Summary: New research indicates that episodes of low blood sugar (hypoglycemia) can weaken the blood-retinal barrier and thereby exacerbate diabetic retinopathy. In diabetic mice, hypoglycemia elevated levels of hypoxia-inducible factor (HIF), a protein known to drive abnormal blood vessel growth and leakage in the retina.
An experimental dual HIF inhibitor, 32-134D, blocked this effect in the study, preventing barrier breakdown and vascular leakage. These results help explain why some patients with strict glucose control or wide glucose fluctuations experience early worsening of diabetic eye disease and point to a potential new therapeutic avenue.
Key findings:
- HIF activation during hypoglycemia: Transient low blood glucose raised retinal HIF levels in diabetic mice, triggering pathways that promote vascular leakage.
- Barrier disruption linked to vision risk: HIF-driven breakdown of the inner blood-retinal barrier (iBRB) contributes to retinal injury and vision loss in diabetes.
- Experimental drug shows efficacy: The HIF inhibitor 32-134D prevented HIF accumulation, reduced expression of vasoactive mediators, and blocked iBRB breakdown in treated diabetic mice.
Source: JHU
Overview of the study
A National Institutes of Health–funded team at the Wilmer Eye Institute, Johns Hopkins Medicine, examined how hypoglycemia affects the retina in diabetic mice. Their work focuses on the blood-retinal barrier, a selective boundary that controls nutrient, ion, protein and water movement into and out of the retina. When this barrier fails, the resulting retinal edema and vascular damage are major drivers of vision loss in diabetic retinopathy.
Published in Science Translational Medicine on April 30, the study identifies hypoxia-inducible factors HIF-1α and HIF-2α as central mediators that accumulate in retinal cells during episodes of low blood glucose. HIF proteins are transcription factors that trigger expression of many vasoactive genes linked to vessel permeability and neovascularization—processes that underlie diabetic retinal disease.
Using controlled hypoglycemic episodes in mice with and without diabetes, researchers found that only diabetic animals showed a significant HIF increase during low blood sugar. That HIF rise was sufficient to induce vesicular transcytosis and breach the inner blood-retinal barrier, producing measurable retinal vascular leakage. Non-diabetic mice did not exhibit these changes under the same hypoglycemic conditions.
To test whether blocking HIF could prevent damage, the investigators administered 32-134D, a pharmacologic inhibitor of both HIF-1 and HIF-2, to diabetic mice before inducing hypoglycemia. Treated mice showed reduced HIF accumulation and lower expression of HIF-dependent vasoactive mediators, which correlated with preserved barrier integrity and reduced vascular leakage.
Corresponding author Akrit Sodhi, M.D., Ph.D., associate professor of ophthalmology at the Johns Hopkins University School of Medicine and the Wilmer Eye Institute, observes that these results shed light on a clinical paradox: tight glycemic control and large glycemic variability can sometimes precede worsening diabetic eye disease. The study suggests that hypoglycemia-driven HIF activation helps explain that phenomenon and supports HIF inhibition as a therapeutic strategy.
The team plans additional preclinical work to further explore HIF biology, iBRB breakdown and the safety and efficacy of 32-134D, with the aim of advancing to clinical testing in patients with diabetic retinopathy.
Contributing authors include Chuanyu Guo, Yueqi Niu, Xuemei Pan, Deepti Sharma, Evan Lau, Yang Jin, Md Amanullah, Kevin Lo, Jiang Qian (Wilmer Eye Institute, Johns Hopkins Medicine); Guillaume Luxardi and Ala Moshiri (University of California, Davis); and Silvia Montaner (University of Maryland). Xuemei Pan is also affiliated with the Shandong University of Traditional Chinese Medicine.
Funding: This research was supported by the National Eye Institute (NIH grants R01EY029750, EY035889, EY032104 and EY001765); Research to Prevent Blindness, Inc.; the Norman Raab Foundation; and the Branna and Irving Sisenwein Professorship in Ophthalmology, among other sources.
About this visual neuroscience research news
Author: Haley Wasserman
Source: JHU
Contact: Haley Wasserman – JHU
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“Hypoglycemia promotes inner blood-retinal barrier breakdown and retinal vascular leakage in diabetic mice” by Akrit Sodhi et al., Science Translational Medicine.
Abstract
Hypoglycemia promotes inner blood-retinal barrier breakdown and retinal vascular leakage in diabetic mice
The blood-retinal barrier (BRB) is a selective physiological boundary that controls the movement of nutrients, waste products, ions, proteins and water to and from the retina. In diabetic retinopathy, breakdown of the inner BRB (iBRB) damages the neurovascular unit and is a central cause of vision loss.
This study demonstrates that hypoglycemia—a common consequence of intensive glucose control and high glycemic variability—causes accumulation of HIF-1α and HIF-2α and induces expression of many HIF-dependent vasoactive mediators in the mouse retina. In diabetic animals, even modest increases in these HIF-driven factors were sufficient to trigger vesicular transcytosis, compromise the iBRB, and increase retinal vascular permeability.
Genetic suppression of HIF-1α or HIF-2α alone did not fully prevent the broad HIF-dependent transcriptional response to hypoglycemia, so the researchers evaluated a dual pharmacologic inhibitor, 32-134D. The compound effectively reduced HIF-1α accumulation and HIF-regulated gene expression in human retinal tissue ex vivo. In diabetic mice, intravitreal 32-134D blocked the hypoglycemia-induced rise in vasoactive genes, preserved iBRB integrity, and prevented retinal hyperpermeability.
Together, these findings provide a mechanistic explanation for early worsening of diabetic retinopathy in patients who experience hypoglycemia during intensive glycemic management and support clinical evaluation of HIF inhibition with 32-134D as a preventive strategy.