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

Progressive dysfunction and failure of insulin-releasing beta-cells are a hallmark of type 2 diabetes (T2D). To study mechanisms of beta-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 beta-cell clusters with similar abundance in both strains. However, after feeding of a diabetogenic diet for 2 days, beta-cell cluster composition markedly differed between strains. Islets of diabetes-resistant mice developed into a protective beta-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 beta-cell identity, such as downregulation of GLUT2, GLP1R, and MafA, and in vitro knockdown of GLUT2 in beta-cells-mimicking its phenotype-decreased stress response and apoptosis. This might explain enhanced beta-cell survival of diabetes-resistant islets. In contrast, beta-cells of diabetes-prone mice responded with expression changes indicating metabolic pressure and endoplasmic reticulum stress, presumably leading to later beta-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 beta-cell failure and diabetes development.

Automated summary

Progressive dysfunction and failure of insulin-releasing beta-cells are key characteristics of type 2 diabetes (T2D). By using islet single-cell RNA sequencing on two obese mouse strains with different susceptibilities to diabetes, the researchers found that the composition of beta-cell clusters differed significantly between strains after feeding them a diabetogenic diet. Diabetes-resistant mice developed a protective beta-cell cluster, while diabetes-prone mice progressed towards stress-related clusters. Further experiments showed that the protective cluster exhibited reduced beta-cell identity and decreased stress response and apoptosis, potentially explaining the enhanced beta-cell survival in diabetes-resistant mice. In contrast, the beta-cells of diabetes-prone mice displayed metabolic pressure and endoplasmic reticulum stress, leading to beta-cell loss. These findings suggest that the failure of diabetes-prone mice to adapt their gene expression in response to rising blood glucose levels contributes to beta-cell failure and the development of diabetes.