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

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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

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

Bibliographical note

Funding Information: Acknowledgments. The skillful technical assistance of Anett Helms (A.S. laboratory) is gratefully acknowledged. Funding. The study was supported by the German Ministry of Education and Research (BMBF: DZD grant 82DZD00302) and the Brandenburg State. Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. P.G. performed data analysis. T.S. performed experiments and data analysis and wrote the manuscript. M.Sta. conceived and designed the experiments and participated in the drafting of the manuscript. M.Ste. performed experiments. M.B. contributed to the acquisition and analysis of data. P.M.S. performed experiments. M.J. performed data analysis. E.Z. performed data analysis. H.A. performed experiments and data analysis. S.R.B. critically edited and revised the manuscript. F.J.T. performed data analysis. H.L. performed study conception and critically edited and revised the manuscript. A.S. performed study conception and design and wrote the manuscript. All authors subsequently edited the manuscript and approved its final version for publication. A.S. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. Parts of this study were presented orally at the 2022 Diabetes Congress of the German Diabetes Association (DDG), Berlin, Germany, 25–28 May 2022. Publisher Copyright: © 2022 by the American Diabetes Association.

King's Authors

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.

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