Gottmann Pascal, Speckmann Thilo, Stadion Mandy, Chawla Prateek, Saurenbach Judith, Ninov Nikolay, Lickert Heiko, Schürmann Annette
Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Nuthetal, Germany.
German Center for Diabetes Research (DZD), München Neuherberg, Germany.
Diabetologia. 2025 Jan;68(1):166-185. doi: 10.1007/s00125-024-06301-6. Epub 2024 Nov 7.
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.
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.Lep [OB] and diabetes-susceptible New Zealand Obese [NZO] mice) on a diabetogenic diet.
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%] < HbA < 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.
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 ).
目的/假设：本研究旨在了解2型糖尿病发病早期胰腺胰岛中非β细胞的作用。
对食用致糖尿病饮食的肥胖小鼠品系（抗糖尿病的B6.V.Lep [OB] 小鼠和糖尿病易感的新西兰肥胖 [NZO] 小鼠）胰岛细胞的单细胞转录组数据进行特定聚类。
精细聚类分析揭示了α细胞、δ细胞和巨噬细胞的几个异质亚群，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，在来自2型糖尿病不同阶段供体的人类胰岛数据集中发现了类似的非β细胞异质性。NZO小鼠中占主导地位的α细胞簇显示出细胞应激迹象和较低的线粒体功能（97个差异表达基因 [DEG]），而这些小鼠的δ细胞表现出成熟标记基因（Hhex和Sst）的较高表达水平，但与OB小鼠相比生长抑素分泌较低（184个DEG）。此外，OB小鼠胰岛中的巨噬细胞簇几乎是NZO小鼠的两倍，并且与OB小鼠的β细胞表现出广泛的细胞间通讯。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），这可能介导抗凋亡作用。与小鼠类似，未患糖尿病的人类比患有糖尿病前期（39 mmol/mol [5.7%] < HbA < 46 mmol/mol [6.4%]）和糖尿病的人类拥有更多的巨噬细胞。
结论/解读：我们的研究表明，非β细胞的转录异质性对胰岛内细胞间通讯有影响，并参与β细胞（功能）异常。
先前研究的scRNA-seq数据可在基因表达综合数据库中获取，基因登录号为GSE159211（https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE159211）。
