American Diabetes Association
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Heterogeneous development of β-cell populations in diabetes-resistant and susceptible mice

posted on 2022-06-30, 18:44 authored by Pascal Gottmann, Thilo Speckmann, Mandy Stadion, Erika Zuljan, Heja Aga, Michael Sterr, Maren Büttner, Patricia Martinez Santos, Markus Jähnert, Stefan R. Bornstein, Fabian J. Theis, Heiko Lickert, Annette Schürmann


Progressive dysfunction and failure of insulin-releasing β-cells is 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. On a control diet, we identified six β-cell clusters with similar abundance in both strains. However, after feeding a diabetogenic diet for two 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 towards 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 to mimick 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 ER stress, presumably leading to later β-cell loss. In conclusion, failure of diabetes-prone mice to adapt gene expression towards a more dedifferentiated state in response to rising blood glucose levels leads to β-cell failure and diabetes development.


The study was supported by the German Ministry of Education and Research (BMBF: DZD grant 82DZD00302) and the Brandenburg State.