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Gottmann, P.* ; Speckmann, T.* ; Stadion, M.* ; Zuljan, E.* ; Aga, H.* ; Sterr, M. ; Büttner, M. ; Santos, P.M.* ; Jähnert, M.* ; Bornstein, S.R.* ; Theis, F.J. ; Lickert, H. ; Schürmann, A.*

Heterogeneous development of β-cell populations In diabetes-resistant and -susceptible mice.

Diabetes 71, 1962-1978 (2022)
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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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Insulin-secretion; Mouse; Gene; Expression; Obesity; Dedifferentiation; Proliferation; Glycosylation; Mechanisms; Pathway
ISSN (print) / ISBN 0012-1797
e-ISSN 1939-327X
Journal Diabetes
Quellenangaben Volume: 71, Issue: 9, Pages: 1962-1978 Article Number: , Supplement: ,
Publisher American Diabetes Association
Publishing Place Alexandria, VA.
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Regeneration Research (IDR)
Institute of Computational Biology (ICB)
Institute of Stem Cell Research (ISF)
Grants Bundesministerium für Bildung und Forschung
Brandenburg State