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Cited by 400Cancer, Hypoxia, and MetabolismDiabetes Management and ResearchMetabolism, Diabetes, and Cancer

Hypoxia and hypoxia-inducible factors in diabetes and its complications

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Catrina, Sergiu-Bogdan, Zheng, Xiaowei·2021·Diabetologia
DOI 10.1007/s00125-021-05380-zPMC PMC7940280
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Abstract

Hypoxia-inducible factors (HIFs) are the key regulators of oxygen homeostasis in response to hypoxia. In diabetes, multiple tissues are hypoxic but adaptive responses to hypoxia are impaired due to insufficient activation of HIF signalling, which results from inhibition of HIF-1α stability and function due to hyperglycaemia and elevated fatty acid levels. In this review, we will summarise and discuss current findings about the regulation of HIF signalling in diabetes and the pathogenic roles of hypoxia and dysregulated HIF signalling in the development of diabetes and its complications. The therapeutic potential of targeting HIF signalling for the prevention and treatment of diabetes and related complications is also discussed. Graphical abstract

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  • Pathological HIF activation plays a key role in diabetic complications including nephropathy, retinopathy, and impaired wound healing, largely by driving aberrant angiogenesis, fibrosis, and vascular dysfunction.

    “In parallel, pathological HIF activation plays a key role in diabetic complications, including nephropathy, retinopathy, and impaired wound healing, largely by driving aberrant angiogenesis, fibrosis, and vascular dysfunction in hypoxic and inflamed tissues [26,232,247].”

    From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [232]

    The ‘HIFs and diabetic retinopathy’ section links HIF-1 to angiogenesis in proliferative retinopathy, and ‘HIFs and diabetic nephropathy’ links increased HIF-1 in mesangial cells to renal fibrosis. But the paper says impaired wound healing is associated with HIF-1 inhibition, not pathological activation; it also describes HIF-1 activation in the diabetic kidney as submaximal overall. The claim therefore reverses the paper’s account of wound healing and overgeneralises its kidney findings. Page numbers were not available in our copy. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Dysregulated HIF signaling contributes to the pathogenesis of metabolic diseases, including diabetes mellitus and its complications.

    “Importantly, dysregulated HIF signaling also contributes to the pathogenesis of metabolic diseases, including diabetes mellitus and its complications [231,232].”

    From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [232]

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References 54 · Cited by 400

Research works printed but not linked: 48

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Authors
Catrina, S.-B., & Zheng, X.
Affiliations
  • Karolinska University Hospital (SE)
  • Karolinska Institutet (SE)
Corresponding author
  • Catrina, Sergiu-Bogdan
  • Zheng, Xiaowei
ORCID
Venue
Diabetologia
Publisher
Springer Science and Business Media LLC
Published
2021-01-26
Volume
64
Issue
4
Pages
709-716
ISSN
  • 0012-186X (ISSN-L)
  • 1432-0428
DOI
10.1007/s00125-021-05380-z
PMC
PMC7940280
OpenAlex
W3125563499
Cited by
400
References
54
Citations by year
2026: 67 · 2025: 83 · 2024: 89 · 2023: 89 · 2022: 60 · 2021: 12
FWCI
7.57
Type
journal article
Language
en
Open access
Licence
Locations
  • Diabetologia (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
Swedish Research Council (013-66-104153-33)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
hypoxia, hypoxia-inducible factor, HIF-1α stability, diabetes mellitus, diabetes complications, oxygen homeostasis, hyperglycemia, fatty acids
MeSH terms
Endothelial PAS Domain-Containing Protein 1, Animals, Blood Glucose, Diabetes Mellitus, Humans, Hypoglycemic Agents, Oxygen, Repressor Proteins, Signal Transduction, Cell Hypoxia, Diabetes Complications, Apoptosis Regulatory Proteins, Basic Helix-Loop-Helix Proteins, Basic Helix-Loop-Helix Transcription Factors, Hypoxia-Inducible Factor 1, alpha Subunit, Molecular Targeted Therapy, Cellular Microenvironment, Prolyl-Hydroxylase Inhibitors

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