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Stopping the Damage From Diabetic Retinopathy

Posted by Ilena Di Toro | Posted on June 20, 2023

Diabetic retinopathy occurs when there is damage to the blood vessels in the retina, and it is the leading cause of blindness for adults in the U.S. Since diabetes causes this and a host of other complications, scientists are working to learn more about what causes diabetic retinopathy in the hopes of developing treatments and possibly reversing this disease. Work done at Johns Hopkins and the University of Alabama at Birmingham highlights two ways diabetes can damage vision and two ways the damage can be stopped.

Work at Johns Hopkins dealt with what happens to eye cells when they are in a low sugar environment. Their work has shown that when there are low levels of glucose, there is an increase in certain retinal cell proteins, which then leads to an overgrowth of blood vessels and worsening diabetic eye disease.

Researchers in the lab of Akrit Sodhi, M.D., Ph.D., the Branna and Irving Sisenwein Professor of Ophthalmology at the Wilmer Eye Institute at Johns Hopkins School of Medicine, studied protein levels in human and mouse retinal cells that grew in low glucose environment, as well as mice that had occasional low blood sugar. They found that low glucose levels in both the human and mice cells lead to a series of molecular changes that lead to excessive blood vessel growth and lead to a decrease in the cells’ ability to break down glucose for energy.

Specifically, they looked at supportive cells for the retina’s neurons, known as Müller glial cells, that rely on glucose for energy production. What the researchers found is that the cells increased production of the GLUT1 gene. This gene makes a protein that brings the glucose into the cells. When the glucose level is low, the cells respond with increased levels of a transcription factor (a gene that regulates the copying of RNA as it makes a protein), known as hypoxia-inducible factor (HIF)-1α. The HIF-1α turns on the cells, including GLUT1, needed to improve their ability to make use of the glucose that is available. This, in turn, preserves the limited oxygen that is available for energy production by retinal neurons.

With low oxygen environments, it’s a different story. When there are low levels of oxygen, as is the case with persons who have diabetic eye disease, the normal response to decreasing glucose triggers a huge amount of HIF-1α protein into the cells’ nucleus. This also leads to an increase in the production of other proteins, such as VEGF and ANGPTL4, which cause the growth of abnormal and leaky blood vessels, leading to vision loss in people with diabetic eye disease. As bad as the increase HIF-1α protein into the cell nucleus is, Sodhi thinks it might serve as a target for developing treatments for diabetic eye disease.

Of course, how does the damage to the eye start? A study done at the University of Alabama at Birmingham looked at Type 1 diabetes and how a leaky small intestine plays a part in diabetic blindness.

Maria Grant, MD, professor in the University of Alabama at Birmingham Department of Ophthalmology and Visual Sciences, led a team of researchers to study the mechanisms that lead to diabetic retinopathy. Researchers looked at the blood from human subjects with Type 1 diabetes and a mouse model to learn more about diabetic retinopathy.

Previous studies by other researchers found that by measuring levels of certain biomarkers and immune cells in the blood, including gut microbial antigens, they found that human subjects with diabetic retinopathy had dysregulated systemic RAS, which is a system of hormones and enzymes that regulate blood pressure and other metabolic changes. They also had acute gut permeability flaws that activated both the adaptive and innate immune response. If that wasn’t bad enough, those with severe diabetic retinopathy also had increased levels of gut permeability biomarkers and a gut microbial antigen. All of this leads to increased levels of the RAS hormone angiotensin II, which can lead to high blood pressure and fluid retention.

Other researchers who used a mouse model for Type 1 diabetes gave the mice a probiotic treatment that prevented intestinal epithelial and endothelial barrier damage. This probiotic is known as the ACE2-producing Lactobacillus paracasei and it was developed by Qiuhong Li, Ph.D., from the University of Florida. Grant’s lab found evidence that several mechanisms contributed the ACE2-reduced gut barrier and the ACE2-lowering of blood sugar. This research demonstrated that dysregulated intestinal RAS leads to the movement of gut microbial antigens into the plasma, which leads to an inflammatory endothelium and subsequently leads to diseases, such as diabetic retinopathy.

“To our knowledge, this study represents the first time that gut barrier disruption has been implicated in the pathogenesis of diabetic retinopathy and also directly links gut leakage with retinopathy severity in human subjects with Type 1 diabetes,” said Maria Grant, M.D., leader of the research team at the University of Alabama at Birmingham Department of Ophthalmology and Visual Sciences.

These projects show that it is not inevitable that diabetic retinopathy will lead blindness. By studying what goes wrong, scientist hope to develop treatments that make things go right.


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