Introduction: GLP-1 is an incretin released by the gut in response to food consumption. Binding to the GLP-1 receptor, (GLP-1R) increases insulin and decreases glucagon secretion by the pancreas, promoting nutrient storage and usage [1]. GLP-1 also acts in the brain to promote satiety. As such, GLP-1R agonists are used in type 2 diabetes (T2D) and obesity to promote glycemic control and decrease weight [2]. The carotid bodies (CBs), peripheral chemoreceptors classically defined as O2 sensors, have also been pointed to be metabolic sensors involved in energy and glucose homeostasis [3]. Herein, we investigated the role of the CBs on the GLP-1 effects on glucose homeostasis.

Material & Methods:  Wistar rats were submitted to 10 weeks of 60% lipid-rich diet (HF) or to a standard diet (NC). After, half of the groups were submitted to carotid sinus nerve (CSN) resection, to abolish CB contribution to GLP-1 effects on metabolism, or to a sham surgery. At a terminal experiment a bolus of liraglutide, a GLP-1R agonist (200 μg/Kg), was administrated in the external carotid artery and glycemia measured for 1h. Insulin, C-peptide, and glucagon in plasma samples were evaluated by a multiplex analysis at 0, 15, 30 and 60min post liraglutide administration. Experiments followed the 2010/63/EU European Union Directive and were approved by NMS Ethics Committee and Portuguese Authority for Animal Health. Differences between data were calculated using One-Way ANOVA and considered significantly different with p-values <0.05.

Results: Liraglutide decreased blood glucose levels by 15.4% and 28.2% in NC and HF animals, effects exacerbated by CSN resection in NC (p<0.05) but not in HF animals. HF diet also increased the time to liraglutide reach a maximal effect on blood glucose (p<0.05) vs NC animals, and impaired the counterregulatory responses to hypoglycemia, effects abolished by CSN resection. Insulin levels increased by 121.6% and 87.2% in response to liraglutide in NC and HF animals, respectively an effect prevented by CSN denervation, with no significative alterations in c-peptide levels between groups. Glucagon levels increased by 44.8% in response to liraglutide administration in NC animals, an effect attenuated in HF diet-animals (20.5% increase). CSN resection in both NC and HF diet animals prevented the counter-regulatory increase in glucagon levels promoted by a decrease in glycemia induced by liraglutide.

Conclusions: CSN resection improves liraglutide effects on blood glucose and insulin levels and on the impaired-HF diet counterregulatory mechanisms to hypoglycemia. CSN resection exacerbates HF-induced impairment of liraglutide positive effects on glucagon secretion, suggesting that CBs modulation of hypoglycemia counterregulatory mechanisms occurs by other mechanism different from glucagon secretion.  These results suggest that targeting GLP-1 action on glucose homeostasis involves the contribution of the CB.