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Nat Med. 2013 Oct;19(10):1331-1337. doi: 10.1038/nm.3295. Epub 2013 Sep 15.

A liver Hif-2α-Irs2 pathway sensitizes hepatic insulin signaling and is modulated by Vegf inhibition.

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Division of Hematology, Stanford University School of Medicine, Stanford, California 94305, USA.
Division of Radiation Oncology Stanford University School of Medicine, Stanford, California 94305, USA.
Regeneron Pharmaceuticals, Incorporated, Tarrytown, New York, 10591, USA.
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville TN 37232, USA.
INSERM U 1060, INRA 1235, Universite de Lyon, Faculté de Médecine Lyon Sud - BP12, 69921 OULLINS Cedex, France.
Abramson Family Cancer Research Institute, Howard Hughes Medical Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, 19104, USA.
UCSF Liver Center, San Francisco General Hospital, 1001 Potrero Ave. Building 40, Room 4102, San Francisco, CA 94110.
Inserm U855/Université Lyon, Faculté Lyon Est Laennec, 7 rue Guillaume Paradin, 69372 Lyon cedex 08, France.
Division of Endocrinology and Metabolism, Stanford University School of Medicine, Stanford, California 94305, USA.
Contributed equally


Insulin initiates diverse hepatic metabolic responses, including gluconeogenic suppression and induction of glycogen synthesis and lipogenesis. The liver possesses a rich sinusoidal capillary network with a higher degree of hypoxia and lower gluconeogenesis in the perivenous zone as compared to the rest of the organ. Here, we show that diverse vascular endothelial growth factor (VEGF) inhibitors improved glucose tolerance in nondiabetic C57BL/6 and diabetic db/db mice, potentiating hepatic insulin signaling with lower gluconeogenic gene expression, higher glycogen storage and suppressed hepatic glucose production. VEGF inhibition induced hepatic hypoxia through sinusoidal vascular regression and sensitized liver insulin signaling through hypoxia-inducible factor-2α (Hif-2α, encoded by Epas1) stabilization. Notably, liver-specific constitutive activation of HIF-2α, but not HIF-1α, was sufficient to augment hepatic insulin signaling through direct and indirect induction of insulin receptor substrate-2 (Irs2), an essential insulin receptor adaptor protein. Further, liver Irs2 was both necessary and sufficient to mediate Hif-2α and Vegf inhibition effects on glucose tolerance and hepatic insulin signaling. These results demonstrate an unsuspected intersection between Hif-2α-mediated hypoxic signaling and hepatic insulin action through Irs2 induction, which can be co-opted by Vegf inhibitors to modulate glucose metabolism. These studies also indicate distinct roles in hepatic metabolism for Hif-1α, which promotes glycolysis, and Hif-2α, which suppresses gluconeogenesis, and suggest new treatment approaches for type 2 diabetes mellitus.

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