New Insight into the Vagus Nerve Regulation of Glucose Homeostasis: A Role for Afferent Signaling and Skeletal Muscle Glucose Uptake

Abstract

The autonomic nervous system (ANS) participates in maintaining glucose homeostasis, in part through vagus nerve signals between the liver and brain stem. However, the role of afferent and efferent vagus nerve signaling in the regulation of glucose homeostasis is unknown. Here we observed electrical stimulation of the cervical vagus nerve significantly reduced blood glucose levels from the baseline level in wildtype, fasted mice as compared with sham stimulated controls (change in blood glucose; sham stimulation vs. stimulated, -14.14 mg/dL ± 13.44 mg/dL vs. -27.14 mg/dL ± 18.54 mg/dL, p = 0.0218). Animals subjected to chemical ablation of the vagus nerve (vagotomy) proximal to the stimulating electrodes failed to respond to the glucose lowering effects of vagus nerve stimulation (change in blood glucose; proximal vagotomy vs. no vagotomy, -6.750 mg/dL ± 14.05 mg/dL vs. -25.22 mg/dL ± 19.14 mg/dL, p = 0.0243). This indicates that afferent vagus nerve signaling can decrease glucose levels. We also observed vagus nerve stimulation failed to mediate significant changes in circulating levels of insulin, glucagon, leptin, or GLP-1. Skeletal muscle glucose uptake is mediated by GLUT4 transporters, a major mechanism for maintaining glucose. To investigate whether skeletal muscle glucose uptake via GLUT4 is required for the glucose lowering effect of vagus nerve stimulation, we generated transgenic mice that lacked the GLUT4 transporter selectively in skeletal muscle. Vagus nerve stimulation resulted in decreases in circulating glucose levels in littermate controls, but not in animals with the GLUT4 transporter knocked out in the skeletal muscle (change in blood glucose; littermate controls vs. GLUT4 KO, -59.63 mg/dL ± 28.37 mg/dL vs. -36.67 mg/dL ± 15.63 mg/dL). Next, to test effects of vagus nerve stimulation in hyperglycemic conditions, obese ob/ob mice with baseline glucose greater than 250 mg/dL were subjected to vagus nerve stimulation. A significant decrease in blood glucose levels from baseline is observed in ob/ob mice as compared to sham stimulated controls (change in blood glucose; stimulated vs. sham stimulated, -84.72 mg/dL ± 27.41 mg/dL vs. -10.65 mg/dL ± 14.05 mg/dL, p = 0.003). Together these findings indicate afferent vagus nerve activity increases glucose uptake in skeletal muscle and lowers serum glucose.