Alpha cells transdifferentiate into delta cells during the progression of autoimmunity in nondiabetic NOD mice

The incidence of type 1 diabetes (T1D) has increased in recent years. Although extensive research has focused on immune damage to insulin-producing beta cells, the pathophysiological effects on other endocrine cells within pancreatic islets remain less well-documented. This study investigates the changes in the number and proportion of alpha, beta, and delta cells, as well as hormone secretion, during the progression of autoimmunity in nondiabetic nonobese diabetic (NOD) mice at different ages. Our findings reveal significant heterogeneity in islet size, endocrine cell composition, and degree of immune infiltration. We propose a novel classification system for islet subtypes based on this observed heterogeneity. Notably, we noticed an age-related increase in delta cells in older nondiabetic NOD mice. In addition, we observed an increase in glucagon and somatostatin double-positive cells following immune cell infiltration in nondiabetic mice. Our further analysis demonstrated that these double-positive cells represent a transdifferentiation process from alpha cells to delta cells, mediated by an alpha cell dedifferentiation intermediate. Moreover, our results indicated that the increased presence of delta cells and somatostatin in pancreatic islets significantly inhibits alpha cell function during the progression of autoimmunity. Thus, our findings provide valuable insights into the dynamic changes in alpha and delta cells throughout the natural history of T1D.<b>NEW & NOTEWORTHY</b> The NOD mouse is widely used as an T1D animal model. Although the mice have the same genetic background, approximately 20% of female NOD mice do not develop diabetes. In this study, we reveal that alpha cells dedifferentiate and then transdifferentiate into delta cells during the progression of autoimmunity in nondiabetic NOD mice. The increased delta cells secrete more somatostatin, which inhibits alpha cell secretion of glucagon, thereby potentially attenuating the increase in blood glucose levels in these mice.