Researchers from the University at Albany and NYU Grossman School of Medicine have found a way to block a key cellular pathway known to drive chronic inflammation and impaired wound healing in people with diabetes.
The breakthrough could offer a new therapeutic option for stopping the harmful effects of both type 1 and type 2 diabetes at the source.
In their latest work, the researchers successfully identified — and developed a small molecule drug to disrupt — an intracellular chain reaction that is a major contributor to diabetes-induced complications. Their findings , published earlier this month, were featured on the cover of Cell Chemical Biology.
"Current treatments for diabetes primarily focus on slowing disease progression; however, they do not address the underlying inflammation that contributes to the complications of diabetes," said co-senior author Alexander Shekhtman, professor in the Department of Chemistry and the RNA Institute at UAlbany. "Our findings point to a promising new pathway for treating diabetes in the future. These study results will serve as a springboard for the development of therapies for both types of diabetes, and for designing markers that can measure how well the new treatment works in live animals."
As of 2021 , more than 38 million Americans — over 11% of the population — were living with diabetes. Current treatments can help patients manage blood sugar, yet there are no medications designed to treat the disease's hallmark inflammation, which spurs a range of pathological complications throughout the body. The team's new small molecule, a compound called RAGE406R, could answer this need.
"RAGE406R targets a very important pathway that we do not yet fully understand," said Shekhtman. "Going forward, I plan to use a combination of classical structural and molecular biology approaches, along with our in-house developed technique, in-cell Nuclear Magnetic Resonance, to elucidate the mechanism that regulates this pathway.
"We also plan to collaborate with a clinical team to support drug development efforts and advance RAGE406R toward the market."
How it Works
In people with diabetes, a type of harmful molecule called "advanced glycation end products" accumulate in tissues throughout the body. These molecules activate a cell surface sensor known as the "Receptor for Advanced Glycation End products" (RAGE), which in turn triggers a molecular structure inside cells called "Diaphanous-1" (DIAPH1). Typically, DIAPH1 supports normal cell functions, but when overstimulated, it leads to chronic inflammation, driving problems like cardiovascular disease and poor wound healing.
Using structural biology techniques, the research team built a model to understand how the RAGE receptor activates DIAPH1. This allowed them to pinpoint a binding site on DIAPH1 that facilitates the pathway.
"For this project, I screened more than 100 different molecules using Nuclear Magnetic Resonance and fluorescence spectroscopy to identify the molecular structure most capable of binding to and inhibiting a pathway that leads to inflammation in patients with diabetes. This is how we arrived at our molecule, RAGE406R," explained co-lead author Parastou Nazarian, a third-year PhD student in the Department of Chemistry at UAlbany.
"Our molecule essentially works by binding to the place on the RAGE receptor that DIAPH1 typically occupies. By blocking this connection, the molecule stops the trigger for inflammation. I believe that the molecular structure we identified — through a combination of chemical and biological approaches — shows strong potential for reducing chronic inflammation."
Demonstrating Potential for Clinical Efficacy
The molecule proved effective when tested in both human cells and mice. RAGE406R significantly reduced levels of a key inflammatory messenger in human cells taken from blood samples of people with type 1 diabetes. The molecules also accelerated wound healing and reduced inflammation response in mice with type 2 diabetes.
These findings confirm that RAGE406R could offer a way to control chronic diabetic complications while also providing specific biomarkers to track drug efficacy in future clinical trials.
"There are currently no treatments that address the root causes of diabetic complications, and our work shows that RAGE406R can, not by lowering the high blood sugar, but instead by blocking the intracellular action of RAGE," said co-senior author Dr. Ann Marie Schmidt, the Dr. Iven Young Professor of Endocrinology at NYU Grossman School of Medicine. "If confirmed by further testing in human trials, the compound could potentially fill gaps in treatment, including that most current drugs work only against type 2 diabetes."
