Key Points• The aim was to explore the effect of combined electrical and physiological modulation of vagal tone on musculoskeletal pain thresholds and gastroduodenal motility.• Eighteen healthy subjects were included in a subject-blinded, sham-controlled, cross-over study with an active protocol including transcutaneous electrical vagal nerve stimulation and deep slow breathing.• Recording of cardiac derived parameters including cardiac vagal tone, moderate pain thresholds to muscle and bone pressure algometry, conditioned pain modulation using a cold pressor test, and a liquid meal ultrasonographic gastroduodenal motility test were performed.• Cardiac vagal tone, thresholds to bone pain, frequency of antral contractions, and gastroduodenal motility index all increased during active treatment compared to sham.• The presented noninvasive approach with combined electrical and physiological modulation of vagal tone enhances gastroduodenal motility and reduces somatic pain sensitivity.• These findings warrant further investigation in patients with disorders characterized with chronic pain and gastrointestinal dysmotility such as functional dyspepsia and irritable bowel syndrome. AbstractBackground The parasympathetic nervous system, whose main neural substrate is the vagus nerve, exerts a fundamental antinociceptive role and influences gastrointestinal sensori-motor function. Our research question was to whether combined electrical and physiological modulation of vagal tone, using transcutaneous electrical vagal nerve stimulation (t-VNS) and deep slow breathing (DSB) respectively, could increase musculoskeletal pain thresholds and enhance gastroduodenal motility in healthy subjects. Methods Eighteen healthy subjects were randomized to a subject-blinded, sham-controlled, cross-over study with an active protocol including stimulation of auricular branch of the vagus nerve, and breathing at full inspiratory capacity and forced full expiration. Recording of cardiac derived parameters including cardiac vagal tone, moderate pain thresholds to muscle, and bone pressure algometry, conditioned pain modulation using a cold pressor test and a liquid meal ultrasonographic gastroduodenal motility test were performed. Key Results Cardiac vagal tone increased during active treatment with t-VNS and DSB

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Aims/hypothesis Glucagon-like peptide 1 (GLP-1) reduces appetite and energy intake in humans, whereas the other incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), seems to have no effect on eating behaviour. Interestingly, studies in rodents have shown that concomitant activation of GIP and GLP-1 receptors may potentiate the satiety-promoting effect of GLP-1, and a novel dual GLP-1/GIP receptor agonist was recently shown to trigger greater weight losses compared with a GLP-1 receptor agonist in individuals with type 2 diabetes. The aim of this study was to delineate the effects of combined GIP and GLP-1 receptor activation on energy intake, appetite and resting energy expenditure in humans. Methods We examined 17 overweight/obese men in a crossover design with 5 study days. On day 1, a 50 g OGTT was performed; on the following 4 study days, the men received an isoglycaemic i.v. glucose infusion (IIGI) plus saline (154 mmol/l NaCl; placebo), GIP (4 pmol kg −1 min −1), GLP-1 (1 pmol kg −1 min −1) or GIP+GLP-1 (4 and 1 pmol kg −1 min −1 , respectively). All IIGIs were performed in a randomised order blinded for the participant and the investigators. The primary endpoint was energy intake as measured by an ad libitum meal after 240 min. Secondary endpoints included appetite ratings and resting energy expenditure, as well as insulin, C-peptide and glucagon responses. Results Energy intake was significantly reduced during IIGI+GLP-1 compared with IIGI+saline infusion (2715 ± 409 vs 4483 ± 568 kJ [mean ± SEM, n = 17], p = 0.014), whereas there were no significant differences in energy intake during IIGI+GIP (4062 ± 520 kJ) or IIGI+GIP+GLP-1 (3875 ± 451 kJ) infusion compared with IIGI+saline (p = 0.590 and p = 0.364, respectively). Energy intake was higher during IIGI+GIP+GLP-1 compared with IIGI+GLP-1 infusion (p = 0.039). Conclusions/interpretation While GLP-1 infusion lowered energy intake in overweight/obese men, simultaneous GIP infusion did not potentiate this GLP-1-mediated effect. Trial registration ClinicalTrials.gov NCT02598791 Funding This study was supported by grants from the Innovation Fund Denmark and the Vissing Foundation.