\(\beta\)-Cell Hyperplasia Induced by Hepatic Insulin Resistance

\(\beta\)-Cell Hyperplasia Induced by Hepatic Insulin Resistance

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\(\beta\)-Cell Hyperplasia Induced by Hepatic Insulin Resistance

dc.contributor.author	Escribano, Oscar
dc.contributor.author	Guillén, Carlos
dc.contributor.author	Nevado, Carmen
dc.contributor.author	Gómez-Hernández, Almudena
dc.contributor.author	Kahn, C. Ronald
dc.contributor.author	Benito, Manuel
dc.date.accessioned	2012-12-07T20:53:29Z
dc.date.issued	2009
dc.identifier.citation	Escribano, 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.issn	0012-1797	en_US
dc.identifier.uri	http://nrs.harvard.edu/urn-3:HUL.InstRepos:10019709
dc.description.abstract	Objective: 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.iso	en_US	en_US
dc.publisher	American Diabetes Association	en_US
dc.relation.isversionof	doi://10.2337/db08-0551	en_US
dc.relation.hasversion	http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2661585/pdf/	en_US
dash.license	LAA
dc.subject	Metabolism	en_US
dc.title	\(\beta\)-Cell Hyperplasia Induced by Hepatic Insulin Resistance	en_US
dc.type	Journal Article	en_US
dc.description.version	Version of Record	en_US
dc.relation.journal	Diabetes	en_US
dash.depositing.author	Kahn, C. Ronald
dc.date.available	2012-12-07T20:53:29Z
dash.affiliation.other	HMS^Medicine-Brigham and Women's Hospital	en_US