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Gottmann, P.* ; Speckmann, T.* ; Stadion, M.* ; Chawla, P.* ; Saurenbach, J.* ; Ninov, N.* ; Lickert, H. ; Schürmann, A.*

Transcriptomic heterogeneity of non-beta islet cells is associated with type 2 diabetes development in mouse models.

Diabetologia, DOI: 10.1007/s00125-024-06301-6 (2024)
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AIMS/HYPOTHESIS: The aim of this work was to understand the role of non-beta cells in pancreatic islets at early stages of type 2 diabetes pathogenesis. METHODS: Specific clustering was employed to single-cell transcriptome data from islet cells of obese mouse strains differing in their diabetes susceptibility (diabetes-resistant B6.V.Lepob/ob [OB] and diabetes-susceptible New Zealand Obese [NZO] mice) on a diabetogenic diet. RESULTS: Refined clustering analysis revealed several heterogeneous subpopulations for alpha cells, delta cells and macrophages, of which 133 mapped to human diabetes genes identified by genome-wide association studies. Importantly, a similar non-beta cell heterogeneity was found in a dataset of human islets from donors at different stages of type 2 diabetes. The predominant alpha cell cluster in NZO mice displayed signs of cellular stress and lower mitochondrial capacity (97 differentially expressed genes [DEGs]), whereas delta cells from these mice exhibited higher expression levels of maturation marker genes (Hhex and Sst) but lower somatostatin secretion than OB mice (184 DEGs). Furthermore, a cluster of macrophages was almost twice as abundant in islets of OB mice, and displayed extensive cell-cell communication with beta cells of OB mice. Treatment of beta cells with IL-15, predicted to be released by macrophages, activated signal transducer and activator of transcription (STAT3), which may mediate anti-apoptotic effects. Similar to mice, humans without diabetes possess a greater number of macrophages than those with prediabetes (39 mmol/mol [5.7%] < HbA1c < 46 mmol/mol [6.4%]) and diabetes. CONCLUSIONS/INTERPRETATION: Our study indicates that the transcriptional heterogeneity of non-beta cells has an impact on intra-islet crosstalk and participates in beta cell (dys)function. DATA AVAILABILITY: scRNA-seq data from the previous study are available in gene expression omnibus under gene accession number GSE159211 ( https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE159211 ).
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Publication type Article: Journal article
Document type Scientific Article
Keywords Beta Cell Protection ; Cell–cell Communication ; Heterogeneity In Islets ; Macrophages ; Type 2 Diabetes; Pancreatic-islets; Macrophages; Insulin; Dysfunction; Proliferation; Inflammation; Obesity; Secretion; Resistant; Release
Language english
Publication Year 2024
HGF-reported in Year 2024
ISSN (print) / ISBN 0012-186X
e-ISSN 1432-0428
Journal Diabetologia
Publisher Springer
Publishing Place Berlin ; Heidelberg [u.a.]
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Regeneration Research (IDR)
Institute of Stem Cell Research (ISF)
POF-Topic(s) 30201 - Metabolic Health
30204 - Cell Programming and Repair
Research field(s) Helmholtz Diabetes Center
Stem Cell and Neuroscience
PSP Element(s) G-502300-001
G-500800-001
Grants Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)
Brandenburg State
German Ministry of Education and Research (BMBF: DZD)
Projekt DEAL
DOI 10.1007/s00125-024-06301-6
WOS ID 001350903800003
Scopus ID 85208532446
PubMed ID 39508880
Erfassungsdatum 2024-11-25
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