Functional recovery of islet β cells in human type 2 diabetes: Transcriptome signatures unveil therapeutic approaches
- Mara Suleiman
- Toshiaki Sawatani
- Marta Tesi
- Xiaoyan Yi
- Theodora Papadopoulou
- Chantal Rufer
- Maria Lytrivi
- Emanuele Bosi
- Frederic Burdet
- Federica Fantuzzi
- Carmela De Luca
- Guido Sebastiani
- Chiara Saponaro
- Licia Anna Pugliese
- Silvia Del Guerra
- Alessandro Pocai
- Paolo De Simone
- Davide Ghinolfi
- Ugo Boggi
- Camille Kessler
- Giuseppina Emanuela Grieco
- Daniela Fignani
- Julie Kerr-Conte
- François Pattou
- Montserrat Nacher
- Eduard Montanya
- Nizar Mourad
- Antoine Buemi
- Valentina Citi
- Alma Martelli
- Giada Benedetti
- Vincenzo Calderone
- Leonardo Rossi
- Aldo Paolicchi
- Francesco Cardarelli
- Francesco Dotta
- Decio L. Eizirik
- Mark Ibberson
- Piero Marchetti
- Miriam Cnop
- Lorella Marselli
2025-10-10
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.