Peripheral neurons that sense glucose relay signals of glucose availability to integrative clusters of neurons in the brain. However, the roles of such signalling pathways in the maintenance of glucose homoeostasis and their contribution to disease are unknown. Here we show that the selective activation of the nerve plexus of the hepatic portal system via peripheral focused ultrasound stimulation (pFUS) improves glucose homoeostasis in mice and rats with insulin-resistant diabetes and in swine subject to hyperinsulinemic-euglycaemic clamps. pFUS modulated the activity of sensory projections to the hypothalamus, altered the concentrations of metabolism-regulating neurotransmitters, and enhanced glucose tolerance and utilization in the three species, whereas physical transection or chemical blocking of the liver–brain nerve pathway abolished the effect of pFUS on glucose tolerance. Longitudinal multi-omic profiling of metabolic tissues from the treated animals confirmed pFUS-induced modifications of key metabolic functions in liver, pancreas, muscle, adipose, kidney and intestinal tissues. Non-invasive ultrasound activation of afferent autonomic nerves may represent a non-pharmacologic therapy for the restoration of glucose homoeostasis in type-2 diabetes and other metabolic diseases.

感知葡萄糖的外周神经元将葡萄糖可用性的信号传递给大脑中的综合神经元簇。然而，此类信号通路在维持葡萄糖稳态中的作用及其对疾病的贡献尚不清楚。在这里，我们表明通过外周聚焦超声刺激 (pFUS) 选择性激活肝门静脉系统的神经丛可改善患有胰岛素抵抗糖尿病的小鼠和大鼠以及接受高胰岛素正常血糖钳夹的猪的葡萄糖稳态。pFUS 调节了下丘脑的感觉投射活动，改变了代谢调节神经递质的浓度，并增强了三个物种的葡萄糖耐量和利用，而肝脑神经通路的物理横断或化学阻断消除了 pFUS 对葡萄糖耐量的影响。来自治疗动物的代谢组织的纵向多组学分析证实了 pFUS 诱导的肝脏、胰腺、肌肉、脂肪、肾脏和肠道组织中关键代谢功能的改变。传入自主神经的非侵入性超声激活可能代表一种非药物疗法，用于恢复 2 型糖尿病和其他代谢疾病中的葡萄糖稳态。