Hypoxia-inducible factors and diabetes
Jenny E. Gunton
Jenny E. Gunton
Published August 18, 2020
Citation Information: J Clin Invest. 2020;130(10):5063-5073. https://doi.org/10.1172/JCI137556.
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Review Series Endocrinology

Hypoxia-inducible factors and diabetes

Abstract

Hypoxia can be defined as a relative deficiency in the amount of oxygen reaching the tissues. Hypoxia-inducible factors (HIFs) are critical regulators of the mammalian response to hypoxia. In normal circumstances, HIF-1α protein turnover is rapid, and hyperglycemia further destabilizes the protein. In addition to their role in diabetes pathogenesis, HIFs are implicated in development of the microvascular and macrovascular complications of diabetes. Improving glucose control in people with diabetes increases HIF-1α protein and has wide-ranging benefits, some of which are at least partially mediated by HIF-1α. Nevertheless, most strategies to improve diabetes or its complications via regulation of HIF-1α have not currently proven to be clinically useful. The intersection of HIF biology with diabetes is a complex area in which many further questions remain, especially regarding the well-conducted studies clearly describing discrepant effects of different methods of increasing HIF-1α, even within the same tissues. This Review presents a brief overview of HIFs; discusses the range of evidence implicating HIFs in β cell dysfunction, diabetes pathogenesis, and diabetes complications; and examines the differing outcomes of HIF-targeting approaches in these conditions.

Authors

Jenny E. Gunton

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Figure 1

bHLH-PAS family and HIF-1 protein.

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bHLH-PAS family and HIF-1 protein. (A) Basic helix-loop-helix–PER-ARNT-S...
(A) Basic helix-loop-helix–PER-ARNT-SIM (bHLH-PAS) family proteins work as heterodimers with a class I and a class II member. (B) HIF-1α protein is regulated by iron and oxygen availability. In the presence of adequate oxygen, iron, and 2-oxo-glutarate (normoxia, left), little HIF-1α escapes rapid hydroxylation (OH), ubiquitination (Ub) by von Hippel-Lindau protein (VHL), and proteolysis. With deficiency of iron (middle) or oxygen (right), HIF-1α protein accumulates and binds to HIF-1β, and then the dimer binds to hypoxia response elements (HREs) to regulate gene expression. HIF, hypoxia inducible factor; AhR, aryl hydrocarbon receptor; SIM, single-minded; CLOCK, circadian locomotor output cycles kaput protein; NPAS, neuronal PAS protein; ARNT, aryl hydrocarbon receptor nuclear translocator; BMAL, bone morphogenetic ARNT-like.