Helper protein worsens diabetic eye disease

November 27, 2019

In a recent study using mice, lab-grown human retinal cells and patient samples, Johns Hopkins Medicine scientists say they found evidence of a new pathway that may contribute to degeneration of the light sensitive tissue at the back of the eye. The findings, they conclude, bring scientists a step closer to developing new drugs for a central vision-destroying complication of diabetes that affects an estimated 750,000 Americans.

The Johns Hopkins research team focused on diabetic macular edema, a form of swelling and inflammation that occurs in people with diabetes when blood vessels in the eye leak their fluids into the portion of the retina that controls detailed vision.

Current therapies for this disease block the protein VEGF, which contributes to abnormal blood vessel growth. However, because the treatment is not adequate for more than half of patients with diabetic macular edema, investigators have long suspected that more factors drive vision loss in these patients.

In the new study, the Johns Hopkins researchers say they found compelling evidence that angiopoietin-like 4 is at play in macular edema. The signaling protein is already well known to be a blood vessel growth factor with roles in heart disease, cancer and metabolic diseases, of which diabetes is one.

A report on the findings was published Sept. 23 in The Journal of Clinical Investigation.

Akrit Sodhi, M.D., Ph.D., associate professor of ophthalmology at the Johns Hopkins University School of Medicine and the Johns Hopkins Wilmer Eye Institute, in collaboration with Silvia Montaner, Ph.D., M.P.H., at the University of Maryland, led the research team and was intrigued by angiopoietin-like 4 after finding, in previous studies, elevated levels of this protein in the eyes of people with a variety of vision-related diseases.

In the new study, Sodhi and his team found that angiopoietin-like 4 acts both independent of, and synergistically with, VEGF activity, and they identified a potential way to block it.

The investigators made their discoveries by exposing human blood vessel tissue cells grown in the lab to low levels of VEGF and angiopoietin-like 4. Knowing that low levels of these factors individually did not generally create an effect, the researchers were surprised to find that in combination, low-level VEGF and low-level angiopoeitin-like 4 had a synergistic effect on vascular cell permeability, and doubled the leakage from retinal vessels in mice.

"This told us that you can have subthreshold levels of both molecules, where neither alone is enough to do anything, but together, produce a huge effect," says Sodhi.

The amplifying effect led the researchers to believe that VEGF and angiopoietin-like 4 might share a protein receptor within vascular cells.

However, similar experiments revealed that angiopoietin-like 4 also increases blood vessel formation independently of VEGF. "This could explain why some patients continue to experience vision loss despite treatment with current anti-VEGF therapies," says Sodhi.

To test this, the team looked to see whether the angiopoietin-like 4 protein bound to one of VEGF's receptors in lab-grown human vascular cells. They found that angiopoietin-like 4 did not bind to the classic VEGF receptor that is a target of current anti-VEGF medicines, but another less studied one called neuropilin.

With the newly identified receptor, the researchers next sought to learn whether a lab-grown version of the receptor could block angiopoietin-like 4 before it was able to interact with blood vessel cells.

To do that, they injected a soluble fragment of the neuropilin receptor into the eyes of mice pharmacologically treated to mimic human diabetes, resulting in a twofold increase in retinal vascular leakage. The treated diabetic mice showed approximately half of the blood vessel leakage as mice who did not receive the treatment, similar to the nondiabetic mice.

To further explore the new receptor-based treatment's potential value for human patients, the researchers grew human blood vessel cells in the lab in fluid samples collected from the eyes of patients with diabetic macular edema, to replicate the conditions and growth factors found naturally inside of the patients' eyes.

One group of such cells was exposed to the soluble receptor neuropilin. The researchers say they observed a marked decrease in the diabetic macular edema cells treated with the receptor compared to untreated cells.

"This gives us some confidence that this approach will work in human eyes as well," says Sodhi, although he cautions that clinical use of a treatment based on their findings will require many more years of research.

Next, the researchers hope to take a look at the molecular interactions between angiopoietin-like 4 and the neuropilin receptor. Doing so, says Sodhi, will allow them to create a refined match that can bind up as much vision-threatening angiopoietin-like 4 in the eye as possible.

Sodhi also hopes the team's discovery will have value in treating cancer and cardiovascular disease, the courses of which also are influenced by uncontrolled blood vessel growth.
-end-
The researchers declare no conflicts of interest.

Other researchers involved in this study include Monika Deshpande, Kathleen Jee and Jordan Vancel of the Johns Hopkins University School of Medicine, and Tao Ma, Deepak Menon, Aumreetam Dinabandhu, Daoyuan Lu and Silvia Montaner of the University of Maryland.

This work was supported by the National Eye Institute (5R01EY025705) and Research to Prevent Blindness.

Johns Hopkins Medicine

Related Diabetes Articles from Brightsurf:

Diabetes drug boosts survival in patients with type 2 diabetes and COVID-19 pneumonia
Sitagliptin, a drug to lower blood sugar in type 2 diabetes, also improves survival in diabetic patients hospitalized with COVID-19, suggests a multicenter observational study in Italy.

Making sense of diabetes
Throughout her 38-year nursing career, Laurel Despins has progressed from a bedside nurse to a clinical nurse specialist and has worked in medical, surgical and cardiac intensive care units.

Helping teens with type 1 diabetes improve diabetes control with MyDiaText
Adolescence is a difficult period of development, made more complex for those with Type 1 diabetes mellitus (T1DM).

Diabetes-in-a-dish model uncovers new insights into the cause of type 2 diabetes
Researchers have developed a novel 'disease-in-a-dish' model to study the basic molecular factors that lead to the development of type 2 diabetes, uncovering the potential existence of major signaling defects both inside and outside of the classical insulin signaling cascade, and providing new perspectives on the mechanisms behind insulin resistance in type 2 diabetes and possibly opportunities for the development of novel therapeutics for the disease.

Tele-diabetes to manage new-onset diabetes during COVID-19 pandemic
Two new case studies highlight the use of tele-diabetes to manage new-onset type 1 diabetes in an adult and an infant during the COVID-19 pandemic.

Genetic profile may predict type 2 diabetes risk among women with gestational diabetes
Women who go on to develop type 2 diabetes after having gestational, or pregnancy-related, diabetes are more likely to have particular genetic profiles, suggests an analysis by researchers at the National Institutes of Health and other institutions.

Maternal gestational diabetes linked to diabetes in children
Children and youth of mothers who had gestational diabetes during pregnancy are at increased risk of diabetes themselves, according to new research published in CMAJ (Canadian Medical Association Journal).

Two diabetes medications don't slow progression of type 2 diabetes in youth
In youth with impaired glucose tolerance or recent-onset type 2 diabetes, neither initial treatment with long-acting insulin followed by the drug metformin, nor metformin alone preserved the body's ability to make insulin, according to results published online June 25 in Diabetes Care.

People with diabetes visit the dentist less frequently despite link between diabetes, oral health
Adults with diabetes are less likely to visit the dentist than people with prediabetes or without diabetes, finds a new study led by researchers at NYU Rory Meyers College of Nursing and East Carolina University's Brody School of Medicine.

Diabetes, but not diabetes drug, linked to poor pregnancy outcomes
New research indicates that pregnant women with pre-gestational diabetes who take metformin are at a higher risk for adverse pregnancy outcomes -- such as major birth defects and pregnancy loss -- than the general population, but their increased risk is not due to metformin but diabetes.

Read More: Diabetes News and Diabetes Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.