Regulation of hypoxia-inducible factor 1 and the loss of the cellular response to hypoxia in diabetes

Diabetes is frequently associated with hypoxia and is known to impair ischaemia-induced neovascularisation and other forms of adaptive cell and tissue responses to low oxygen levels. Hyperglycaemia appears to be the driving force of such deregulation. Recent data indicate that destabilisation of hypoxia-inducible factor 1 (HIF-1) is most likely the event that transduces hyperglycaemia into the loss of the cellular response to hypoxia in most diabetic complications. HIF-1 is a critical transcription factor involved in oxygen homeostasis that regulates a variety of adaptive responses to hypoxia, including angiogenesis, metabolic reprogramming and survival. Thus, destabilisation of HIF-1 is likely to have a negative impact on cell and tissue adaptation to low oxygen. Indeed, destabilisation of HIF-1 by high glucose levels has serious consequences in various organs and tissues, including myocardial collateralisation, wound healing, renal, neural and retinal function, as a result of poor cell and tissue responses to low oxygen. This review aims to integrate and summarise some of the most recent developments, including new proposed molecular models, on this research topic, particularly in terms of their implications for potential therapeutic approaches for the prevention or treatment of some of the diabetic complications characterised by impaired cellular and tissue responses to hypoxia.