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

Resumen

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. Concurrently, there was a huge increase of IR-A in the hyperplastic beta cells. More importantly, as assessed in mouse beta-cell lines, IR-A, but not IR-B, confers a proliferative capability to beta-cells in response to insulin or IGF-1 that may account for beta-cell hyperplasia induced by liver insulin resistance in iLIRKO mice. Thus, our results in iLIRKO mice suggest a liver-pancreatic endocrine axis, IGF-1 being a liver factor that might contribute together with insulin to compensatory pancreatic islet hyperplasia through IR-A.