Accumulating evidence suggests that hypoxia and inappropriate responses to hypoxia due to dysregulated HIF-1 signalling are important pathogenic factors, occurring both in tissues central for the development of diabetes (pancreatic beta cells and adipose tissue) and in tissues susceptible to diabetes complications (nerves, retina, heart, blood vessels, kidney and wounds).
HIFs and impaired wound healing in diabetes
The pathogenic relevance of HIF-1 inhibition in diabetes was initially observed in diabetic wounds [11, 12]. Inhibited HIF-1 signalling contributes to impaired wound healing in diabetes, with induction of HIF-1 function promoting wound healing by increasing angiogenesis and fibroblast proliferation and migration in mouse models of diabetes [11, 20, 21]. As an iron-chelating agent clinically used to treat iron toxicity, deferoxamine (desferrioxamine) can reduce oxidative stress and induce HIF-1 activation, thereby accelerating diabetic wound healing . A topical drug delivery system has been recently optimised and a clinical trial (ClinicalTrials.gov registration no. NCT03137966) is planned to test its efficacy in patients with diabetic foot ulcers.
HIFs and diabetic nephropathy
Hypoxia is present in the kidney of individuals with type 1 diabetes and type 2 diabetes [22, 23]; in animal models it is found as early as three days after the induction of diabetes, predominantly in the medullary region (reviewed recently in ). Hypoxia in renal tubules is the driving force for tubular atrophy and interstitial fibrosis, which can further reinforce glomerular pathology during the development of diabetic nephropathy . Renal tubular hypoxia is mainly attributable to increased oxygen consumption due to increased flux through the Na+–glucose cotransporter and increased mitochondrial uncoupling-induced leak respiration . Tubular hypoxia promotes extracellular matrix expansion, resulting in further decreases in oxygen delivery and the initiation of a vicious cycle that contributes to the development of diabetic nephropathy .
The regulation of HIF-1 in diabetic kidney depends on the cell type. In mesangial cells, high glucose increases the expression of HIF-1α and its target gene ADAM17, which accelerates renal fibrosis [19, 25]. However, HIF-1 is inhibited by high glucose levels in proximal tubular cells in hypoxia, which can be reversed by PHD inhibition and VHL deficiency [16, 26]. Overall, HIF-1 activation in the diabetic kidney is submaximal relative to the degree of hypoxia. Although absolute HIF-1α levels in diabetic kidney may remain unchanged or even increase, they are significantly lower relative to those in profound hypoxia . Indeed, HIF-1 induction by PHD inhibitors can prevent the progression of diabetic nephropathy in animal models of both type 1 and type 2 diabetes [8, 27].
HIFs and diabetic hearts
Cardiovascular disorders, including CHD, heart failure and diabetic cardiomyopathy, are the leading cause of mortality in individuals with diabetes and their prognosis is poor after myocardial infarction or heart failure.
Properly activated HIF-1 signalling is vital for cardiac survival after myocardial ischaemia or heart failure . However, HIF-1 signalling is inhibited in poorly controlled diabetes in direct connection with metabolic control . Recently, fatty acids were suggested to play an additional role in HIF repression in cardiomyocytes with a type 2 diabetes-like phenotype . Reversal of HIF-1 inhibition in diabetic hearts by pharmacological inhibition of PHD improved cardiac recovery after ischaemia in a rat model of type 2 diabetes .
Diabetes accelerates atherosclerosis by inducing endothelial dysfunction, inter-plaque haemorrhage and plague destabilisation. Although HIF-1 has been reported to have both beneficial and pathological roles in experimental atherosclerosis, genetic and pharmacological inhibition of PHD protects against the development of atherosclerosis in high-fat-diet-fed LDL receptor-deficient mice .
HIFs and diabetic retinopathy
Diabetic retinopathy has a progressive evolution. The initial, non-proliferative, phase is characterised by a loss of pericyte function resulting in microvascular abnormalities. These lead to hypoxia, an increased expression of angiogenic factors and subsequent neovascularisation, which characterise what is known as the proliferative phase. While the detrimental role of HIF-1 as a central stimulator of angiogenesis in the proliferative phase of diabetic retinopathy is established, proper HIF-1 function during the early stage of diabetic retinopathy is protective, due to its anti-inflammatory, antiapoptotic and antioxidative effects . Indeed, the HIF-1A (also known as HIF1A) Pro582Ser polymorphism, which is resistant to inhibition by hyperglycaemia, is protective against the development of severe diabetic retinopathy .
HIFs in adipose tissue and obesity
Hypoxia in adipose tissue is an early event in the course of obesity and leads to dysregulated adipokine production, inflammation and the metabolic syndrome. However, the role of HIF signalling in the development of obesity and metabolic disease is still controversial.
Some studies suggest a detrimental role of HIF activation in the pathogenesis of obesity and metabolic diseases. Exposure to hypoxia inhibits insulin signalling in adipocytes through HIF-1 and HIF-2 . Genetic or pharmacological HIF-1 inactivation can prevent or reverse obesity-induced inflammation and insulin resistance [10, 33]. This is confirmed by data showing insulin resistance and adipose tissue fibrosis in transgenic mice overexpressing Hif1a .
However, recent studies using genetic or pharmacological PHD inhibition revealed a beneficial role of HIF activation in metabolic diseases. PHD2-hypomorphic mice, whether fed normal chow or a high-fat diet, displayed reduced adiposity, adipose tissue inflammation and hepatic steatosis, along with improved glucose tolerance and insulin sensitivity . Adipose PHD2 deficiency or pharmacological PHD2 inhibition also increased adipose mass; however, reduced adipocyte lipolysis and normal glucose tolerance were also observed . Moreover, the PHD inhibitor FG-4497 can reverse the metabolic dysfunction in aged or HDF-fed mice and in ob/ob mice .
The discrepancies between the results of these studies may stem from the distinct animal models used. However, they may also reflect the complex role of HIF signalling in metabolic diseases and stress the fundamental importance of adequate HIF function (neither too much nor too little) for the maintenance of homeostasis in hypoxic adipose tissue. Further investigations are warranted to elucidate the role of HIF-1 in obesity and metabolic diseases.
HIFs and pancreatic beta cell function
Pancreatic islets from diabetic mice are hypoxic and high glucose induces hypoxia in beta cells and in isolated islets .
The protective role of HIF signalling in islet function and survival is the subject of a recent, excellent review . Several studies have reported a protective role of HIF signalling for islet function and survival [38, 39]. Knockdown of HIF-1α or HIF-1β in beta cells was shown to inhibit glucose-stimulated insulin release. Interestingly, reduced HIF-1α and HIF-1β expression have been observed in the islets of individuals with type 2 diabetes, suggesting that islet HIF-1 inhibition may be a pathogenic mechanism in type 2 diabetes [38, 40]. Indeed, mice with a beta cell-specific HIF-1α deletion are more susceptible to type 1 diabetes after exposure to coxsackieviruses or beta cell toxin . HIF-1 is also activated in beta cells during the pre-diabetes period of type 1 diabetes, where it is suggested to have a protective role .
Conversely, other studies have pointed to a potentially deleterious effect of HIF-1 on islet function. For instance, VHL gene deletion induces beta cell dysfunction that can be reversed by deletion of HIF-1α. Moreover, mice with beta cell or pancreas-specific VHL knockout develop glucose intolerance with impaired insulin secretion [43,44,45]. These results are in line with a recent study showing that mice with beta cell-specific HIF-1β knockout are protected from high-fat-diet-induced diabetes , suggesting a detrimental role of HIF-1 activation in beta cell function.
Taken together, these results indicate an important role for HIF-1 in regulating beta cell function and glucose tolerance. They also point to the importance of balanced HIF-1 signalling for proper beta cell function. Extremely low or extremely high HIF-1 levels after HIF-1 deletion, homozygous VHL deletion, severe hypoxia or HIF-1α overexpression are deleterious, while an increase in HIF-1α in response to hypoxia is beneficial for beta cell function and glucose tolerance.
HIF-1A polymorphism and diabetes
The HIF-1A Pro582Ser polymorphism confers resistance to hyperglycaemia-mediated inhibition of HIF-1 activity and protects against the development of diabetic nephropathy, severe diabetic retinopathy and diabetic foot ulcers [7, 31, 47]. The HIF-1A Pro582Ser polymorphism is also protective against the occurrence of diabetes in the Japanese population .
HIFs and epigenetic regulation in diabetes
HIFs control the expression and/or activity of epigenetic regulators that facilitate adaptation to hypoxia. Epigenetic regulation, including DNA methylation, histone modification and non-coding RNA, is also involved in the regulation and function of HIF signalling  and the pathogenesis of diabetes and its complications . Epigenetic regulation seems to be an important mechanism underlying HIF regulation and function in response to hypoxia in diabetes. Its significance as a potential therapeutic target warrants further investigation.