NYC Gazette

Researchers at the Icahn School of Medicine at Mount Sinai, New York, have developed a new approach to protect insulin-producing beta cells from glucolipotoxicity, a condition associated with type 2 diabetes (T2D). The findings were published on March 2, 2025, in Nature Communications and could lead to innovative treatments for beta cell dysfunction.

This research offers potential new treatments that could shield pancreatic insulin-producing cells. This may slow or prevent diabetes progression, reduce reliance on insulin therapy, and improve blood sugar control over time. Current therapies mainly focus on managing blood sugar levels. However, this approach aims to directly address beta cell loss.

“This is an exciting step forward in our understanding of beta cell protection and the prevention of diabetes deterioration,” said Dr. Liora S. Katz from the Icahn School of Medicine. “For the first time, we’ve shown that it’s possible to use small molecules to fine-tune carbohydrate response element binding protein (ChREBP) activity in a way that could have major therapeutic implications.”

Globally, over 500 million people suffer from diabetes due to insulin resistance or beta cell failure. In T2D patients, prolonged exposure to high glucose and fatty acid levels can cause beta cell dysfunction and death.

ChREBP is crucial for regulating glucose metabolism and exists as ChREBPα and ChREBPβ isoforms. This study introduces "molecular glues" that enhance interactions between ChREBPα and 14-3-3 proteins in pancreatic beta cells.

These molecular glues strengthen the bond between 14-3-3 proteins and ChREBPα within the cytoplasm of beta cells. Under glucolipotoxic conditions, ChREBPα enters the nucleus causing excess production of ChREBPβ which damages or kills beta cells. The molecular glue prevents ChREBPα from entering the nucleus by keeping it anchored in the cytoplasm.

Tests on primary human beta cells showed these molecular glues significantly mitigated glucolipotoxicity's harmful effects while preserving function and identity of beta cells—a significant breakthrough since transcription factors like ChREBP were previously considered "undruggable."

“Our findings suggest a completely new strategy for preserving beta cell function in diabetes,” said Dr. Donald K. Scott at Icahn School of Medicine. “This approach could complement existing diabetes treatments and help prevent disease progression.”

Ongoing research aims to refine these compounds for clinical application by optimizing them for therapeutic use through preclinical testing models.

The study was conducted alongside teams from Eindhoven University of Technology in the Netherlands and University Duisburg-Essen Germany supported by various grants including NIH/NIDDK R01DK130300 USA Human Islet Adenoviral Core HIAC P30DK020541 European Union ERC Advanced Grant PPI-Glue (101098234) Netherlands Ministry Education Culture Science Gravity program (024001035), Netherlands Organization Scientific Research ECHO grant (711018003), DFG-funded CRC1093 Supramolecular Chemistry Proteins.