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An. R. Acad. Nac. Farm., 2010, 76 (1): 23-44

ARTÍCULO

Beta-cell hyperplasia induced by hepatic
insulin resistance: Role of a liver-pancreatic
endocrine axis

Óscar Escribano 1, 2, Almudena Gómez-Hernández 1, 2,
Manuel Benito de las Heras 1, 2 *

1 Department of Biochemistry and Molecular Biology II.
Faculty of Pharmacy. Complutense University of Madrid. Spain.
2 CIBER of Diabetes and Related Metabolic Diseases (CIBERDEM).
ISCIII. Spain.
Recibido el 2 de noviembre de 2009.

ABSTRACT

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 IR knockout mouse (iLIRKO). Using this
approach, we were able to induce variable IR deletion in a tissue-
specific manner (liver mosaicism). These mice demonstrate
progressive hepatic and extra hepatic insulin resistance, without liver
dysfunction. Initially there is hyperinsulinemia and increased beta-
cell mass in parallel to IR deletion by the liver. Our results with
iLIRKO demonstrate 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 undergo a failure
in the insulin secretion that leads to uncontrolled diabetes. In this
context, iLIRKO mice induced IGF-1 in parallel to IR (IR) deletion
in the liver. This resulted in an increase of circulating IGF-1.

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