In contrast to reports of diabetes-induced dedifferentiated β cells157,166, we found an increased expression of transcription factors associated with β-cell identity and the regulation of insulin genes, such as Pdx1, Isl1, and Nkx6.1, indicating a compensatory regulatory response aimed at overcoming the absence of Neurod1. Similarly, an enrichment of Wnt4 and Ffar4 in Neurod1CKO may indicate an adaptive response by the dysfunctional β cells to enhance their metabolic maturation and stimulate failing insulin secretion161,172. Here, ISL1 is linked to diabetes mellitus.