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

IF 8.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Diabetologia Pub Date : 2024-11-07 DOI:10.1007/s00125-024-06301-6
Pascal Gottmann, Thilo Speckmann, Mandy Stadion, Prateek Chawla, Judith Saurenbach, Nikolay Ninov, Heiko Lickert, Annette Schürmann
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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

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非β胰岛细胞转录组异质性与小鼠模型中 2 型糖尿病的发生有关
目的/假设这项工作的目的是了解非β细胞在 2 型糖尿病发病早期阶段在胰岛中的作用。方法对肥胖小鼠品系(糖尿病耐药 B6.V.Lepob/ob [OB]和糖尿病易感新西兰肥胖 [NZO] 小鼠)的胰岛细胞的单细胞转录组数据进行了特异性聚类分析。结果细化聚类分析发现了多个不同的α细胞、δ细胞和巨噬细胞亚群,其中 133 个亚群与全基因组关联研究确定的人类糖尿病基因相对应。重要的是,在一个来自处于 2 型糖尿病不同阶段的供体的人类胰岛数据集中也发现了类似的非贝塔细胞异质性。NZO小鼠的主要α细胞集群显示出细胞压力和线粒体能力降低的迹象(97个差异表达基因[DEGs]),而这些小鼠的δ细胞显示出较高的成熟标志基因(Hhex和Sst)表达水平,但体泌素分泌却低于OB小鼠(184个差异表达基因)。此外,OB 小鼠胰岛中巨噬细胞群的数量几乎是 OB 小鼠的两倍,并与 OB 小鼠的 beta 细胞进行广泛的细胞间交流。用预计由巨噬细胞释放的 IL-15 处理β细胞,可激活信号转导和转录激活因子(STAT3),从而起到抗凋亡的作用。与小鼠类似,与糖尿病前期(39 mmol/mol [5.7%] <HbA1c<46mmol/mol[6.4%])和糖尿病患者相比,未患糖尿病的人类拥有更多的巨噬细胞。结论/解释我们的研究表明,非β细胞的转录异质性对胰岛内串联有影响,并参与了β细胞(功能障碍)。先前研究的scRNA-seq数据可在基因表达总库中查阅,基因登录号为GSE159211 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE159211)。图文摘要
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来源期刊
Diabetologia
Diabetologia 医学-内分泌学与代谢
CiteScore
18.10
自引率
2.40%
发文量
193
审稿时长
1 months
期刊介绍: Diabetologia, the authoritative journal dedicated to diabetes research, holds high visibility through society membership, libraries, and social media. As the official journal of the European Association for the Study of Diabetes, it is ranked in the top quartile of the 2019 JCR Impact Factors in the Endocrinology & Metabolism category. The journal boasts dedicated and expert editorial teams committed to supporting authors throughout the peer review process.
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