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Open Access 07-11-2024 | Type 2 Diabetes | Extended Article

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

Authors: Pascal Gottmann, Thilo Speckmann, Mandy Stadion, Prateek Chawla, Judith Saurenbach, Nikolay Ninov, Heiko Lickert, Annette Schürmann

Published in: Diabetologia

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Abstract

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).

Graphical Abstract

Appendix
Available only for authorised users
Literature
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go back to reference Grarup N, Andersen G, Krarup NT et al (2008) Association testing of novel type 2 diabetes risk alleles in the JAZF1, CDC123/CAMK1D, TSPAN8, THADA, ADAMTS9, and NOTCH2 loci with insulin release, insulin sensitivity, and obesity in a population-based sample of 4,516 glucose-tolerant middle-aged Danes. Diabetes 57(9):2534–2540. https://doi.org/10.2337/DB08-0436CrossRefPubMedPubMedCentral Grarup N, Andersen G, Krarup NT et al (2008) Association testing of novel type 2 diabetes risk alleles in the JAZF1, CDC123/CAMK1D, TSPAN8, THADA, ADAMTS9, and NOTCH2 loci with insulin release, insulin sensitivity, and obesity in a population-based sample of 4,516 glucose-tolerant middle-aged Danes. Diabetes 57(9):2534–2540. https://​doi.​org/​10.​2337/​DB08-0436CrossRefPubMedPubMedCentral
Metadata
Title
Transcriptomic heterogeneity of non-beta islet cells is associated with type 2 diabetes development in mouse models
Authors
Pascal Gottmann
Thilo Speckmann
Mandy Stadion
Prateek Chawla
Judith Saurenbach
Nikolay Ninov
Heiko Lickert
Annette Schürmann
Publication date
07-11-2024
Publisher
Springer Berlin Heidelberg
Keyword
Type 2 Diabetes
Published in
Diabetologia
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-024-06301-6

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