ArticleNature medicine2013
A liver Hif-2α-Irs2 pathway sensitizes hepatic insulin signaling and is modulated by Vegf inhibition.
Article in Nature medicine, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 71 papers.
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Who cites it
71 citing papers in PubMed, 101 citations in OpenAlex.
- Hypoxia in MASLD: a spatial determinant of the pathogenesis.Trends in molecular medicine · 2026Review
- IRP1 deficiency alters mitochondrial metabolism and protects against metabolic syndrome pathologies.JCI insight · 2026Article
- Elucidating the Molecular Network Underpinning Hypoxia Adaptation in the Liver of Silver Carp (Animals : an open access journal from MDPI · 2025Article
- Stroke in High-Altitude Areas.Brain and behavior · 2025Review
- Leptin and Insulin in COPD: Unveiling the Metabolic-Inflammatory Axis-A Narrative Review.Journal of clinical medicine · 2025Review
- [Adaptive Regulation of Glucose Metabolism and Diseases in High-Altitude Areas].Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition · 2024Review
- Prone positioning is associated with increased insulin requirements in mechanically ventilated patients with COVID-19.Scientific reports · 2024Article
- Comorbidity Genes of Alzheimer's Disease and Type 2 Diabetes Associated with Memory and Cognitive Function.International journal of molecular sciences · 2024Review
- Hypoxia-Induced Signaling in Gut and Liver Pathobiology.Annual review of pathology · 2024Review
- Comprehensive analysis of hypoxia-related genes in diagnosis and immune infiltration in acute myocardial infarction: based on bulk and single-cell RNA sequencing data.Frontiers in molecular biosciences · 2024Article
- Dysregulation of hypoxia-inducible factor 1α in the sympathetic nervous system accelerates diabetic cardiomyopathy.Cardiovascular diabetology · 2023Article
- Regulation of erythroid differentiation in K562 cells by the EPAS1-IRS2 axis under hypoxic conditions.Frontiers in cell and developmental biology · 2023Article
- Hypoxia signaling in human health and diseases: implications and prospects for therapeutics.Signal transduction and targeted therapy · 2022Review
- Hypoxia Promotes Glioma Stem Cell Proliferation by Enhancing the 14-3-3Journal of immunology research · 2022Article
- Prenatal alcohol-induced sex differences in immune, metabolic and neurobehavioral outcomes in adult rats.Brain, behavior, and immunity · 2021Article
- Mild chronic hypoxia-induced HIF-2α interacts with c-MYC through competition with HIF-1α to induce hepatocellular carcinoma cell proliferation.Cellular oncology (Dordrecht, Netherlands) · 2021Article
- The transcriptional coregulator CITED2 suppresses expression of IRS-2 and impairs insulin signaling in endothelial cells.American journal of physiology. Endocrinology and metabolism · 2021Article
- Review
- HIF-1α is necessary for activation and tumour-promotion effect of cancer-associated fibroblasts in lung cancer.Journal of cellular and molecular medicine · 2021Article
- Endothelial TFEB (Transcription Factor EB) Improves Glucose Tolerance via Upregulation of IRS (Insulin Receptor Substrate) 1 and IRS2.Arteriosclerosis, thrombosis, and vascular biology · 2021Article
11 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
22 authors at 3 institutions in 1 country.
Funding
Abstract
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.