Pancreatic Beta Cell Microrna-26a Alleviates Type 2 Diabetes By Improving Peripheral Insulin Sensitivity And Preserving Beta Cell Function

Type 2 diabetes (T2D) is characterized by insulin resistance along with pancreatic beta cell failure. beta 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 beta-cell-derived exosomes in metabolic homeostasis is poorly understood. Here, we report that microRNA-26a (miR-26a) in beta cells not only modulates insulin secretion and beta 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 beta cells alleviates obesity-induced insulin resistance and hyperinsulinemia. Mechanistically, miR-26a in beta cells enhances peripheral insulin sensitivity via exosomes. Meanwhile, miR-26a prevents hyperinsulinemia through targeting several critical regulators of insulin secretion and beta cell proliferation. These findings provide a new paradigm for the far-reaching systemic functions of beta cells and offer opportunities for the treatment of T2D.