Diabetes relief in mice by glucose-sensing insulin-secreting human α-cells

Cell-identity switches, in which terminally differentiated cells are converted into different cell types when stressed, represent a widespread regenerative strategy in animals, yet they are poorly documented in mammals. In mice, some glucagon-producing pancreatic alpha-cells and somatostatin-producing delta-cells become insulin-expressing cells after the ablation of insulin-secreting beta-cells, thus promoting diabetes recovery. Whether human islets also display this plasticity, especially in diabetic conditions, remains unknown. Here we show that islet non-beta-cells, namely alpha-cells and pancreatic polypeptide (PPY)-producing gamma-cells, obtained from deceased non-diabetic or diabetic human donors, can be lineage-traced and reprogrammed by the transcription factors PDX1 and MAFA to produce and secrete insulin in response to glucose. When transplanted into diabetic mice, converted human alpha-cells reverse diabetes and continue to produce insulin even after six months. Notably, insulin-producing alpha-cells maintain expression of alpha-cell markers, as seen by deep transcriptomic and proteomic characterization. These observations provide conceptual evidence and a molecular framework for a mechanistic understanding of in situ cell plasticity as a treatment for diabetes and other degenerative diseases.