Vision loss is a complication for many diabetic patients. In patients with diabetic retinopathy, the principal cause of vision loss is the breakdown of the inner blood-retinal barrier (iBRB)—an important boundary that regulates the flow of nutrients, waste, and water in and out of the retina—due to damage to the neurovascular unit.
Now, researchers suggest that hypoglycemia results in the accumulation of the transcription factors hypoxia-inducible factor-1α (HIF-1α) and HIF-2α, altering gene expression in the mouse retina. In turn, the promotion of a breakdown of the blood-retinal barrier led to an accumulation of vasoactive mediators, which increases retinal permeability.
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.
This work is published in Science Translational Medicine in the paper, “Hypoglycemia promotes inner blood-retinal barrier breakdown and retinal vascular leakage in diabetic mice.”
“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 Akrit Sodhi, MD, PhD, associate 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.”
The findings suggest that 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 leads to overgrowth and leakage of blood vessels in the retina. Now, scientists have found that HIF plays a role 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. More specifically, the work showed that “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.” 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.
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.
The post Vision Loss in Diabetic Mice Promoted by Hypoglycemia, Treated with HIF Inhibitors appeared first on GEN - Genetic Engineering and Biotechnology News.
Now, researchers suggest that hypoglycemia results in the accumulation of the transcription factors hypoxia-inducible factor-1α (HIF-1α) and HIF-2α, altering gene expression in the mouse retina. In turn, the promotion of a breakdown of the blood-retinal barrier led to an accumulation of vasoactive mediators, which increases retinal permeability.
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.
This work is published in Science Translational Medicine in the paper, “Hypoglycemia promotes inner blood-retinal barrier breakdown and retinal vascular leakage in diabetic mice.”
“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 Akrit Sodhi, MD, PhD, associate 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.”
The findings suggest that 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 leads to overgrowth and leakage of blood vessels in the retina. Now, scientists have found that HIF plays a role 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. More specifically, the work showed that “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.” 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.
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.
The post Vision Loss in Diabetic Mice Promoted by Hypoglycemia, Treated with HIF Inhibitors appeared first on GEN - Genetic Engineering and Biotechnology News.