New drug could prevent diabetes complications not resolved by blood sugar control, study finds
An experimental drug compound could prevent and treat certain complications of diabetes, such as poor wound healing and widespread inflammation. And it works regardless of blood sugar control, suggests a new study in mice and human cells.
The cornerstone of diabetes care is controlling blood sugar levels through diet and exercise, maintaining a healthy weight, and injecting the hormone insulin to help remove glucose from the bloodstream. But while maintaining blood sugar within a target range reduces the risk of diabetes complications will emerge, this does not eliminate the risk.
“The complications of diabetes – which are actually the problems that make people sick, that shorten their life expectancy and that just make them sick – are only partially alleviated by tight blood sugar control,” said the study co-author. Dr Ann Marie Schmidtprofessor of medicine at NYU Grossman School of Medicine and director of the Diabetes Research Program at NYU Langone Health.
This raises questions about what other contributors to diabetes complications might be and whether they can be treated.
For decades, Schmidt and his colleagues sought to answer these questions, and their efforts led to the development of a new experimental drug. In their latest work, published in October in the journal Cellular chemical biologythe team tested the drug’s effects on laboratory mice and human cells.
The results show that such a drug has “great potential” to limit or prevent several complications of diabetes, Timothy Perkinsassistant professor of pathology at the University of Pittsburgh, wrote in a comment on the study.
Block complications at the source
The new drug compound targets a protein called RAGE, which interacts with a second protein called DIAPH1. Schmidt and his colleagues first described RAGE in the 1990sfinding 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 that line blood vessels. It passes through the cell membrane, with one end interacting with substances outside the cell and the other relaying signals inside the cell. The outer part of the protein interacts with advanced glycation end products (AGEs) – proteins that have sugars stuck to them.
“Once they’re stuck there, they have a gain of function that allows them to disrupt and damage endothelial cells, the cells that line all the blood vessels in our body,” Schmidt told Live Science. It is known that AGEs accumulate in the body with normal aging and that, in the context of certain chronic diseases, including diabetes, they accumulate more quickly than usual.
RAGE, which stands for “AGE receptor,” is activated by this accumulation of sugar-coated proteins, which triggers harmful changes inside the cell, including processes that accelerate inflammation. It turns out that these changes rely on the interaction of RAGE with a second protein inside the cell: DIAPH1. (The team had I have already tried to prevent the AGEs from connecting in RAGE, but did not find success with this approach.)
With advice from the co-author Alexander Shekhtmanstructural biologist at the State University of New York at Albany, the researchers took a closer look at the interaction of RAGE and DIAPH1. They built a detailed model of how the two proteins interact in the presence of AGEs and also studied the downstream cellular consequences of this exchange.
They showed that initially, DIAPH1 starts with an activated cellular brake that restrains its activity, but after interacting with RAGE, these brakes are torn away. The full consequences of this situation are not yet understood, Schmidt noted, but from what we know, it “seems to have pathological consequences.”
Schmidt, Shekhtman and their team previously searched for molecules that could block the interaction of RAGE and DIAPH1. Among 58,000 moleculesthe team focused on a product that seemed promising and found in initial experiments on mice 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 testing suggests it has 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 the compound to the mice’s wounds helped both alleviate inflammation and speed healing. The researchers also showed that the drug could reduce inflammation in allergic mice when administered orally, but they did not test this oral administration in diabetic mice.
Looking ahead, it will be important to study RAGE in many cell types, because it likely does different things in different cell types, Perkins noted in his commentary.
Much more work is needed before the drug can be tested on humans, including more testing on laboratory animals, Schmidt stressed. But she suggested that, if the drug does win approval, it would be best for patients to start using it soon after being diagnosed with diabetes. Ideally, RAGE therapy should be combined with tight blood sugar control, before the snowball effect of AGE accumulation can begin, she said. You would want to “mitigate this spiral of constantly creating more AGEs,” she said.
Beyond diabetes, RAGE is also known to contribute to inflammatory diseases of the lungs, such as asthma and chronic obstructive pulmonary disease (COPD), Perkins noted. He suggested that these might be additional contexts in which drugs that disrupt the RAGE-DIAPH1 interaction might be useful.
This article is for informational purposes only and is not intended to offer medical advice.
