{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T20:28:34Z","timestamp":1791059314083,"version":"4.1.0"},"reference-count":26,"publisher":"American Physiological Society","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Endocrinology and Metabolism"],"published-print":{"date-parts":[[2008,9]]},"abstract":"<jats:p> 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\u00b7kg<jats:sup>\u22121<\/jats:sup>\u00b7min<jats:sup>\u22121<\/jats:sup>) 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 \u223c60\u201380%. Hyperinsulinemia (\u223c1.6 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<jats:sub>2<\/jats:sub>-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. <\/jats:p>","DOI":"10.1152\/ajpendo.90370.2008","type":"journal-article","created":{"date-parts":[[2008,7,30]],"date-time":"2008-07-30T03:28:29Z","timestamp":1217388509000},"page":"E692-E697","source":"Crossref","is-referenced-by-count":16,"title":["Effects of hyperinsulinemia on hepatic metalloproteinases and their tissue inhibitors"],"prefix":"10.1152","volume":"295","author":[{"given":"Guenther","family":"Boden","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiwei","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Kresge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Mozzoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Cheung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"R1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra011775"},{"key":"R2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2007.03.056"},{"key":"R3","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.54.12.3458"},{"key":"R4","doi-asserted-by":"publisher","DOI":"10.2337\/db07-1261"},{"key":"R5","doi-asserted-by":"publisher","DOI":"10.1016\/S0167-4838(99)00279-4"},{"key":"R6","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.20.12.2527"},{"key":"R7","doi-asserted-by":"crossref","unstructured":"Cusi K, Maezono K, Osman A, Pendergrass M, Patti ME, Pratipanawatr T, DeFronzo RA, Kahn CR, Mandarino LJ. 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