Hypoxia-inducible factors and diabetes

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-1 alpha 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-1 alpha protein and has wide-ranging benefits, some of which are at least partially mediated by HIF-1 alpha. Nevertheless, most strategies to improve diabetes or its complications via regulation of HIF-1 alpha 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-1 alpha, even within the same tissues. This Review presents a brief overview of HIFs; discusses the range of evidence implicating HIFs in beta cell dysfunction, diabetes pathogenesis, and diabetes complications; and examines the differing outcomes of HIF-targeting approaches in these conditions.