On the Pathogenesis of Selective Insulin Resistance in Isolated Hepatocytes [Molecular Bases of Disease]

April 14th, 2015 by Cook, J. R., Langlet, F., Kido, Y., Accili, D.

The development of insulin resistance in the liver is a key pathophysiologic event in the development of type 2 diabetes. Although insulin loses its ability to suppress glucose production, it largely retains its capacity to drive lipogenesis. This selective insulin resistance results in the characteristic hyperglycemia and dyslipidemia of type 2 diabetes. The delineation of two branched pathways of insulin receptor signaling to glucose vs. triglyceride production, one through FoxO and the other through SREBP1-c, provides a mechanism to account for this pathophysiological abnormality. We tested the complementary hypothesis that selective insulin resistance arises due to different intrinsic sensitivities of glucose production vs. de novo lipogenesis to insulin, as a result of cell-autonomous downregulation of insulin receptor number in response to chronic hyperinsulinemia. We demonstrate in mouse primary hepatocytes that chronic hyperinsulinemia abrogates insulin inhibition of glucose production, but not its stimulation of de novo lipogenesis. Using a competitive inhibitor of insulin receptor, we show that there is a fourfold difference between levels of insulin receptor inhibition required to cause resistance of glucose production vs. lipogenesis to the actions of insulin. Our data support a parsimonious model in which differential insulin receptor activation underlies the selective insulin resistance of glucose production relative to lipogenesis, but that both processes require signaling through Akt1/2.