Constant hepatic ATP concentrations during prolonged fasting and absence of effects of Cerbomed Nemos® on parasympathetic tone and hepatic energy metabolism

Abstract

ObjectiveBrain insulin-induced improvement in glucose homeostasis has been proposed to be mediated by the parasympathetic nervous system. Non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) activating afferent branches of the vagus nerve may prevent hyperglycemia in diabetes models. We examined the effects of 14-min taVNS vs sham stimulation by Cerbomed Nemos® on glucose metabolism, lipids, and hepatic energy homeostasis in fasted healthy humans (n = 10, age 51 ± 6 yrs, BMI 25.5 ± 2.7 kg/m2).MethodsHeart rate variability (HRV), reflecting sympathetic and parasympathetic nerve activity, was measured before, during and after taVNS or sham stimulation. Endogenous glucose production was determined using [6,6-2H2]glucose, and hepatic concentrations of triglycerides (HCL), adenosine triphosphate (ATP), and inorganic phosphate (Pi) were quantified from 1H/31P magnetic resonance spectroscopy at baseline and for 180 min following stimulation.ResultstaVNS did not affect circulating glucose, free fatty acids, insulin, glucagon, or pancreatic polypeptide. Rates of endogenous glucose production (P = 0.79), hepatic HCL, ATP, and Pi were also not different (P = 0.91, P = 0.48 and P = 0.24) between taVNS or sham stimulation. Hepatic HCL, ATP, and Pi remained constant during prolonged fasting for 3 h. No changes in heart rate or shift in cardiac autonomic function from HRV towards sympathetic or parasympathetic predominance were detected.ConclusionNon-invasive vagus stimulation by Cerbomed Nemos® does not acutely modulate the autonomic tone to the visceral organs and thereby does not affect hepatic glucose and energy metabolism. This technique is therefore unable to mimic brain insulin-mediated effects on peripheral homeostasis in humans.

No modulation of postprandial metabolism by transcutaneous auricular vagus nerve stimulation: a cross-over study in 15 healthy men

“…the rhythmic contractions of the stomach 13 . In contrast, 14 min of taVNS did not modulate the autonomic tone to visceral organs up to 120 min post stimulation in a recent study 17 .…”

Moving beyond belief: A narrative review of potential biomarkers for transcutaneous vagus nerve stimulation

“…RMSSD, pNNx, RSA, or HF HRV; Laborde et al, 2017; Task Force of The European Society of Cardiology & The North American Society of Pacing and Electrophysiology, 1996). Other indices, including the LF/HF ratio which was found to be influenced by tragus stimulation in some studies (Antonino et al, 2017;Clancy et al, 2014;Weise et al, 2015) but not in others (Couck et al, 2017;Gancheva et al, 2018), are influenced by other factors than vagal activity, and thus should not be interpreted as a definite sign that the vagus nerve is activated.…”

“…In a second study, the authors found that one hour of right ear cymba concha stimulation did not affect any HRV parameter after controlling for confounders (De Couck et al, 2017). Similarly, in 10 healthy individuals, stimulation of the left cymba concha did not significantly affect HF HRV (Gancheva et al, 2018). During a fear conditioning procedure, stimulation of the left cymba concha did not significantly affect RMSSD throughout generalization and extinction learning (A.…”

“…Secondly, there is large heterogeneity between studies in the tested samples, ranging from healthy adults to children to heart failure patients. Thirdly, stimulation intensities vary considerably between studies: whereas the sensory threshold for stimulation of the cymba concha lies somewhere between 0.5 and 1.5mA (De Couck et al, 2017;Gancheva et al, 2018), studies that stimulate at the tragus vary anywhere from roughly 4 mA (Badran, Dowdle, et al, 2018b;Jacobs et al, 2015) up to 50 (Antonino et al, 2017;Clancy et al, 2014). It seems unlikely that the sensory threshold of the tragus lies a hundred times higher than that of the cymba concha, indicating that certain settings besides the frequency, stimulation wavelength and target current may differ between these devices.…”

International Consensus Based Review and Recommendations for Minimum Reporting Standards in Research on Transcutaneous Vagus Nerve Stimulation (Version 2020)

“…Other more physiologically oriented studies have investigated the influence of tVNS on cardiac activity (Brock et al, 2017 ; De Couck et al, 2017 ; Lamb et al, 2017 ; Gancheva et al, 2018 ; Borges et al, 2019 ; Bretherton et al, 2019 ; Koenig et al, 2019 ; Paleczny et al, 2019 ; Tobaldini et al, 2019 ; Tran et al, 2019 ); autonomic outflow (Sclocco et al, 2017 ); sympathetic nerve activity (Clancy et al, 2014 ) or cardiac baroreflex sensitivity (Antonino et al, 2017 ); atrial fibrillation (Stavrakis et al, 2015 ); cardiac mechanical function (Tran et al, 2019 ); vagal sensory evoked potentials (Fallgatter et al, 2003 , 2005 ; Polak et al, 2009 ; Leutzow et al, 2013 ); persistent hiccups (Schulz-Stübner and Kehl, 2011 ); visual bistable perception (Keute et al, 2019a ); nociceptive neuromodulation (Napadow et al, 2012 ; Busch et al, 2013 ; Laqua et al, 2014 ; Usichenko et al, 2017b ; Janner et al, 2018 ); tumor necrosis factor-alpha (Brock et al, 2017 ); hepatic energy metabolism (Gancheva et al, 2018 ); whole blood culture-derived cytokines and chemokines (Lerman et al, 2016 ); salivary hormones (Ventura-Bort et al, 2018 ; Koenig et al, 2019 ; Warren et al, 2019 ); pupil diameter (Warren et al, 2019 ); gastroduodenal or gastrointestinal motility (Frøkjaer et al, 2016 ; Juel et al, 2017 ); muscle activity in the gastrointestinal tract (Hong et al, 2019 ), gastric frequency (Teckentrup et al, 2020 ); electroencephalography (Hyvärinen et al, 2015 ; Keute et al, 2018 ; Lewine et al, 2019 ) and event-related potentials (Lewine et al, 2019 ), specifically the P3/P300 event-related potential (Ventura-Bort et al, 2018 ; Warren et al, 2019 ); cortical excitability (Capone et al, 2015 ) and changes in blood-oxygen-level-dependent (BOLD) functional Magnetic Resonance Imaging (fMRI) (Kraus et al,...…”