title: Effects of hyperinsulinemia on hepatic metalloproteinases and their tissue inhibitors.
abstract: 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 approximately 60-80%. Hyperinsulinemia ( approximately 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 NH(2)-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.
authors.affiliation: Temple University Hospital, Philadelphia, PA 19140, USA. bodengh@tuhs.temple.edu
authors.forename: Guenther
authors.initials: G
authors.lastname: Boden
authors.forename: Weiwei
authors.initials: W
authors.lastname: Song
authors.forename: Karen
authors.initials: K
authors.lastname: Kresge
authors.forename: Maria
authors.initials: M
authors.lastname: Mozzoli
authors.forename: Peter
authors.initials: P
authors.lastname: Cheung
mesh_terms: D000199:Actins / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D015309:Glucose Clamp Technique; D006493:Heparin / Q000378:metabolism; D006946:Hyperinsulinism / Q000201:enzymology*; D047468:Immunoprecipitation; D007328:Insulin / Q000097:blood; D050356:Lipid Metabolism; D008099:Liver / Q000201:enzymology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D045726:Metalloproteases / Q000378:metabolism*; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism*
chemical_list: D000199:Actins; D007328:Insulin; D019715:Tissue Inhibitor of Metalloproteinase-1; D019714:Tissue Inhibitor of Metalloproteinases; D019716:Tissue Inhibitor of Metalloproteinase-2; D012313:RNA; D006493:Heparin; D045726:Metalloproteases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9