Imeglimin enhances α-to-β reprograming mediated by PDX1 in β-cell ablated islets

As diabetes mellitus results from the absolute or relative deficiency of insulin secretion from pancreatic β cells, considerable efforts have been directed toward the efficient generation of surrogate β cells. Although insulin-producing cells can be generated from pancreatic α cells through the induction of defined transcription factors such as PDX1 and MAFA, it remains challenging to generate functional β cells suitable for future regenerative therapies for diabetes. As the antidiabetic agent imeglimin has been demonstrated to affect pancreatic cell plasticity in vitro, we investigated its potential to modulate α-to-β reprogramming. In our transgenic mouse model, the exogenous expression of PDX1 in α cells reprogrammed approximately 16.5 % of PDX1-expressing α cells into insulin-producing cells, which was significantly enhanced by imeglimin administration for 2 and 4 weeks (by 27.8 % and 48.7 %, respectively). After β-cell ablation by alloxan administration, the reprogramming efficiency was further enhanced by imeglimin (58.4 %), accompanied by a significant increase in α-cell-derived insulin-producing cells with silenced glucagon expression. Notably, imeglimin significantly reduced the number of reprogrammed α cells not expressing insulin and glucagon, suggesting its potential benefit in maintaining the function of surrogate β cells under diabetic conditions. Thus, imeglimin treatment in PDX1-expressing α cells helps to efficiently induce α-to-β reprogramming, which may contribute to the establishment of cell therapies for diabetes.