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Pathogenesis of selective insulin resistance in isolated hepatocytes.
Cook, Joshua R; Langlet, Fanny; Kido, Yoshiaki; Accili, Domenico.
Affiliation
  • Cook JR; From the Department of Medicine, Columbia University, New York, New York 10032 and.
  • Langlet F; From the Department of Medicine, Columbia University, New York, New York 10032 and.
  • Kido Y; the Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
  • Accili D; From the Department of Medicine, Columbia University, New York, New York 10032 and da230@columbia.edu.
J Biol Chem ; 290(22): 13972-80, 2015 May 29.
Article in En | MEDLINE | ID: mdl-25873396
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Insulin Resistance / Receptor, Insulin / Hepatocytes / Liver Type of study: Etiology_studies / Prognostic_studies Limits: Animals Language: En Journal: J Biol Chem Year: 2015 Document type: Article Country of publication: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Insulin Resistance / Receptor, Insulin / Hepatocytes / Liver Type of study: Etiology_studies / Prognostic_studies Limits: Animals Language: En Journal: J Biol Chem Year: 2015 Document type: Article Country of publication: United States