HIF-1α accumulation in response to transient hypoglycemia may worsen diabetic eye disease

Tight glycemic control (TGC), the cornerstone of diabetic management, reduces the incidence and progression of diabetic microvascular disease. However, TGC can also lead to transient episodes of hypoglycemia, which have been associated with adverse outcomes in patients with diabetes. Here, we demonstrate that low glucose levels result in hypoxia-inducible factor (HIF)-1-dependent expression of the glucose transporter, Glut1, in retinal cells. Enhanced nuclear accumulation of HIF-1α was independent of its canonical post-translational stabilization but instead dependent on stimulation of its translation and nuclear localization. In the presence of hypoxia, this physiologic response to low glucose resulted in a marked increase in the secretion of the HIF-dependent vasoactive mediators that promote diabetic retinopathy. Our results provide a molecular explanation for how early glucose control, as well as glycemic variability (i.e., oscillating serum glucose levels), contributes to diabetic eye disease. These observations have important implications for optimizing glucose management in patients with diabetes. [Display omitted] •Diabetic patients experience brief episodes of low glucose (hypoglycemia) each day•In retinal glial cells, hypoglycemia promotes the HIF-dependent expression of GLUT1•Hypoglycemia increases expression of HIF-dependent angiogenic mediators•This physiologic response causes paradoxical worsening of diabetic retinopathy Guo et al. show that transient episodes of hypoglycemia enhance the nuclear accumulation of HIF-1α, resulting in increased expression of GLUT1 in retinal glial cells. In the presence of hypoxia, this physiologic response results in a pathologic increase in the secretion of HIF-dependent angiogenic mediators that worsen diabetic eye disease.