RT Journal Article
SR Electronic
T1 β-Cell Hyperplasia Induced by Hepatic Insulin Resistance
JF Diabetes
JO Diabetes
FD American Diabetes Association
SP 820
OP 828
DO 10.2337/db08-0551
VO 58
IS 4
A1 Escribano, Oscar
A1 Guillén, Carlos
A1 Nevado, Carmen
A1 Gómez-Hernández, Almudena
A1 Kahn, C. Ronald
A1 Benito, Manuel
YR 2009
UL http://diabetes.diabetesjournals.org/content/58/4/820.abstract
AB 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 β-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 β-cell mass. Ultimately, the β-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 β-cells of iLIRKO mice and IGF-1–induced proliferation was higher than in the controls. In mouse β-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 β-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.