Epidemiological studies demonstrate an association between breast cancer (BC) and systemic dysregulation of glucose metabolism. However, how BC influences glucose homeostasis remains unknown. We show that BC-derived extracellular vesicles (EVs) suppress pancreatic insulin secretion to impair glucose homeostasis. EV-encapsulated miR-122 targets PKM in β-cells to suppress glycolysis and ATP-dependent insulin exocytosis. Mice receiving high-miR-122 EVs or bearing BC tumours exhibit suppressed insulin secretion, enhanced endogenous glucose production, impaired glucose tolerance and fasting hyperglycaemia. These effects contribute to tumour growth and are abolished by inhibiting EV secretion or miR-122, restoring PKM in β-cells or supplementing insulin. Compared with non-cancer controls, patients with BC have higher levels of circulating EV-encapsulated miR-122 and fasting glucose concentrations but lower fasting insulin; miR-122 levels are positively associated with glucose and negatively associated with insulin. Therefore, EV-mediated impairment of whole-body glycaemic control may contribute to tumour progression and incidence of type 2 diabetes in some patients with BC.

流行病学研究表明乳腺癌 (BC) 与全身性葡萄糖代谢失调之间存在关联。然而，BC 如何影响葡萄糖稳态仍不清楚。我们发现，BC 衍生的细胞外囊泡 (EV) 会抑制胰腺胰岛素分泌，从而损害葡萄糖稳态。 EV 封装的 miR-122 靶向 β 细胞中的PKM ，抑制糖酵解和 ATP 依赖性胰岛素胞吐作用。接受高 miR-122 EV 或携带 BC 肿瘤的小鼠表现出胰岛素分泌抑制、内源性葡萄糖产生增强、糖耐量受损和空腹高血糖。这些作用有助于肿瘤生长，并可通过抑制 EV 分泌或 miR-122、恢复 β 细胞中的PKM或补充胰岛素来消除。与非癌症对照相比，BC 患者的循环 EV 封装的 miR-122 和空腹血糖浓度较高，但空腹胰岛素较低； miR-122 水平与葡萄糖呈正相关，与胰岛素呈负相关。因此，EV介导的全身血糖控制受损可能会导致某些BC患者的肿瘤进展和2型糖尿病的发生。