Researchers at Mount Sinai’s Icahn School of Medicine in New York have uncovered a groundbreaking method to protect insulin-producing beta cells from the damaging effects of glucolipotoxicity—an environmental condition linked to the development of type 2 diabetes (T2D). Their study, published in Nature Communications on March 2, 2025, presents a promising new approach to targeting beta cell dysfunction and could pave the way for innovative treatments for diabetes.
This discovery has the potential to significantly alter the management of T2D by introducing a strategy that directly protects beta cells, instead of just managing blood sugar levels. If successful, it could reduce the reliance on insulin therapy and provide long-term improvements in blood glucose control. The strategy focuses on preventing the loss of beta cells, which are essential for maintaining proper insulin function.
Liora S. Katz, PhD, the study’s lead author and Associate Professor of Medicine in Endocrinology, Diabetes, and Bone Disease at Icahn School of Medicine, commented on the significance of the findings. “For the first time, we’ve demonstrated the potential of using small molecules to fine-tune the activity of carbohydrate response element-binding protein (ChREBP), offering significant therapeutic promise.”
Currently, over 500 million people worldwide are affected by diabetes, a condition that arises from insulin resistance or beta cell failure. In T2D, glucolipotoxicity, a condition caused by prolonged exposure to high glucose and fatty acid levels, contributes to the progressive dysfunction and death of beta cells.
ChREBP is a transcription factor that plays a critical role in regulating glucose metabolism, existing in two isoforms: ChREBPα and ChREBPβ. The new study identifies small molecules, known as “molecular glues,” which enhance the interaction between ChREBPα and 14-3-3 proteins in pancreatic beta cells. Under normal conditions, ChREBPα is held in the cytoplasm by 14-3-3 proteins. However, in the presence of glucolipotoxicity, ChREBPα migrates to the nucleus, triggering the production of ChREBPβ, which damages beta cells. By using molecular glues to strengthen the binding between ChREBPα and 14-3-3 proteins, the research prevents ChREBPα from entering the nucleus, thus averting beta cell damage.
The study’s results in primary human beta cells show that these molecular glues significantly mitigate the toxic effects of glucolipotoxicity, preserving beta cell function and identity. This marks a major advancement in diabetes research, as transcription factors like ChREBP were once deemed “undruggable.” Moreover, the research suggests that molecular glues could have broader applications in other diseases.
Donald K. Scott, PhD, Professor of Medicine at Icahn School of Medicine, remarked, “This novel approach presents an entirely new strategy to preserve beta cell function in diabetes. It could complement current treatments and slow disease progression.”
The research team is now working on refining these compounds and preparing for clinical trials. Future studies will focus on optimizing the molecular glues for use in preclinical models of diabetes.
The collaborative research involved teams from Eindhoven University of Technology in the Netherlands and the University of Duisburg-Essen in Germany, with support from the National Institutes of Health (NIH), the Netherlands Ministry of Education, Culture and Science, and the European Research Council (ERC), among other funding sources.
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