title: Pathogenesis of selective insulin resistance in isolated hepatocytes.
abstract: The development of insulin resistance (IR) 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 IR results in the characteristic hyperglycemia and dyslipidemia of type 2 diabetes. The delineation of two branched pathways of insulin receptor (InsR) signaling to glucose versus triglyceride production, one through FoxO and the other through SREBP-1c, provides a mechanism to account for this pathophysiological abnormality. We tested the complementary hypothesis that selective IR arises due to different intrinsic sensitivities of glucose production versus de novo lipogenesis to insulin as a result of cell-autonomous down-regulation of InsR number in response to chronic hyperinsulinemia. We demonstrate in mouse primary hepatocytes that chronic hyperinsulinemia abrogates insulin's inhibition of glucose production, but not its stimulation of de novo lipogenesis. Using a competitive inhibitor of InsR, we show that there is a 4-fold difference between levels of InsR inhibition required to cause resistance of glucose production versus lipogenesis to the actions of insulin. Our data support a parsimonious model in which differential InsR activation underlies the selective IR of glucose production relative to lipogenesis, but both processes require signaling through Akt1/2.
authors: From the Department of Medicine, Columbia University, New York, New York 10032 and.
authors: Joshua R
authors: JR
authors: Cook
authors: From the Department of Medicine, Columbia University, New York, New York 10032 and.
authors: Fanny
authors: F
authors: Langlet
authors: the Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
authors: Yoshiaki
authors: Y
authors: Kido
authors: From the Department of Medicine, Columbia University, New York, New York 10032 and da230@columbia.edu.
authors: Domenico
authors: D
authors: Accili
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism; D001786:Blood Glucose / Q000737:chemistry; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D006946:Hyperinsulinism / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry; D050155:Lipogenesis; D008074:Lipoproteins / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D001786:Blood Glucose; D007328:Insulin; D008055:Lipids; D008074:Lipoproteins; D011972:Receptor, Insulin; C514862:Akt1 protein, mouse; C494922:Akt2 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose
keywords: FOXO; atherosclerosis; diabetes; gluconeogenesis; glucose metabolism; insulin receptor; insulin resistance; lipid metabolism; lipogenesis; lipoprotein metabolism; liver