Hypoxia and hypoxia-inducible factors in diabetes and its complications

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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.

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The online version contains a slideset of the figures for download, available at 10.1007/s00125-021-05380-z.

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Hypoxia-inducible factor 1alpha induces fibrosis and insulin resistance in white adipose tissue.

Nils Halberg, Tayeba Khan, Maria Trujillo … (2009)

Adipose tissue can undergo rapid expansion during times of excess caloric intake. Like a rapidly expanding tumor mass, obese adipose tissue becomes hypoxic due to the inability of the vasculature to keep pace with tissue growth. Consequently, during the early stages of obesity, hypoxic conditions cause an increase in the level of hypoxia-inducible factor 1alpha (HIF1alpha) expression. Using a transgenic model of overexpression of a constitutively active form of HIF1alpha, we determined that HIF1alpha fails to induce the expected proangiogenic response. In contrast, we observed that HIF1alpha initiates adipose tissue fibrosis, with an associated increase in local inflammation. "Trichrome- and picrosirius red-positive streaks," enriched in fibrillar collagens, are a hallmark of adipose tissue suffering from the early stages of hypoxia-induced fibrosis. Lysyl oxidase (LOX) is a transcriptional target of HIF1alpha and acts by cross-linking collagen I and III to form the fibrillar collagen fibers. Inhibition of LOX activity by beta-aminoproprionitrile treatment results in a significant improvement in several metabolic parameters and further reduces local adipose tissue inflammation. Collectively, our observations are consistent with a model in which adipose tissue hypoxia serves as an early upstream initiator for adipose tissue dysfunction by inducing a local state of fibrosis.

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Advances in Hypoxia-Inducible Factor Biology.

Adrian L Harris, Hani Choudhry (2018)

Hypoxia-inducible factor (HIF), a central regulator for detecting and adapting to cellular oxygen levels, transcriptionally activates genes modulating oxygen homeostasis and metabolic activation. Beyond this, HIF influences many other processes. Hypoxia, in part through HIF-dependent mechanisms, influences epigenetic factors, including DNA methylation and histone acetylation, which modulate hypoxia-responsive gene expression in cells. Hypoxia profoundly affects expression of many noncoding RNAs classes that have clinicopathological implications in cancer. HIF can regulate noncoding RNAs production, while, conversely, noncoding RNAs can modulate HIF expression. There is recent evidence for crosstalk between circadian rhythms and hypoxia-induced signaling, suggesting involvement of molecular clocks in adaptation to fluxes in nutrient and oxygen sensing. HIF induces increased production of cellular vesicles facilitating intercellular communication at a distance-for example, promoting angiogenesis in hypoxic tumors. Understanding the complex networks underlying cellular and genomic regulation in response to hypoxia via HIF may identify novel and specific therapeutic targets.

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Proximal Tubulopathy: Prime Mover and Key Therapeutic Target in Diabetic Kidney Disease.

Richard Gilbert (2017)

The current view of diabetic kidney disease, based on meticulously acquired ultrastructural morphometry and the utility of measuring plasma creatinine and urinary albumin, has been almost entirely focused on the glomerulus. While clearly of great importance, changes in the glomerulus are not the major determinant of renal prognosis in diabetes and may not be the primary event in the development of diabetic kidney disease either. Indeed, advances in biomarker discovery and a greater appreciation of tubulointerstitial histopathology and the role of tubular hypoxia in the pathogenesis of chronic kidney disease have given us pause to reconsider the current "glomerulocentric" paradigm and focus attention on the proximal tubule that by virtue of the high energy requirements and reliance on aerobic metabolism render it particularly susceptible to the derangements of the diabetic state. Such findings raise important issues for therapeutic advances specifically targeting the pathophysiological perturbations that develop in this part of the nephron.

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Author and article information

Contributors

Sergiu-Bogdan Catrina:

ORCID: https://orcid.org/0000-0002-6914-3902

Sergiu-Bogdan.Catrina@ki.se

Xiaowei Zheng:

ORCID: https://orcid.org/0000-0002-2648-1119

Xiaowei.zheng@ki.se

Journal

Journal ID (nlm-ta): Diabetologia

Journal ID (iso-abbrev): Diabetologia

Title: Diabetologia

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 0012-186X

ISSN (Electronic): 1432-0428

Publication date (Electronic): 26 January 2021

Publication date PMC-release: 26 January 2021

Publication date (Print): 2021

Volume: 64

Issue: 4

Pages: 709-716

Affiliations

[1 ]GRID grid.4714.6, ISNI 0000 0004 1937 0626, Department of Molecular Medicine and Surgery, , Karolinska Institutet, ; Stockholm, Sweden

[2 ]GRID grid.24381.3c, ISNI 0000 0000 9241 5705, Department of Endocrinology and Diabetes, , Karolinska University Hospital, ; Stockholm, Sweden

[3 ]Center for Diabetes, Academic Specialist Centrum, Stockholm, Sweden

Author information

Sergiu-Bogdan Catrina https://orcid.org/0000-0002-6914-3902

Xiaowei Zheng https://orcid.org/0000-0002-2648-1119

Article

Publisher ID: 5380

DOI: 10.1007/s00125-021-05380-z

PMC ID: 7940280

PubMed ID: 33496820

SO-VID: b4498b76-149f-40ac-a886-c3b6e45e74dc

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 18 September 2020

Date accepted : 26 November 2020

Funding

Funded by: Swedish Research Council

Award ID: 013-66-104153-33

Custom metadata

ScienceOpen disciplines: Endocrinology & Diabetes

Keywords: diabetes,diabetes complications,diabetic foot ulcer,diabetic nephropathy,diabetic retinopathy,hypoxia,hypoxia-inducible factor,insulin resistance,prolyl hydroxylase inhibitor,review

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ScienceOpen disciplines: Endocrinology & Diabetes

Keywords: diabetes, diabetes complications, diabetic foot ulcer, diabetic nephropathy, diabetic retinopathy, hypoxia, hypoxia-inducible factor, insulin resistance, prolyl hydroxylase inhibitor, review

Hypoxia and hypoxia-inducible factors in diabetes and its complications

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Most cited references 52

Hypoxia-inducible factor 1alpha induces fibrosis and insulin resistance in white adipose tissue.

Advances in Hypoxia-Inducible Factor Biology.

Proximal Tubulopathy: Prime Mover and Key Therapeutic Target in Diabetic Kidney Disease.

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