Beta-Cell hyperplasia induced by hepatic insulin resistance: role of a liver-pancreas endocrine axis through insulin receptor A isoform.
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).


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.
Escribano
Oscar
O
Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Complutense University of Madrid, Madrid, Spain.
Guillén
Carlos
C
Nevado
Carmen
C
Gómez-Hernández
Almudena
A
Kahn
C Ronald
CR
Benito
Manuel
M
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D005091:Exons; D019204:GTP-Binding Proteins / Q000235:genetics; D005838:Genotype; D005947:Glucose / Q000378:metabolism; D006965:Hyperplasia; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology*; D007515:Islets of Langerhans / Q000503:physiopathology*; D008099:Liver / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D064547:Myxovirus Resistance Proteins; D016133:Polymerase Chain Reaction; D011972:Receptor, Insulin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D007328:Insulin; D064547:Myxovirus Resistance Proteins; D011972:Receptor, Insulin; D019204:GTP-Binding Proteins; D005947:Glucose