Functional recovery of islet β cells in human type 2 diabetes: Transcriptome signatures unveil therapeutic approaches

Suleiman, M.; Sawatani, T.; Tesi, M.; Yi, X.; Papadopoulou, T.; Rufer, C.; Lytrivi, M.; Bosi, E.; Burdet, F.; Fantuzzi, F.; De Luca, C.; Sebastiani, G.; Saponaro, C.; Pugliese, L. A.; Guerra, S. D.; Pocai, A.; De Simone, P.; Ghinolfi, D.; Boggi, U.; Kessler, C.; Grieco, G. E.; Fignani, D.; Kerr-Conte, J.; Pattou, F.; Nacher, M.; Montanya, E.; Mourad, N.; Buemi, A.; Citi, V.; Martelli, A.; Benedetti, G.; Calderone, V.; Rossi, L.; Paolicchi, A.; Cardarelli, F.; Dotta, F.; Eizirik, D. L.; Ibberson, M.; Marchetti, P.; Cnop, M.; Marselli, L.

doi:10.1126/sciadv.ads2905

Remission of type 2 diabetes (T2D) can occur after hypocaloric diet, bariatric surgery, or pharmacological treatments and associates with improved β cell function. Here, we studied islets from nondiabetic (n = 15) and T2D (n = 21) donors. We examined whether T2D β cell dysfunction can be rescued, charted the underlying molecular mechanisms by RNA sequencing, and mined transcriptomes for drug targets. Glucose responsiveness of T2D β cells improved in 60% of preparations after 3-day culture in euglycemic conditions. This was accompanied by changes in expression of >400 genes involved in functional or inflammatory pathways. Drug repurposing and target identification analyses predicted chemical and genetic hits, including JAK inhibitors, which were validated in a β cell line, human islets, and db/db mice. Therefore, defective β cell glucose responsiveness in T2D can recover, demonstrating β cell functional plasticity. The recovery associates with transcriptomic traits, pointing to targetable defects to induce T2D remission.

Functional recovery of islet β cells in human type 2 diabetes: Transcriptome signatures unveil therapeutic approaches / Suleiman, M., Sawatani, T., Tesi, M., Yi, X., Papadopoulou, T., Rufer, C., Lytrivi, M., Bosi, E., Burdet, F., Fantuzzi, F., De Luca, C., Sebastiani, G., Saponaro, C., Pugliese, L.A., Guerra, S.D., Pocai, A., De Simone, P., Ghinolfi, D., Boggi, U., Kessler, C., et al.. - In: SCIENCE ADVANCES. - ISSN 2375-2548. - 11:41(2025). [10.1126/sciadv.ads2905]