In industrialised nations, diabetic retinopathy (DR) is the primary cause of blindness in people. Microvasculopathy and neurodegeneration are both implicated in the processes of DR development, with neuronal damage occurring before microvascular abnormalities, which is frequently overlooked in the clinic. Most current treatment methods, such as anti-vascular endothelial growth factor (anti-VEGF) antibodies, are aimed at treating the advanced phases (diabetic macular edoema and proliferative diabetic retinopathy) and do not address neuronal degeneration. As a result, novel treatment approaches addressing both vascular and neural damage are urgently required. The hypoxia-inducible factor 1 (HIF1)–6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) pathway is important in diabetic islet pathophysiology. Recent research has emphasised the importance of pathways in pathologic angiogenesis and neurodegeneration, two important features of DR. Along with VEGF, PFKFB3 plays an important role in sprouting angiogenesis by regulating endothelial tip-cell competition. Furthermore, PFKFB3-driven glycolysis reduces neurons’ antioxidative ability, resulting in neuronal loss and reactive gliosis.
As a result, the HIF1-PFKFB3 signalling pathway is unusual in that it is an ubiquitous pathogenic component in numerous cell types in the retina in both the early and late phases of DR. Thus, a metabolic point-of-intervention based on HIF1-PFKFB3 targeting merits further investigation in DR.