Mara Suleiman, Toshiaki Sawatani, Marta Tesi, Xiaoyan Yi, Theodora A. Papadopoulou, Chantal Rufer, Maria Lytrivi, Emanuele Bosi, Frédéric 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 I. Mourad, Antoine Buémi, Valentina Citi, Alma Martelli, Giada Benedetti, Vincenzo Calderone, Leonardo Rossi, Aldo Paolicchi, Francesco Cardarelli, Francesco Dotta, Décio L. Eizirik, Mark Ibberson, Piero Marchetti, Miriam Cnop, Lorella Marselli
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.