New research from Johns Hopkins Medicine is shedding light on an unexpected contributor to diabetic retinopathy: low blood sugar. This serious eye condition, a common complication of both type 1 and type 2 diabetes, has long been associated with high blood sugar levels. However, a new study funded by the National Institutes of Health and published in Science Translational Medicine suggests that episodes of hypoglycemia may also play a damaging role—specifically by weakening the blood-retinal barrier and promoting vision loss.

Diabetic retinopathy is one of the leading causes of blindness in adults. It occurs when prolonged exposure to fluctuating blood sugar levels damages the tiny blood vessels in the retina, the light-sensitive tissue at the back of the eye. While high glucose has been the main focus of treatment and prevention efforts, this new research indicates that low glucose events can be equally harmful, particularly in individuals with diabetes who experience wide swings in blood sugar levels.

The study, led by scientists at the Wilmer Eye Institute at Johns Hopkins, focused on a protein known as hypoxia-inducible factor (HIF). HIF is known to accumulate in retinal cells during periods of low oxygen or low glucose. In the context of diabetic retinopathy, HIF appears to act as a molecular switch, triggering the production of other proteins that cause blood vessels in the retina to leak or grow abnormally—both hallmarks of the disease.

In their experiments, researchers induced hypoglycemia in mice with and without diabetes. The diabetic mice exhibited elevated levels of HIF during these low blood sugar episodes, which in turn led to a breakdown in the blood-retinal barrier and leakage from retinal blood vessels. In contrast, non-diabetic mice did not show this same response, suggesting that diabetes alters how the retina reacts to glucose fluctuations.

One aspect I found particularly striking was how the study connects the dots between tight glucose control—often seen as the gold standard in diabetes management—and potential worsening of eye disease. Dr. Akrit Sodhi, the study’s corresponding author and an associate professor of ophthalmology at Johns Hopkins, noted that patients who experience high glycemic variability, characterized by swings from very low to very high blood sugar, may be at greater risk for progression of diabetic retinopathy. This insight could have significant implications for how clinicians balance glucose targets with the need to avoid hypoglycemia.

To further explore the role of HIF, the team tested an experimental drug, 32-134D, designed to inhibit the protein. Diabetic mice that received this treatment before being subjected to low blood sugar showed significantly lower levels of HIF. As a result, the harmful cascade of protein activity that leads to blood-retinal barrier breakdown was curtailed. These findings suggest that targeting HIF could be a promising therapeutic avenue for preventing or slowing the progression of diabetic retinopathy, especially in patients prone to hypoglycemic episodes.

While the current research is limited to animal models, the implications for human treatment are compelling. The team plans to continue studying the mechanisms behind HIF activation and hopes to launch clinical trials of 32-134D in the future. If successful, this could mark a significant advancement in the treatment of diabetic eye disease, offering a new strategy alongside existing therapies that primarily address high blood sugar and its long-term effects.

In addition to the potential for new treatment options, this study underscores the importance of personalized diabetes management. Patients and healthcare providers may need to reconsider how aggressively blood sugar is controlled, particularly in individuals who are newly diagnosed or who experience frequent hypoglycemic events. The balance between preventing long-term complications and avoiding short-term lows is more delicate than previously understood.

Researchers from multiple institutions contributed to the study, including the University of California, Davis, and the University of Maryland. Funding was provided by the National Eye Institute and other supporting organizations, reflecting the collaborative effort behind this important work on diabetic retinopathy and vision loss.

As research continues, the hope is that therapies targeting HIF will not only preserve vision but also improve the quality of life for millions of people living with diabetes. For now, the study serves as a timely reminder that both high and low blood sugar levels deserve careful attention when it comes to managing this complex disease.

Read more at sciencedaily.com