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

Pascal Gottmann, Thilo Speckmann, Mandy Stadion, Erika Zuljan, Heja Aga, Michael Sterr, Maren Buttner, Patrícia Martínez Santos, Markus Jahnert, Stefan R. Bornstein, Fabian J. Theis, Heiko Lickert, Annette Schurmann*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1962-1978
Number of pages17
JournalDiabetes
Volume71
Issue number9
DOIs
Publication statusPublished - Sept 2022

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