Escribano, OscarGuillén, CarlosNevado, CarmenGómez-Hernández, AlmudenaKahn, C.Benito, Manuel2012-12-072009Escribano, 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): 820-828.0012-1797http://nrs.harvard.edu/urn-3:HUL.InstRepos:10019709Objective: 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-USMetabolismJournal Article2012-12-0710.2337/db08-0551