An experimental drug compound could prevent and treat some complications of diabetes, such as poor wound healing and severe inflammation. And it works independently of blood sugar control, new research in mice and human cells suggests.
The cornerstone of diabetes treatment is controlling blood sugar levels through diet and exercise, maintaining a healthy weight, and administering the hormone insulin, which helps remove glucose from the bloodstream. But while maintaining blood sugar levels in the target range reduces the likelihood of diabetes complications appears, this does not eliminate the risk.
“The complications of diabetes—which are actually the problems that make people sick, shorten their lives, and just make them feel worse—are only partially mitigated by strict blood sugar control,” said study co-author. Dr. Anne Marie SchmidtProfessor of Medicine at New York University Grossman School of Medicine and Director of the Diabetes Research Program at New York University Langone Health.
This raises questions about what other causes of diabetic complications may be and whether they can be treated.
For decades, Schmidt and his colleagues tried to answer these questions, and their efforts led to the development of a new experimental drug. In his latest work, published in October in the journal Cell chemical biologyThe team tested the drug's effect on laboratory mice and human cells.
The results suggest that such a drug has “great potential” for limiting or preventing some complications of diabetes. Timothy Perkinsassistant professor of pathology at the University of Pittsburgh, wrote in the article comment at school.
Blocking complications at the source
The new drug compound targets a protein called RAGE, which interacts with a second protein called DIAPH1. Schmidt and colleagues first described RAGE in the 1990s.finding that it plays a role in vascular complications of diabetes such as heart disease.
The RAGE protein is found in many types of cells, including immune cells and cells lining blood vessels. It spans the cell membrane, with one end interacting with substances outside the cell and the other transmitting signals inside the cell. The outer part of the protein interacts with advanced glycation end products (AGEs), which are proteins with sugars stuck to them.
“Once they get stuck there, they have a gain of function and they can actually perturb and damage endothelial cells, the cells that line every blood vessel in our body,” Schmidt told Live Science. AGEs are known to accumulate in the body during normal aging, and in some chronic diseases, including diabetes, they accumulate faster than normal.
RAGE, which stands for AGE receptor, is activated by the accumulation of sugar-coated proteins, and this triggers harmful changes within the cell, including processes that increase inflammation. It turns out that these changes depend on the interaction of RAGE with a second protein inside the cell: DIAPH1. (The team had I previously tried to block the AGE connection in RAGE, but didn't have success with this approach.)
Led by co-author Alexander Shekhtmanstructural biologist at the State University of New York at Albany, the researchers took a closer look at the interaction between RAGE and DIAPH1. They built a detailed model of how the two proteins interact in the presence of AGEs, and also examined the consequences of this exchange on downstream cells.
They showed that DIAPH1 initially begins by engaging a cellular brake that restrains its activity, but after interacting with RAGE, these brakes are released. The full consequences of this are not yet understood, Schmidt noted, but as far as we know, it “appears to have pathological consequences.”
Schmidt, Shechtman and their team previously looked for molecules that could block the interaction between RAGE and DIAPH1. Among 58,000 moleculesthe team settled on one that looked promising and, in initial experiments in mice, found that it reduced diabetes complications. such as kidney disease and cardiac ischemia. An analogue of this original molecule was used for the new study because tests showed it had a better safety profile.
In cells from patients with type 1 diabetes, the drug compound blocked the interaction between RAGE and DIAPH1 and subsequently reduced inflammatory signals. In laboratory mice with diabetes, topical application of this compound to wounds helped both reduce inflammation and speed up healing. The researchers also showed that the drug could reduce inflammation in allergic mice when taken orally, but they did not test its oral delivery in diabetic mice.
Perkins noted in his commentary that in the future it will be important to study RAGE in many cell types, since it likely has different functions in different cell types.
Before the drug can be tested in humans, much more work will be required, including on laboratory animals, Schmidt emphasized. But she suggested that if the drug wins approval, it would be better for patients to start using it soon after they are diagnosed with diabetes. Ideally, RAGE therapy should be combined with tight blood sugar control before the snowball effect of AGE accumulation begins, she says. You would like to “mitigate this spiral of constantly creating more AGEs,” she said.
In addition to diabetes, RAGE is also known to contribute to inflammatory lung diseases such as asthma and chronic obstructive pulmonary disease (COPD), Perkins noted. He speculated that there may be additional situations in which drugs that disrupt the RAGE-DIAPH1 interaction may be useful.
This article is for informational purposes only and is not intended to provide medical advice.
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