AURICULAR VAGAL NERVE STIMULATION IMPROVES HYPERGLYCEMIA BY ENHANCING RELEASE OF POSTPRANDIAL INCRETIN HORMONES AND VAGAL EFFERENT ACTIVITY IN TYPE 2 DIABETIC RATS

Background & Aim: Despite advancements in pharmacotherapies, glycemia is poorly controlled in a large proportion of patients with type 2 diabetes (T2D). The vagus nerve regulates energy metabolism. Previous studies have shown that vagal nerve stimulation (VNS) reduces blood glucose in diabetic rodent models. However, noninvasive auricular VNS (aVNS) is more feasible than invasive VNS in clinical practice. This study aimed to explore the effects and possible mechanisms of aVNS on glycemic control in T2D rats.
Methods: A T2D rat model (n=12) induced by high-fat diet combined with a low dose of streptozotocin was used to validate the aVNS method. one pair of auricular electrodes were implanted in the right ear and one auricular electrode in the left ear for aVNS. The VNS electrodes were implanted at left cervical vagus. The oral glucose tolerance test (OGTT) was performed in a number of sessions with different methods of aVNS but fixed parameters (0.5ms, 5Hz, 10 s on/90 s off and 90% motor threshold: 90% of the minimum stimulation intensity). Plasma glucagon-like peptide-1 (GLP-1) , norepinephrine (NE) and pancreatic polypeptide (PP) level were measured. In the other two OGTT sessions, rats were treated with either Exendin 9-39 (GLP-1 antagonist) or Exendin 9-39 plus aVNS to investigate the possible mechanism involving GLP-1.
Results: 1) Acute one-time VNS, Bilateral aVNS and Unilateral aVNS significantly decreased blood glucose during OGTT at 15 min compared to the sham (P<0.01, P<0.01, P<0.05 vs. Sham, respectively, Fig.1A). The mean AUC was significantly reduced with Unilateral aVNS during the 3-h OGTT (P<0.01 vs. Sham, Fig.1B). 2) After glucose administration, the plasma GLP-1 concentration increased at 30 min and decreased 30 min later in type 2 diabetic rats. Acute unilateral aVNS increased plasma GLP-1 level at 30 min after glucose administration (P<0.05, vs. Sham, Fig.2). 3) The GLP-1 antagonist exendin 9-39 blocked the hypoglycemic effect of unilateral aVNS (P>0.05, Uni-aVNS+ Exendin 9-39 vs sham). 4) Unilateral aVNS enhanced vagal activity: Plasma PP (reflecting vagal activity) was increased, whereas plasma NE (reflecting sympathetic activity) was decreased (P<0.05 vs. Sham).
Conclusions: aVNS which can be implemented noninvasively, like VNS, reduced blood glucose in type 2 diabetic rats by increasing GLP-1 release and enhancing vagal efferent activity. (Partially supported by NIH grants (R01DK131524 and R01DK107754)).