhs.temple.edu)




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[Abstract] [Full Text] [PDF]


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