Summary: New research reveals that hypoglycemia may worsen diabetic retinopathy by breaking down the blood-retinal barrier. In diabetic mice, low blood sugar increased levels of hypoxia-inducible factor (HIF), a protein linked to abnormal blood vessel growth and leakage.
Blocking HIF with an experimental drug prevented this damage, suggesting a promising new therapeutic target. These findings offer insights into why patients with tight glucose control or fluctuating blood sugar levels may experience worsening eye disease.
Key Facts:
- HIF Activation During Hypoglycemia: Low blood sugar raised HIF levels in diabetic mice, triggering retinal blood vessel leakage.
- Barrier Breakdown Linked to Vision Loss: HIF-driven disruption of the blood-retinal barrier may worsen diabetic retinopathy.
- Experimental Drug Shows Promise: Blocking HIF with 32-134D prevented retinal leakage and offers a potential new treatment approach.
Source: JHU
In a new National Institutes of Health-funded study led by scientists at the Wilmer Eye Institute, Johns Hopkins Medicine researchers say they have determined that low blood sugar, or hypoglycemia, may promote a breakdown of the blood-retinal barrier, an important boundary that regulates the flow of nutrients, waste and water in and out of the retina.
The research, which investigated the phenomenon in diabetic mice, provides insights into the origin of diabetic retinopathy, specifically in patients with episodes of hypoglycemia. Diabetic retinopathy, a severe complication of both type 1 and type 2 diabetes, can cause permanent vision damage if left untreated.
The full study, published in Science Translational Medicine on April 30, explains that a specific protein known as hypoxia-inducible factor (HIF) accumulates in certain cells in the retina during periods of low blood sugar.
HIF has been implicated in diabetic retinopathy and other eye diseases before. The protein can trigger a chain reaction, switching on overproduction of other proteins which lead to overgrowth and leakage of blood vessels in the retina. Now, scientists have found that HIF is a player in how the blood-retinal barrier breaks down during hypoglycemia.
Researchers tested HIF’s role in hypoglycemia by inducing periods of low blood sugar in mice with and without diabetes. Their experiments showed that mice with diabetes had higher levels of HIF during hypoglycemia, enough to promote the breakdown of the blood-retinal barrier and cause leakage in retinal blood vessels, while mice without diabetes did not experience higher levels of HIF.
This breakdown in diabetic retinopathy contributes to irreversible damage to the retina and vision loss.
The team investigated further by testing an experimental drug known as 32-134D, which inhibits the HIF protein. Some diabetic mice received an injection of 32-134D prior to induced episodes of low blood sugar, and researchers observed lower HIF levels, in turn preventing the expression of proteins that promote the breakdown of the blood-retinal barrier and blood 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,” says 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.
“Our findings underscore why therapies targeting HIF will be an effective approach to prevent or treat diabetic retinopathy.”
Researchers are planning future studies on HIF, the breakdown of the blood-retinal barrier and 32-134D, and hope to conduct clinical studies of 32-134D in patients with diabetic retinopathy.
Additional authors for this study include Chuanyu Guo, Yueqi Niu, Xuemei Pan, Deepti Sharma, Evan Lau, Yang Jin, Md Amanullah, Kevin Lo and Jiang Qian of the Wilmer Eye Insitute, Johns Hopkins Medicine; Guillaume Luxardi and Ala Moshiri of the University of California, Davis; and Silvia Montaner of the University of Maryland. Xuemei Pan also has affiliations to the Shandong University of Traditional Chinese Medicine.
Funding: This work was supported by the National Eye Institute, NIH grants R01EY029750, EY035889, EY032104 and EY001765; the Research to Prevent Blindness, Inc., Special Scholar Award and unrestricted grants to the Wilmer Eye Institute, Johns Hopkins Medicine; the Norman Raab Foundation; and the Branna and Irving Sisenwein Professorship in Ophthalmology.
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) serves as a physiological boundary regulating the passage of nutrients, waste, ions, proteins, and water to and from the retina.
In patients with diabetic retinopathy, breakdown of the inner BRB (iBRB) results in damage to the neurovascular unit and is a principal cause of vision loss in the diabetic population.
Here, we demonstrate that hypoglycemia, a common consequence of tight glycemic control and high glycemic variability, results in accumulation of the transcription factors hypoxia-inducible factor-1α (HIF-1α) and HIF-2α and the expression of dozens of HIF-dependent vasoactive mediators in the mouse retina.
In diabetic mice, this modest increase in HIF-dependent hyperpermeability factors was sufficient to promote vesicular transcytosis, breakdown of the iBRB, and retinal vascular permeability.
Genetic inhibition of either HIF-1α or HIF-2α resulted in an incomplete inhibition of the broad increase in HIF-regulated vasoactive gene expression in response to hypoglycemia.
We therefore evaluated a pharmacologic dual HIF-1 and HIF-2 inhibitor, 32-134D, as a therapeutic approach to prevent hypoglycemia-induced HIF-dependent vasoactive gene expression. 32-134D effectively inhibited HIF-1α accumulation and HIF-regulated gene expression in human retinal tissue.
In diabetic mice, intravitreal administration of 32-134D prevented the increase in expression of HIF-regulated vasoactive genes after transient episodes of hypoglycemia, blocking both breakdown of the iBRB and the promotion of retinal vascular hyperpermeability.
Collectively, these observations help explain why patients with diabetes initiating tight glycemic control have worsening of their diabetic retinopathy and provide the foundation for clinical studies assessing HIF inhibition with 32-134D for its prevention.
