M1 macrophage-derived exosomes impair beta cell insulin secretion via miR-212-5p by targeting SIRT2 and inhibiting Akt/GSK-3β/β-catenin pathway in mice

• Published in: Diabetologia 2021-09, Vol.64 (9), p.2037-2051
• Main Authors: Qian, Bin, Yang, Yang, Tang, Ningyuan, Wang, Jiahui, Sun, Peng, Yang, Nan, Chen, Fang, Wu, Tijun, Sun, Tong, Li, Yating, Chang, Xiaoai, Zhu, Yunxia, Zhang, Yaqin, Han, Xiao
• Format: Article
• Language: English
• Subjects: AKT protein; Animals; beta Catenin - genetics; beta Catenin - metabolism; Beta cells; Bone marrow; Cell injury; Cell interactions; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - metabolism; DNA microarrays; Exosomes; Exosomes - metabolism; Glycogen Synthase Kinase 3 beta - genetics; Glycogen Synthase Kinase 3 beta - metabolism; Glycogen Synthase Kinase 3 beta - pharmacology; High fat diet; Human Physiology; Inflammation; Insulin; Insulin Secretion; Internal Medicine; Macrophages; Macrophages - metabolism; Medicine; Medicine & Public Health; Metabolic Diseases; Mice; Mice, Inbred C57BL; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Obesity; Phenotypes; Proto-Oncogene Proteins c-akt - metabolism; Rodents; Secretion; Sirtuin 2 - metabolism; Sirtuin 2 - pharmacology; β-Catenin
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-021-05489-1

Aims/hypothesis Macrophage levels are elevated in pancreatic islets, and the resulting inflammatory response is a major contributor to beta cell failure during obesity and type 2 diabetes mellitus. Previous studies by us and others have reported that exosomes released by macrophages play important roles in mediating cell-to-cell communication, and represent a class of inflammatory factors involved in the inflammatory process associated with type 2 diabetes mellitus. However, to date, no reports have demonstrated the effect of macrophage-derived exosomes on beta cells, and little is known regarding their underlying mechanisms in beta cell injury. Thus, we aimed to study the impact of macrophage-derived exosomes on islet beta cell injury in vitro and in vivo. Methods The phenotypic profiles of islet-resident macrophages were analysed in C57BL/6J mice fed a high-fat diet (HFD). Exosomes were collected from the medium of cultured bone marrow-derived macrophages (BMDMs) and from isolated islet-resident macrophages of HFD-fed mice (HFD-Exos). The role of exosomes secreted by inflammatory M1 phenotype BMDMs (M1-Exos) and HFD-Exos on beta cell function was assessed. An miRNA microarray and quantitative real-time PCR (qPCR) were conducted to test the level of M1-Exos-derived miR-212-5p in beta cells. Then, miR-212-5p was overexpressed or inhibited in M1-Exos or beta cells to determine its molecular and functional impact. Results M1-polarised macrophages were enriched in the islets of obese mice. M1 macrophages and islet-resident macrophages of HFD-fed mice impaired beta cell insulin secretion in an exosome-dependent manner. miR-212-5p was notably upregulated in M1-Exos and HFD-Exos. Enhancing the expression of miR-212-5p impaired beta cell insulin secretion. Blocking miR-212-5p elicited a significant improvement in M1-Exos-mediated beta cell insulin secretion during injury. Mechanistically, M1-Exos mediated an intercellular transfer of the miR-212-5p, targeting the sirtuin 2 gene and regulating the Akt/GSK-3β/β-catenin pathway in recipient beta cells to restrict insulin secretion. Conclusions/interpretation A novel exosome-modulated mechanism was delineated for macrophage-beta cell crosstalk that drove beta cell dysfunction and should be explored for its therapeutic utility. Graphical abstract