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Cited by 230Pancreatic function and diabetesDiabetes and associated disordersDiabetes Treatment and Management

Hypoxia-inducible factor-1α regulates β cell function in mouse and human islets

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Cheng, Kim, Ho, Kenneth, Stokes, Rebecca, Scott, Christopher, Lau, Sue Mei, Hawthorne, Wayne J., O’Connell, Philip J., Loudovaris, Thomas +13 more·2010·Journal of Clinical Investigation
DOI 10.1172/jci35846PMC PMC2877560
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Abstract

Hypoxia-inducible factor-1alpha (HIF-1alpha) is a transcription factor that regulates cellular stress responses. While the levels of HIF-1alpha protein are tightly regulated, recent studies suggest that it can be active under normoxic conditions. We hypothesized that HIF-1alpha is required for normal beta cell function and reserve and that dysregulation may contribute to the pathogenesis of type 2 diabetes (T2D). Here we show that HIF-1alpha protein is present at low levels in mouse and human normoxic beta cells and islets. Decreased levels of HIF-1alpha impaired glucose-stimulated ATP generation and beta cell function. C57BL/6 mice with beta cell-specific Hif1a disruption (referred to herein as beta-Hif1a-null mice) exhibited glucose intolerance, beta cell dysfunction, and developed severe glucose intolerance on a high-fat diet. Increasing HIF-1alpha levels by inhibiting its degradation through iron chelation markedly improved insulin secretion and glucose tolerance in control mice fed a high-fat diet but not in beta-Hif1a-null mice. Increasing HIF-1alpha levels markedly increased expression of ARNT and other genes in human T2D islets and improved their function. Further analysis indicated that HIF-1alpha was bound to the Arnt promoter in a mouse beta cell line, suggesting direct regulation. Taken together, these findings suggest an important role for HIF-1alpha in beta cell reserve and regulation of ARNT expression and demonstrate that HIF-1alpha is a potential therapeutic target for the beta cell dysfunction of T2D.

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  • In pancreatic β cells, excessive HIF-1α signaling driven by hypoxia, glucotoxicity, or oxidative stress impairs mitochondrial metabolism and ATP production, compromising glucose-stimulated insulin secretion.

    “In pancreatic β cells, excessive HIF-1α signaling - driven by hypoxia, glucotoxicity, or oxidative stress - impairs mitochondrial metabolism and ATP production, thereby compromising glucose stimulated insulin secretion [[238], [239], [240]].”

    From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [239]

    The Discussion (page unavailable) says very high HIF-1α levels, including those associated with severe hypoxia, are deleterious to β-cell function; the section on methods of increasing HIF-1α reports impaired glucose-stimulated insulin secretion after marked HIF-1α overexpression. But the paper attributes reduced ATP generation to decreased HIF-1α, not excessive signaling, and does not establish impaired mitochondrial metabolism or glucotoxicity and oxidative stress as causes of the claimed pathway. (LLM, conf=0.88)

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Research works printed but not linked: 68

  1. Hofer T, Wenger H, Gassmann M. Oxygen sensing, HIF-1α stabilization and potential therapeutic strategies. Pflugers Arch. 2002;443(4):503-507.
  2. Semenza GL. Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol. 1999;15:551-578.
  3. Kotch LE, Iyer NV, Laughner E, Semenza GL. Defective vascularization of HIF-1α-null embryos is not associ- ated with VEGF deficiency but with mesenchymal cell death. Dev Biol. 1999;209(2):254-267.
  4. Cowden Dahl KD, et al. Hypoxia-inducible factors 1{alpha} and 2{alpha} regulate trophoblast differ- entiation. Mol Cell Biol. 2005;25(23):10479-10491.
  5. Ryan HE, Lo J, Johnson RS. HIF-1[alpha] is required for solid tumor formation and embryonic vascular- ization. EMBO J. 1998;17(11):3005-3015.
  6. Buchler P, et al. Hypoxia-inducible factor 1 regu- lates vascular endothelial growth factor expres- sion in human pancreatic cancer. Pancreas. 2003; 26(1):56-64.
  7. Walmsley SR, et al. Hypoxia-induced neutrophil survival is mediated by HIF-1alpha-dependent NF- kappaB activity. J Exp Med. 2005;201(1):105-115.
  8. Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab. 2006;3(3):187-197.
  9. Kim JW, Tchernyshyov I, Semenza GL, Dang CV. HIF- 1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adap- tation to hypoxia. Cell Metab. 2006;3(3):177-185.
  10. Hopfl G, et al. Rescue of hypoxia-inducible fac- tor-1α-deficient tumor growth by wild-type cells is independent of vascular endothelial growth factor. Cancer Research. 2002;62(10):2962-2970.
  11. Maxwell PH, Pugh CW, Ratcliffe PJ. Activation of the HIF pathway in cancer. Curr Opin Genet Dev. 2001; 11(3):293-299.
  12. Ryan HE, et al. Hypoxia-inducible factor-1α is a positive factor in solid tumor growth. Cancer Research. 2000;60(15):4010-4015.
  13. Semenza GL. HIF-1 and human disease: one highly involved factor. Genes Dev. 2000;14(16):1983-1991.
  14. Woodward ER, Maher ER. Von Hippel-Lindau dis- ease and endocrine tumour susceptibility. Endocr Relat Cancer. 2006;13(2):415-425.
  15. Guillemin K, Krasnow MA. The hypoxic response: Huffing and HIFing. Cell. 1997;89(1):9-12.
  16. Kewley RJ, Whitelaw ML, Chapman-Smith A. The mammalian basic helix-loop-helix/PAS family of transcriptional regulators. Int J Biochem Cell Biol. 2004;36(2):189-204.
  17. Bunn HF, Poyton RO. Oxygen sensing and molec- ular adoption to hypoxia. Physiological Reviews. 1996;76(3):839-885.
  18. Lee JW, Bae SH, Jeong JW, Kim SH, Kim KW. Hypoxia- inducible factor (HIF-1alpha): its protein stability and biological functions. Exp Mol Med. 2004;36(1):1-12.
  19. Gunton JE, et al. Loss of ARNT/HIF1beta medi- ates altered gene expression and pancreatic-islet dysfunction in human type 2 diabetes. Cell. 2005; 122(3):337-349.
  20. Wang XL, et al. Ablation of ARNT/HIF1β in liver alters gluconeogenesis, lipogenic gene expression, and serum ketones. Cell Metabolism. 2009;9(5):428-439.
  21. Lum JJ, et al. The transcription factor HIF-1alpha plays a critical role in the growth factor-dependent regulation of both aerobic and anaerobic glycoly- sis. Genes Dev. 2007;21(9):1037-1049.
  22. Ratcliffe PJ. HIF-1 and HIF-2: working alone or togeth- er in hypoxia. J Clin Invest. 2007;117(4):862-865.
  23. Ruas JL, Poellinger L. Hypoxia-dependent activa- tion of HIF into a transcriptional regulator. Semin Cell Dev Biol. 2005;16(4-5):514-522.
  24. Salceda S, Caro J. Hypoxia-inducible factor 1α (HIF- 1α) protein is rapidly degraded by the ubiquitin- proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox induced changes. J Biol Chem. 1997;272(36):22642-22647.
  25. Triantafyllou A, Liakos P, Tsakalof A, Georgatsou E, Simos G, Bonanou S. Cobalt induces hypoxia- inducible factor-1alpha (HIF-1alpha) in HeLa cells by an iron-independent, but ROS-, PI-3K-and MAPK-dependent mechanism. Free Radic Res. 2006; 40(8):847-856.
  26. Maxwell PH, et al. The tumour suppressor pro- tein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature. 1999; 399(6733):271-275.
  27. Epstein ACR, et al. C. elegans EGL-9 and mamma- lian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell. 2001; 107(1):43-54.
  28. Stroka DM, et al. HIF-1 is expressed in normoxic tis- sue and displays an organ-specific regulation under systemic hypoxia. FASEB J. 2001;15(13):2445-2453.
  29. Cramer T, et al. HIF-1α is essential for myeloid cell- mediated inflammation. Cell. 2003;112(5):645-657.
  30. Bonello S, et al. Reactive oxygen species activate the HIF-1alpha promoter via a functional NFkappaB site. Arterioscler Thromb Vasc Biol. 2007;27(4):755-761.
  31. Biswas S, Gupta MK, Chattopadhyay D, Mukho- padhyay CK. Insulin-induced activation of hypox- ia-inducible factor-1 requires generation of reac- tive oxygen species by NADPH oxidase. Am J Physiol Heart Circ Physiol. 2007;292(2):H758-H766.
  32. Zelzer E, Levy Y, Kahana C, Shilo BZ, Rubinstein M, Cohen B. Insulin induces transcription of target genes through the hypoxia inducible factor HIF- 1alpha/ARNT. EMBO J. 1998;17(17):5085-5094.
  33. Jiang BH, Jiang G, Zheng JZ, Lu Z, Hunter T, Vogt PK. Phosphatidylinositol 3-kinase signalling controls levels of hypoxia-inducible factor 1. Cell Growth Differ. 2001;12(7):363-369.
  34. Treins C, Giorgetti-Peraldi S, Murdaca J, Semenza GL, Van Obberghen E. Insulin stimulates hypoxia- inducible factor 1 through a phosphatidylinositol 3-kinase/target of rapamycin-dependent signalling pathway. J Biol Chem. 2002;277(31):27975-27981.
  35. Doronzo G, Russo I, Mattiello L, Riganti C, Anfossi G, Trovati M. Insulin activates hypoxia-inducible factor-1alpha in human and rat vascular smooth muscle cells via phosphatidylinositol-3 kinase and mitogen-activated protein kinase pathways: impair- ment in insulin resistance owing to defects in insu- lin signalling. Diabetologia. 2006;49(5):1049-1063.
  36. Carlsson PO, Liss P, Andersson A, Jansson L. Measure- ments of oxygen tension in native and transplanted rat pancreatic islets. Diabetes. 1998;47(7):1027-1032.
  37. Carlsson PO, Palm F. Oxygen tension in isolated transplanted rat islets and in islets of rat whole-pan- creas transplants. Transpl Int. 2002;15(11):581-585.
  38. Puri S, Cano DA, Hebrok M. A role for von Hip- pel-Lindau protein in pancreatic beta-cell function. Diabetes. 2009;58(2):433-441.
  39. Zehetner J, et al. pVHL is a regulator of glucose metabolism and insulin secretion in pancreatic beta-cells. Genes Dev. 2008;22(22):3135-3146.
  40. Tomita S, et al. Defective brain development in mice lacking the Hif-1alpha gene in neural cells. Mol Cell Biol. 2003;23(19):6739-6749.
  41. Gerich JE. The genetic basis of type 2 diabetes mel- litus: impaired insulin secretion versus impaired insulin sensitivity. Endocr Rev. 1998;19(4):491-503.
  42. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased beta- cell apoptosis in humans with type 2 diabetes. Dia- betes. 2003;52(1):102-110.
  43. Marchetti P, et al. Pancreatic islets from type 2 dia- betic patients have functional defects and increased apoptosis that are ameliorated by metformin. J Clin Endocrinol Metab. 2004;89(11):5535-5541.
  44. Del Guerra S, et al. Functional and molecular defects of pancreatic islets in human type 2 diabe- tes. Diabetes. 2005;54(3):727-735.
  45. Deng S, et al. Structural and functional abnormali- ties in the islets isolated from type 2 diabetic sub- jects. Diabetes. 2004;53(3):624-632.
  46. Hu FB, et al. Dietary fat intake and the risk of coro- nary heart disease in women. N Engl J Med. 1997; 337(21):1491-1499.
  47. Miller WC, Niederpruem MG, Wallace JP, Linde- man AK. Dietary fat, sugar, and fiber predict body fat content. J Am Diet Assoc. 1994;94(6):612-615.
  48. Fukuda R, Zhang H, Kim J, Shimoda L, Dang CV, Semenza GL. HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells. Cell. 2007;129(1):111-122.
  49. Gnarra JR, et al. Defective placental vasculogenesis causes embryonic lethality in VHL-deficient mice. Proc Natl Acad Sci U S A. 1997;94(17):9102-9107.
  50. Kleymenova E, Everitt JI, Pluta L, Portis M, Gnarra JR, Walker CL. Susceptibility to vascular neoplasms but no increased susceptibility to renal carcino- genesis in Vhl knockout mice. Carcinogenesis. 2004; 25(3):309.
  51. Chetty R, Kennedy M, Ezzat S, Asa SL. Pancreatic endocrine pathology in von Hippel-Lindau disease: an expanding spectrum of lesions. Endocr Pathol. 2004;15(2):141-148.
  52. Perigny M, et al. Pancreatic endocrine microadeno- matosis in patients with von Hippel-Lindau disease: characterization by VHL/HIF pathway proteins expression. Am J Surg Pathol. 2009;33(5):739-748.
  53. Lott ST, et al. High frequency loss of heterozygos- ity in von Hippel-Lindau (VHL)-associated and spo- radic pancreatic islet cell tumors evidence for a step- wise mechanism for malignant conversion in VHL Tumorigenesis 1. Cancer Res. 2002;62(7):1952-1955.
  54. Hammel PR, et al. Pancreatic involvement in von Hippel-Lindau disease. Gastroenterology. 2000; 119(4):1087-1095.
  55. Pollard PJ, et al. Accumulation of Krebs cycle inter- mediates and over-expression of HIF1{alpha} in tumours which result from germline FH and SDH mutations. Hum Mol Genet. 2005;14(15):2231-2239.
  56. Ciara MM, Diana EB, Deborah JM, Bruce GR, Mar- garet RZ. K40E: a novel succinate dehydrogenase (SDH)B mutation causing familial phaeochromo- cytoma and paraganglioma. Clin Endocrinol (Oxf). 2004;61(4):510-514.
  57. Ascherio A, Rimm EB, Giovannucci E, Willett WC, Stampfer MJ. Blood donations and risk of coronary heart disease in men. Circulation. 2001;103(1):52-57.
  58. De Sanctis V, Zurlo MG, Senesi E, Boffa C, Cavallo L, Di Gregorio F. Insulin dependent diabetes in thalassaemia. Arch Dis Child. 1988;63(1):58-62.
  59. Ford ES, Cogswell ME. Diabetes and serum ferritin concentration among US adults. Diabetes Care. 1999; 22(12):1978-1983.
  60. Fernandez-Real JM, Lopez-Bermejo A, Ricart W. Iron stores, blood donation, and insulin sensitivity and secretion. Clin Chem. 2005;51(7):1201-1205.
  61. Jiang R, Manson JE, Meigs JB, Ma J, Rifai N, Hu FB. Body iron stores in relation to risk of type 2 diabetes in apparently healthy women. JAMA. 2004; 291(6):711-717.
  62. Wrede CE, Buettner R, Bollheimer LC, Scholmerich J, Palitzsch KD, Hellerbrand C. Association between serum ferritin and the insulin resistance syndrome in a representative population. Eur J Endocrinol. 2006;154(2):333-340.
  63. Salonen JT, Tuomainen TP, Nyyssonen K, Lakka HM, Punnonen K. Relation between iron stores and non-insulin-dependent diabetes in men: case-control study. BMJ. 1999;317(7160):727.
  64. Fernández-Real JM, et al. Serum ferritin as a com- ponent of the insulin resistance syndrome. Diabetes Care. 1998;21(1):62-68.
  65. Lee DH, Folsom AR, Jacobs DRJ. Dietary iron intake and type 2 diabetes incidence in postmeno- pausal women: the Iowa Women's Health Study. Diabetologia. 2004;47(2):185-194.
  66. Fernandez-Real JM, Penarroja G, Castro A, Garcia- Bragado F, Hernandez-Aguado I, Ricart W. Blood let- ting in high-ferritin type 2 diabetes: effects on insu- lin sensitivity and beta-cell function. Diabetes. 2002; 51(4):1000-1004.
  67. Miyazaki J, et al. Establishment of a pancreatic beta cell line that retains glucose inducible insu- lin secretion: Special reference to expression of glucose transporter isoforms. Endocrinology. 1990; 127(1):126-132.
  68. Gunton JE, Delhanty PJ, Takahashi S, Baxter RC. Metformin rapidly increases insulin receptor acti- vation in human liver and signals preferentially through insulin-receptor substrate-2. J Clin Endo- crinol Metab. 2003;88(3):1323-1332.

Cited by

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Authors
Cheng, K., Ho, K., Stokes, R., Scott, C., Lau, S. M., Hawthorne, W. J., O’Connell, P. J., Loudovaris, T., Kay, T. W., Kulkarni, R. N., Okada, T., Wang, X. L., Yim, S. H., Shah, Y., Grey, S. T., Biankin, A. V., Kench, J. G., Laybutt, D. R., Gonzalez, F. J., Kahn, C. R., & Gunton, J. E.
Affiliations
  • Garvan Institute of Medical Research (AU)
  • The University of Sydney (AU)
  • Joslin Diabetes Center (US)
  • National Institutes of Health (US)
Corresponding author
Gunton, Jenny E.
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2010-06-01
Volume
120
Issue
6
Pages
2171-2183
ISSN
0021-9738 (ISSN-L)
DOI
10.1172/jci35846
PMC
PMC2877560
OpenAlex
W2158255229
Cited by
230
References
13
Citations by year
2026: 7 · 2025: 8 · 2024: 14 · 2023: 18 · 2022: 17 · 2021: 14 · 2020: 11 · 2019: 17 · 2018: 15 · 2017: 11 · 2016: 14 · 2015: 6 · 2014: 19 · 2013: 20 · 2012: 26
FWCI
19.93
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Pfizer
  • Diabetes Australia Research Trust
  • Diabetes Australia
  • Cancer Institute NSW
  • Royal Australasian College of Physicians
  • Servier
  • National Institutes of Health
  • Medical Research Council
  • National Health and Medical Research Council
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK60837-02, R01 DK-67536, R01 DK-33201, K08 DK02885, K08DK002885, R01DK060837, R01DK033201, R01DK067536)
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Keywords
hypoxia-inducible factor-1α, beta-cell function, pancreatic islets, type 2 diabetes, beta-cell reserve, insulin secretion, impaired glucose tolerance, high-fat diet, iron chelation, ARNT, transcriptional regulation
MeSH terms
Animals, Hypoxia, Cell Line, Glucose, Humans, Insulin, Mice, Inbred C57BL, Transcription Factors, Mice, Knockout, Insulin-Secreting Cells, Mice, Hypoxia-Inducible Factor 1, alpha Subunit

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