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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.Lep ob/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%] < HbA 1c < 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 )., Competing Interests: Acknowledgements: The skilful technical assistance of E. Arlt and A. Helms (Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke [DIfE], Nuthetal, Germany) is gratefully acknowledged. In addition, the assistance of A. Teichmann and C. Gumz (DIfE) for islet picking is gratefully acknowledged. Servier Medical Art was used to create the graphical abstract, which is licensed under CC BY 4.0 ( https://creativecommons.org/licenses/by/4.0/ ). Some of the data were presented as a poster at the DDG conference in 2024 with the title ‘The role of non-beta cell heterogeneity in the pathogenesis of type 2 diabetes’. In addition, the research is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation; 491394008). 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 ). Funding: Open Access funding enabled and organized by Projekt DEAL. The study was supported by the German Ministry of Education and Research (BMBF: DZD grant 82DZD03D03) and the Brandenburg State; as well as the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) project numbers 407395267, 525802829 and 491394008. Authors’ relationships and activities: The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work. Contribution statement: PG performed data analysis, designed figures and wrote the manuscript, TS performed data analysis, did experiments and wrote the manuscript. MS and JS did experiments. PC and NN performed data analysis and critically edited and revised the manuscript. HL performed study conception and critically edited and revised the manuscript, AS performed study conception and design, and critically edited and revised the manuscript. All authors subsequently edited the manuscript, and approved its final version for publication. AS is the guarantor of this work., (© 2024. The Author(s).)