Hypoxia-inducible factors and diabetes
Jenny E. Gunton
Jenny E. Gunton
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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 3

HIF-1α and diabetes: effects and unknowns.

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HIF-1α and diabetes: effects and unknowns. Purple “OH” indicates hydroxy...
Purple “OH” indicates hydroxylation of HIF-1α on proline residues, and blue “OH” indicates hydroxylation on asparagine residues. In the liver, HIF-2α rather than HIF-1α primarily mediates some effects, as indicated. Red arrows indicate primarily deleterious effects of either increasing or decreasing hypoxia, green indicates beneficial effects, and “~” indicates neutral effects. Question marks indicate unknowns and areas for potential future investigation. †Whole-body hypoxia is decreased on chow, but improved on high-fat diet. *Note that while hypoxia is clearly a feature of macrovascular disease, hypoxic pre-exposure before the event (i.e., stroke or myocardial infarct) improves outcomes. Overall, fully hydroxylated HIF and severe hypoxia are both deleterious.