Diabetic retinopathy is the leading cause of blindness in working-age Americans and one of the top reasons for vision loss worldwide (1). It can affect people with either type 1 or type 2 diabetes, and existing treatments are invasive and limited in scope.
Tight glucose control — moderating blood sugar levels through diet, exercise, and medication — can help prevent or delay the progression of diabetic retinopathy, but people often experience a surge in retinopathy during the first 12 to 18 months after initiating treatment.
Researchers postulate that this phenomenon occurs because the retina is “shocked” when glucose levels fall in response to insulin therapy and glucose control, said Lars Michael Larsen, an ophthalmologist at the University of Copenhagen. “This has always been a paradox,” he added. Retinopathy stabilizes after a year or so, but the initial damage can be significant.
New research from Akrit Sodhi, an ophthalmologist at Johns Hopkins University School of Medicine, and his team revealed that low blood sugar, or hypoglycemia, exacerbates damage to the retinal vasculature by altering gene expression in retinal cells (2). In mice, an experimental drug blocked these gene expression changes and offered some protection against retinopathy, providing a potential solution to the treatment paradox.
Diabetic retinopathy develops when blood vessels in the back of the eye break down. The damaged vessels leak blood and fluid, which can lead to inflammation and blood vessel proliferation, compromising vision over time.
“Diabetic retinopathy is almost expected in patients with diabetes,” said Sodhi. “If it is allowed to progress, with time, it will lead to vision loss.”
Diabetic retinopathy is almost expected in patients with diabetes.
- Akrit Sodhi, Johns Hopkins University School of Medicine
In an earlier study, Sodhi and his colleagues found that short intervals of hypoglycemia drove up the production of hypoxia inducible factor (HIF), a protein that regulates the expression of many different genes, including ones that control blood vessel growth (3). In this new study, the researchers compared the consequences of elevated HIF in mice with and without diabetes.
The mice without diabetes tolerated HIF, but mice that were diabetic for as little as three months showed signs of vascular leakage, indicating breakdown of the blood-retinal barrier in response to hypoglycemia-induced HIF accumulation. The experimental cancer drug 32-134D, which blocks HIF activity, prevented this effect.
The gold standard drugs for treating diabetic retinopathy — vascular endothelial growth factor (VEGF) inhibitors — target VEGF, which is just one of the proteins that HIF regulates. Blocking HIF reduced VEGF activity and dialed down expression of other genes involved with blood vessel growth in diabetic mice. Given that HIF modulates hundreds of genes, the researchers will have to monitor for other unwanted effects in future studies.
“We are looking at taking this drug into patients,” said Sodhi. “There's potential benefit and also things we have to look out for with HIF inhibition.”
Larsen, who was not involved in the new research, said that the results from this new study are encouraging. Translated into clinical practice, “it means we should prioritize stability of glycemia,” he added, not just lowering blood sugar.
References
- Lundeen, E.A. et al. Prevalence of Diabetic Retinopathy in the US in 2021. JAMA Ophthalmol 141, 747–754 (2023).
- Guo, C. et al. Hypoglycemia promotes inner blood-retinal barrier breakdown and retinal vascular leakage in diabetic mice. Sci Transl Med 17, eadq5355 (2025).
- Guo, C. et al. HIF-1α accumulation in response to transient hypoglycemia may worsen diabetic eye disease. Cell Rep 42,111976 (2023).
