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

Remission of type 2 diabetes (T2D) can occur after hypocaloric diet, bariatric surgery, or pharmacological treatments and associates with improved beta cell function. Here, we studied islets from nondiabetic (n = 15) and T2D (n = 21) donors. We examined whether T2D beta cell dysfunction can be rescued, charted the underlying molecular mechanisms by RNA sequencing, and mined transcriptomes for drug targets. Glucose responsiveness of T2D beta 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 beta cell line, human islets, and db/db mice. Therefore, defective beta cell glucose responsiveness in T2D can recover, demonstrating beta cell functional plasticity. The recovery associates with transcriptomic traits, pointing to targetable defects to induce T2D remission.