Hypoxia and hypoxia-inducible factors in diabetes and its complications

Abstract

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.

Keywords: Diabetes; Diabetes complications; Diabetic foot ulcer; Diabetic nephropathy; Diabetic retinopathy; Hypoxia; Hypoxia-inducible factor; Insulin resistance; Prolyl hydroxylase inhibitor; Review.

Fig. 1

Regulation of HIF-1 under non-diabetic and diabetic conditions. (a) In normoxia, HIF-1α is hydroxylated by PHD in the presence of Fe²⁺ and 2-oxoglutarate (2-OG). The hydroxylated HIF-1α is recognised by VHL, which mediates the ubiquitylation and proteasomal degradation of HIF-1α. Succinate can inhibit the PHD-mediated degradation of HIF-1α. HIF-1α can also be hydroxylated at an asparagine residue (N803) by factor-inhibiting HIF-1 (FIH-1), which prevents the recruitment of coactivators. (b) Under hypoxic and non-diabetic conditions, HIF-1α is stabilised and translocates to the nucleus, where it dimerises with HIF-1β on the HRE of target genes, recruits coactivators including p300, and activates the transcription of HIF-1 target genes that mediate adaptive responses to hypoxia. (c) In diabetes, despite profound hypoxia, HIF-1α stability and function are inhibited, leading to insufficient HIF-1 activation and, therefore, impaired adaptive responses to hypoxia. Mechanistically, hyperglycaemia not only promotes PHD-mediated HIF-1α degradation but also induces methylglyoxal-mediated modification of HIF-1α, which facilitates the carboxy terminus of Hsp70-interacting protein (CHIP)-mediated HIF-1α ubiquitylation. Methylglyoxal also inhibits HIF-1 dimerisation and coactivator recruitment through modification of p300. Moreover, elevated fatty acids can promote PHD-mediated HIF-1α degradation by decreasing succinate levels in type 2 diabetes. This figure is available as part of a downloadable slideset

Fig. 2

Impaired responses to hypoxia due to HIF-1 inhibition in diabetes contribute to the development of diabetes and diabetes complications. (a) Under non-diabetic conditions, HIF-1 signalling is induced in response to lowered oxygen levels, leading to homeostasis in hypoxia. (b) Under diabetic conditions, although tissues are more hypoxic, HIF-1 signalling is inhibited resulting in impaired adaptive responses to hypoxia, contributing to the development of diabetes and its complications. This figure is available as part of a downloadable slideset