Division of Endocrinology and Metabolism, National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China.
Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China.
PLoS Biol. 2020 Feb 24;18(2):e3000603. doi: 10.1371/journal.pbio.3000603. eCollection 2020 Feb.
Type 2 diabetes (T2D) is characterized by insulin resistance along with pancreatic β cell failure. β cell factors are traditionally thought to control glucose homeostasis by modulating insulin levels, not insulin sensitivity. Exosomes are emerging as new regulators of intercellular communication. However, the role of β-cell-derived exosomes in metabolic homeostasis is poorly understood. Here, we report that microRNA-26a (miR-26a) in β cells not only modulates insulin secretion and β cell replication in an autocrine manner but also regulates peripheral insulin sensitivity in a paracrine manner through circulating exosomes. MiR-26a is reduced in serum exosomes of overweight humans and is inversely correlated with clinical features of T2D. Moreover, miR-26a is down-regulated in serum exosomes and islets of obese mice. Using miR-26a knockin and knockout mouse models, we showed that miR-26a in β cells alleviates obesity-induced insulin resistance and hyperinsulinemia. Mechanistically, miR-26a in β cells enhances peripheral insulin sensitivity via exosomes. Meanwhile, miR-26a prevents hyperinsulinemia through targeting several critical regulators of insulin secretion and β cell proliferation. These findings provide a new paradigm for the far-reaching systemic functions of β cells and offer opportunities for the treatment of T2D.
2 型糖尿病（T2D）的特征是胰岛素抵抗伴随着胰岛β细胞功能衰竭。传统上认为β细胞因子通过调节胰岛素水平而不是胰岛素敏感性来控制血糖稳态。外泌体作为细胞间通讯的新调节剂而出现。然而，β细胞来源的外泌体在代谢稳态中的作用知之甚少。在这里，我们报告β细胞中的 microRNA-26a（miR-26a）不仅以自分泌方式调节胰岛素分泌和β细胞复制，而且还通过循环外泌体以旁分泌方式调节外周胰岛素敏感性。超重人群血清外泌体中的 miR-26a 减少，与 T2D 的临床特征呈负相关。此外，肥胖小鼠的血清外泌体和胰岛中 miR-26a 下调。使用 miR-26a 敲入和敲除小鼠模型，我们表明β细胞中的 miR-26a 通过外泌体减轻肥胖引起的胰岛素抵抗和高胰岛素血症。在机制上，β细胞中的 miR-26a 通过外泌体增强外周胰岛素敏感性。同时，miR-26a 通过靶向胰岛素分泌和β细胞增殖的几个关键调节因子来防止高胰岛素血症。这些发现为β细胞的深远系统功能提供了一个新的范例，并为 T2D 的治疗提供了机会。
