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dc.contributor.authorEscribano, Oscar
dc.contributor.authorGuillén, Carlos
dc.contributor.authorNevado, Carmen
dc.contributor.authorGómez-Hernández, Almudena
dc.contributor.authorKahn, C. Ronald
dc.contributor.authorBenito, Manuel
dc.date.accessioned2012-12-07T20:53:29Z
dc.date.issued2009
dc.identifier.citationEscribano, Oscar, Carlos Guillén, Carmen Nevado, Almudena Gómez-Hernández, C. Ronald Kahn, and Manuel Benito. 2009. \(\beta\)-cell hyperplasia induced by hepatic insulin resistance. Diabetes 58(4): 820-828.en_US
dc.identifier.issn0012-1797en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:10019709
dc.description.abstractObjective: Type 2 diabetes results from a combination of insulin resistance and impaired insulin secretion. To directly address the effects of hepatic insulin resistance in adult animals, we developed an inducible liver-specific insulin receptor knockout mouse (iLIRKO). Research Design and Methods: Using this approach, we were able to induce variable insulin receptor (IR) deficiency in a tissue-specific manner (liver mosaicism). Results: iLIRKO mice presented progressive hepatic and extrahepatic insulin resistance without liver dysfunction. Initially, iLIRKO mice displayed hyperinsulinemia and increased \(\beta\)-cell mass, the extent of which was proportional to the deletion of hepatic IR. Our studies of iLIRKO suggest a cause-and-effect relationship between progressive insulin resistance and the fold increase of plasma insulin levels and \(\beta\)-cell mass. Ultimately, the \(\beta\)-cells failed to secrete sufficient insulin, leading to uncontrolled diabetes. We observed that hepatic IGF-1 expression was enhanced in iLIRKO mice, resulting in an increase of circulating IGF-1. Concurrently, the IR-A isoform was upregulated in hyperplastic \(\beta\)-cells of iLIRKO mice and IGF-1–induced proliferation was higher than in the controls. In mouse \(\beta\)-cell lines, IR-A, but not IR-B, conferred a proliferative capacity in response to insulin or IGF-1, providing a potential explanation for the \(\beta\)-cell hyperplasia induced by liver insulin resistance in iLIRKO mice. Conclusions: Our studies of iLIRKO mice suggest a liver-pancreas endocrine axis in which IGF-1 functions as a liver-derived growth factor to promote compensatory pancreatic islet hyperplasia through IR-A.en_US
dc.language.isoen_USen_US
dc.publisherAmerican Diabetes Associationen_US
dc.relation.isversionofdoi://10.2337/db08-0551en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2661585/pdf/en_US
dash.licenseLAA
dc.subjectMetabolismen_US
dc.title\(\beta\)-Cell Hyperplasia Induced by Hepatic Insulin Resistanceen_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalDiabetesen_US
dash.depositing.authorKahn, C. Ronald
dc.date.available2012-12-07T20:53:29Z
dash.affiliation.otherHMS^Medicine-Brigham and Women's Hospitalen_US
dc.identifier.doi10.2337/db08-0551*
dash.contributor.affiliatedKahn, C.


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