National Institutes of Health-funded researchers at Johns Hopkins Medicine's Wilmer Eye Institute have identified a critical mechanism by which hypoglycemia contributes to diabetic retinopathy progression and demonstrated that an experimental drug can prevent this damage. The findings, published in Science Translational Medicine on April 30, provide new insights into why strict glucose control sometimes paradoxically worsens diabetic eye disease.
HIF Protein Drives Retinal Barrier Breakdown
The research team discovered that low blood sugar promotes breakdown of the blood-retinal barrier, an essential boundary regulating nutrient, waste, and water flow in the retina. During hypoglycemic episodes, a protein called hypoxia-inducible factor (HIF) accumulates in specific retinal cells, triggering a cascade that leads to blood vessel overgrowth and leakage.
In experiments with diabetic mice, researchers induced periods of low blood sugar and observed that diabetic animals showed elevated HIF levels sufficient to compromise the blood-retinal barrier and cause retinal blood vessel leakage. Mice without diabetes did not experience these elevated HIF levels during hypoglycemia, highlighting the unique vulnerability of diabetic patients.
Experimental Drug Prevents Retinal Damage
The team tested an experimental compound known as 32-134D, which inhibits HIF protein activity. Diabetic mice that received 32-134D injections prior to induced hypoglycemic episodes showed lower HIF levels and prevented expression of proteins that promote blood-retinal barrier breakdown and vessel leakage.
"These studies help explain why patients with diabetes who are initially started on tight glucose control, the cornerstone of diabetic management, or those who have high glycemic variability (transient episodes of very low-followed by very high-serum glucose levels), experience worsening of their diabetic eye disease," said corresponding author Akrit Sodhi, M.D., Ph.D., associate professor of ophthalmology and the Branna and Irving Sisenwein Professor of Ophthalmology at the Johns Hopkins University School of Medicine and the Wilmer Eye Institute.
Clinical Implications and Future Research
The findings address a longstanding clinical puzzle regarding why some diabetic patients experience retinopathy progression despite improved glucose control. Diabetic retinopathy, a severe complication affecting both type 1 and type 2 diabetes patients, can cause permanent vision damage if untreated.
"Our findings underscore why therapies targeting HIF will be an effective approach to prevent or treat diabetic retinopathy," Sodhi explained. The research team is planning future studies investigating HIF, blood-retinal barrier breakdown, and the experimental drug 32-134D, with hopes to advance to clinical trials in diabetic retinopathy patients.
The study provides a mechanistic explanation for the retinal damage observed in patients with glycemic variability and suggests that HIF-targeting therapies could offer a new therapeutic approach for preventing vision loss in diabetic patients.
