• Hypoglycemia in diabetic mice increases HIF levels, promoting blood-retinal barrier breakdown and retinal vascular leakage, worsening diabetic retinopathy.
• An experimental drug, 32-134D, inhibits HIF and prevents retinal damage in diabetic mice, indicating a potential therapeutic target.
• The findings explain why tight glucose control or fluctuating blood sugar levels can worsen diabetic eye disease, highlighting the importance of HIF-targeting therapies.

New research from Johns Hopkins Medicine's Wilmer Eye Institute reveals that low blood sugar, or hypoglycemia, can exacerbate diabetic retinopathy by promoting the breakdown of the blood-retinal barrier. The study, conducted on diabetic mice, found that hypoglycemia increases levels of hypoxia-inducible factor (HIF), a protein linked to abnormal blood vessel growth and leakage in the retina. Blocking HIF with an experimental drug, 32-134D, prevented this damage, suggesting a promising therapeutic approach for preventing or treating diabetic retinopathy.

• What: Hypoglycemia can worsen diabetic retinopathy by promoting the breakdown of the blood-retinal barrier due to increased HIF levels.
• Who: Researchers at the Wilmer Eye Institute, Johns Hopkins Medicine, led by Akrit Sodhi, conducted the study on diabetic mice.
• When: The study was published in Science Translational Medicine on April 30, 2025 (based on the article date).
• Where: The research was conducted at Johns Hopkins Medicine's Wilmer Eye Institute and involved collaborations with the University of California, Davis, and the University of Maryland.

The study provides a crucial link between hypoglycemia and the progression of diabetic retinopathy, challenging the traditional focus solely on hyperglycemia. The identification of HIF as a key mediator in the breakdown of the blood-retinal barrier opens new avenues for therapeutic intervention. The successful use of the experimental drug 32-134D to block HIF and prevent retinal damage offers a promising outlook for future clinical trials and potential treatments for diabetic retinopathy. However, further research is needed to validate these findings in human subjects and to assess the long-term safety and efficacy of HIF inhibitors.

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.

Our findings underscore why therapies targeting HIF will be an effective approach to prevent or treat diabetic retinopathy.

The research demonstrates that hypoglycemia can exacerbate diabetic retinopathy through a HIF-mediated mechanism, offering a new understanding of the disease's progression. The experimental drug 32-134D shows promise as a potential therapeutic agent by inhibiting HIF and preventing retinal damage. While further studies are needed, these findings represent a significant step forward in the development of targeted treatments for diabetic retinopathy, particularly for patients experiencing fluctuating blood sugar levels.