Heterogeneous Development of b-Cell Populations in Diabetes-Resistant and-Susceptible Mice

Progressive dysfunction and failure of insulin-releasing b-cells are a hallmark of type 2 diabetes (T2D). To study mechanisms of b-cell loss in T2D, we performed islet single-cell RNA sequencing of two obese mouse strains differing in their diabetes susceptibility. With mice on a control diet, we identified six b-cell clusters with similar abundance in both strains. However, after feeding of a diabetogenic diet for 2 days, b-cell cluster composition markedly differed between strains. Islets of diabetesresistant mice developed into a protective b-cell cluster (Beta4), whereas those of diabetes-prone mice progressed toward stress-related clusters with a strikingly different expression pattern. Interestingly, the protective cluster showed indications of reduced b-cell identity, such as downregulation of GLUT2, GLP1R, and MafA, and in vitro knockdown of GLUT2 in b-cells— mimicking its phenotype—decreased stress response and apoptosis. This might explain enhanced b-cell survival of diabetes-resistant islets. In contrast, b-cells of diabetes-prone mice responded with expression changes indicating metabolic pressure and endoplasmic reticulum stress, presumably leading to later b-cell loss. In conclusion, failure of diabetes-prone mice to adapt gene expression toward a more dedifferentiated state in response to rising blood glucose levels leads to b-cell failure and diabetes development.