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

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