Transcutaneous vagus nerve stimulation has no anti-inflammatory effect in diabetes.

Chronic inflammation is associated with diabetes and contributes to the development and progression of micro- and macrovascular complications. Transcutaneous vagus nerve stimulation (tVNS) has been proposed to reduce levels of circulating inflammatory cytokines in non-diabetics by activating the cholinergic anti-inflammatory pathway. We investigated the anti-inflammatory potential of tVNS as a secondary endpoint of a randomized controlled trial in people with diabetes (NCT04143269). 131 people with diabetes (type 1: n = 63; type 2: n = 68), gastrointestinal symptoms and various degrees of autonomic neuropathy were included and randomly assigned to self-administer active (n = 63) or sham (n = 68) tVNS over two successive study periods: (1) Seven days with four daily administrations and, (2) 56 days with two daily administrations. Levels of systemic inflammatory cytokines (IL-6, IL-8, IL-10, TNF-α, IFN-γ) were quantified from blood samples by multiplex technology. Information regarding age, sex, diabetes type, and the presence of cardiac autonomic neuropathy (CAN) was included in the analysis as possible confounders. No differences in either cytokine were seen after study period 1 and 2 between active and sham tVNS (all p-values > 0.08). Age, sex, diabetes type, presence of CAN, and baseline levels of inflammatory cytokines were not associated with changes after treatment (all p-values > 0.07). A tendency towards slight reductions in TNF-α levels after active treatment was observed in those with no CAN compared to those with early or manifest CAN (p = 0.052). In conclusion, tVNS did not influence the level of systemic inflammation in people with diabetes.

Transcutaneous vagal nerve stimulation for treating gastrointestinal symptoms in individuals with diabetes: a randomised, double-blind, sham-controlled, multicentre trial.

AIMS/HYPOTHESIS: Diabetic gastroenteropathy frequently causes debilitating gastrointestinal symptoms. Previous uncontrolled studies have shown that transcutaneous vagal nerve stimulation (tVNS) may improve gastrointestinal symptoms. To investigate the effect of cervical tVNS in individuals with diabetes suffering from autonomic neuropathy and gastrointestinal symptoms, we conducted a randomised, sham-controlled, double-blind (participants and investigators were blinded to the allocated treatment) study. METHODS: This study included adults (aged 20-86) with type 1 or 2 diabetes, gastrointestinal symptoms and autonomic neuropathy recruited from three Steno Diabetes Centres in Denmark. Participants were randomly allocated 1:1 to receive active or sham stimulation. Active cervical tVNS or sham stimulation was self-administered over two successive study periods: 1 week of four daily stimulations and 8 weeks of two daily stimulations. The primary outcome measures were gastrointestinal symptom changes as measured using the gastroparesis cardinal symptom index (GCSI) and the gastrointestinal symptom rating scale (GSRS). Secondary outcomes included gastrointestinal transit times and cardiovascular autonomic function. RESULTS: Sixty-eight participants were randomised to the active group, while 77 were randomised to the sham group. Sixty-three in the active and 68 in the sham group remained for analysis in study period 1, while 62 in each group were analysed in study period 2. In study period 1, active and sham tVNS resulted in similar symptom reductions (GCSI: -0.26 ± 0.64 vs -0.17 ± 0.62, p=0.44; GSRS: -0.35 ± 0.62 vs -0.32 ± 0.59, p=0.77; mean ± SD). In study period 2, active stimulation also caused a mean symptom decrease that was comparable to that observed after sham stimulation (GCSI: -0.47 ± 0.78 vs -0.33 ± 0.75, p=0.34; GSRS: -0.46 ± 0.90 vs -0.35 ± 0.79, p=0.50). Gastric emptying time was increased in the active group compared with sham (23 min vs -19 min, p=0.04). Segmental intestinal transit times and cardiovascular autonomic measurements did not differ between treatment groups (all p>0.05). The tVNS was well-tolerated. CONCLUSIONS/INTERPRETATION: Cervical tVNS, compared with sham stimulation, does not improve gastrointestinal symptoms among individuals with diabetes and autonomic neuropathy. TRIAL REGISTRATION: ClinicalTrials.gov NCT04143269 FUNDING: The study was funded by the Novo Nordisk Foundation (grant number NNF180C0052045).

MRI-Based Quantification of Pan-Alimentary Function and Motility in Subjects with Diabetes and Gastrointestinal Symptoms.

Background: Diabetes-induced gastrointestinal (GI) symptoms are common but difficult to correctly diagnose and manage. We used multi-segmental magnetic resonance imaging (MRI) to evaluate structural and functional GI parameters in diabetic patients and to study the association with their symptomatic presentation. Methods: Eighty-six participants (46 with diabetes and GI symptoms, 40 healthy controls) underwent baseline and post-meal MRI scans at multiple timepoints. Questionnaires were collected at inclusion and following the scans. Data were collected from the stomach, small bowel, and colon. Associations between symptoms and collected data were explored. Utilizing machine learning, we determined which features differentiated the two groups the most. Key Results: The patient group reported more symptoms at inclusion and during MRI scans. They showed 34% higher stomach volume at baseline, 40% larger small bowel volume, 30% smaller colon volume, and less small bowel motility postprandially. They also showed positive associations between gastric volume and satiety scores, gastric emptying time and reflux scores, and small bowel motility and constipation scores. No differences in gastric emptying were observed. Small bowel volume and motility were used as inputs to a classification tool that separated patients and controls with 76% accuracy. Conclusions: In this work, we studied structural and functional differences between patients with diabetes and GI symptoms and healthy controls and observed differences in stomach, small bowel, and colon volumes, as well as an adynamic small bowel in patients with diabetes and GI symptoms. Associations between recorded parameters and perceived symptoms were also explored and discussed.

Pan-alimentary assessment of motility, luminal content, and structures: an MRI-based framework.

BACKGROUND: Gastrointestinal symptoms originating from different segments overlap and complicate diagnosis and treatment. In this study, we aimed to develop and test a pan-alimentary framework for the evaluation of gastrointestinal (GI) motility and different static endpoints based on magnetic resonance imaging (MRI) without contrast agents or bowel preparation. METHODS: Twenty healthy volunteers (55.6 ± 10.9 years, BMI 30.8 ± 9.2 kg/m2) underwent baseline and post-meal MRI scans at multiple time points. From the scans, the following were obtained: Gastric segmental volumes and motility, emptying half time (T50), small bowel volume and motility, colonic segmental volumes, and fecal water content. Questionnaires to assess GI symptoms were collected between and after MRI scans. KEY RESULTS: We observed an increase in stomach and small bowel volume immediately after meal intake from baseline values (p<.001 for the stomach and p=.05 for the small bowel). The volume increase of the stomach primarily involved the fundus (p<.001) in the earliest phase of digestion with a T50 of 92.1 ± 35.3 min. The intake of the meal immediately elicited a motility increase in the small bowel (p<.001). No differences in colonic fecal water content between baseline and 105 min were observed. CONCLUSION & INFERENCES: We developed a framework for a pan-alimentary assessment of GI endpoints and observed how different dynamic and static physiological endpoints responded to meal intake. All endpoints aligned with the current literature for individual gut segments, showing that a comprehensive model may unravel complex and incoherent gastrointestinal symptoms in patients.

A novel MRI-based three-dimensional model of stomach volume, surface area, and geometry in response to gastric filling and emptying.

BACKGROUND: Gastric motility and accommodation have a critical role in maintaining normal gastrointestinal homeostasis. Different modalities can be adopted to quantify those processes, that is, scintigraphy to measure emptying time and intragastric Barostat for accommodation assessment. However, magnetic resonance imaging (MRI) can assess the same parameters noninvasively without ionizing radiation. Our study aimed to develop a detailed three-dimensional (3D) MRI model of the stomach to describe gastric volumes, surface areas, wall tension distribution, and interobserver agreement. METHODS: Twelve healthy volunteers underwent an MRI protocol of six axial T2-weighted acquisitions. Each dataset was used to construct a 3D model of the stomach: First, the volumes of the whole stomach, gastric liquid, and air were segmented. After landmark placing, a raw 3D model was generated from segmentation data. Subsequently, irregularities were removed, and the model was divided into compartments. Finally, surface area and 3D geometry parameters (inverse curvatures) were extracted. The inverse curvatures were used as a proxy for wall tension distribution without measuring the intragastric pressure. KEY RESULTS: The model was able to describe changes in volume and surface geometry for each compartment with a distinct pattern in response to filling and emptying. The surface tension was distributed nonhomogeneously between compartments and showed dynamical changes at various time points. CONCLUSION & INFERENCES: The presented model offers a detailed tool for evaluating gastric volumes, surface geometry, and wall tension in response to filling and emptying and will provide insights into gastric emptying and accommodation in diseases such as diabetic gastroparesis.

Indentation of a pressurized silicon stomach model - A non-invasive study of gastric wall stiffness and pressurized gastric content stiffness.

BACKGROUND AND AIMS: Evaluation of gastric wall stiffness and intragastric pressure is essential for detailed assessments of gastric accommodation. However, non-invasive assessments are needed for large scale clinical studies and none of the existing methods takes abdominal wall effect into the calculation. This study aimed to assess gastric wall stiffness and gastric content stiffness as a proxy for intragastric pressure using novel mechanical modeling and non-invasive indentation tests on a silicon stomach model. METHODS: A silicon stomach model (scaling 1:1 with the human stomach) was indented using a pressure algometer at intragastric pressures from 0 to 0.8 kPa. Wall thicknesses and luminal cross-sectional areas along the stomach were measured with ultrasound images. The gastric wall stiffness was compared between measurements from tensile tests on strips cut from the silicon stomach and estimations from a shell indentation model. The pressurized gastric content stiffness was predicted from a bonded two-layer axisymmetric half-space indentation model. RESULTS: The gastric wall stiffness estimated from the shell indentation model showed no difference to measurements from the mechanical tests on the cutting strips (p = 0.14). The predicted gastric content stiffness was strongly associated with the intragastric pressure (r > 0.83, p < 0.001). CONCLUSIONS: The mechanical model developed in this study can simultaneously predict the gastric wall stiffness and the pressurized gastric content stiffness. In future studies, the method can be applied to reveal intragastric pressure conditions non-invasively via the pressurized gastric content stiffness during gastric accommodation and emptying such as with magnetic resonance imaging.

The effect of duloxetine on mechanistic pain profiles, cognitive factors and clinical pain in patients with painful knee osteoarthritis-A randomized, double-blind, placebo-controlled, crossover study.

BACKGROUND: Duloxetine is indicated in the management of pain in osteoarthritis. Evidence suggests that duloxetine modulates central pain mechanisms and cognitive factors, and these factors are assumed contributing to the analgesic effect. This proof-of-mechanism, randomized, placebo-controlled, crossover, double-blinded trial evaluated the effect of duloxetine on quantitative sensory testing (QST), cognitive factors and clinical pain in patients with osteoarthritis and to predict the analgesic effect. METHODS: Twenty-five patients completed this cross-over study with either 18-week duloxetine (maximum 60 mg/daily) followed by placebo or vice-versa. Pressure pain thresholds, temporal summation of pain and conditioned pain modulation were assessed using cuff algometry. The Hospital Anxiety and Depression Scale and the Pain Catastrophizing Scale evaluated cognitive factors. Clinical pain was assessed using Brief Pain Inventory and Western Ontario and McMaster Universities Osteoarthritis Index. Linear regression models were used to predict the analgesic effect of duloxetine. RESULTS: Depending on the clinical pain outcome, 40%-68% of patients were classified as responders to duloxetine. Linear regression models predicted the analgesic effect (predictive value of 45%-75% depending on clinical pain outcome parameter) using a combination of pretreatment QST parameters, cognitive factors and clinical pain. No significant changes were found for QST, cognitive factors or clinical pain on a group level when comparing duloxetine to placebo. CONCLUSION: A combination of pretreatment QST, cognitive factors and clinical pain was able to predict the analgesic response of duloxetine. However, in this relatively small study, duloxetine did not selectively modulate QST, cognitive factors or clinical pain intensity when compared with placebo. SIGNIFICANCE: Duloxetine is proposed as a treatment for chronic pain. Pre-clinical trials suggest that duloxetine provides analgesia through modulation of descending pain inhibitory pathways or through improvements in cognitive factors. The current study demonstrates that pretreatment mechanistic pain profiling, cognitive factors and clinical pain can predict the analgesic effect of duloxetine and that only a subset of patients might benefit from duloxetine treatment.

Quantification of gastric emptying with magnetic resonance imaging in healthy volunteers: A systematic review.

BACKGROUND: Several magnetic resonance imaging (MRI) protocols have been used to assess gastric emptying (GE) with MRI. This systematic review summarizes the current literature on the topic. The aim was to provide an overview of the available imaging protocols and underline the items that appear most agreed upon and those that deserve further investigation. METHODS: According to PRISMA guidelines, two independent reviewers conducted a systematic literature search with a pre-specified strategy in different databases. Peer-reviewed articles that utilized MRI techniques to assess GE in healthy volunteers (HVs) were included. The quality and the outcomes of the studies were reported and analyzed. KEY RESULTS: The literature search yielded 30 studies (531 HVs, weighted mean age 27.4, weighted mean body mass index 23.0 kg/m2 ), T2-weighted sequences, balanced turbo field echo, and balanced gradient echo were evenly utilized, with volunteers in the supine position (74% of the studies). After overnight fasting, both liquid (56%) and mixed (44%) meals were equally utilized. Segmentation of the volumes was predominantly performed manually (63%) with a reported mean T50 ranging from 7 to 330 min. CONCLUSIONS & INFERENCES: As observed in this systematic review, MRI is a flexible tool for assessing GE. Different protocols were analyzed, showing an equal capacity to assess the GE. However, many items in these protocols still require further investigation to obtain a common standard and increase this assessment quality.

Gastrointestinal function in diabetes is affected regardless of asymptomatic appearance.

BACKGROUND: Gastrointestinal dysmotility may exist without concomitant symptoms. We hypothesize that asymptomatic individuals with diabetes have altered gastrointestinal function associated with age, cardiac vagal tone and glycaemic control. METHODS: One hundred fifty-four asymptomatic participants (61 with type 1 diabetes (T1D), 70 type 2 diabetes (T2D) and 23 healthy volunteers (HV)) underwent wireless motility capsule investigation. Transit times, motility indices and pH were retrieved. Age, cardiac vagal tone, glucose and haemoglobin A1c levels were collected. RESULTS: In T1D, prolongation of colonic (p = 0.03) and whole-gut transit times (p = 0.04) were shown. Transpyloric pH rise was decreased in T1D (p = 0.001) and T2D (p = 0.007) and was associated with cardiac vagal tone (p = 0.03) or glucose (p = 0.04) and haemoglobin A1c (p = 0.005). Ileocaecal pH fall was decreased in T2D (p < 0.001). CONCLUSIONS: Gastrointestinal function was altered in asymptomatic individuals with diabetes. These findings call for further investigations of gastrointestinal function in order to identify risk factors or even predictors for diabetic enteropathy, particularly when glycaemic control is impaired.

Diabetic Gastroenteropathy: Soothe the Symptoms or Unravel a Cure?

Autonomic neuropathy in patients with diabetes mellitus, and especially complications related to gastrointestinal neuropathy, are often overlooked in the clinic. Diabetic gastroenteropathy affects every segment of the gastrointestinal tract and generates symptoms that may include nausea, early satiety, vomiting, abdominal pain, constipation, and diarrhea. Severe cases can be complicated by weight loss, dehydration, and electrolyte disturbances. The pathophysiology is complex, the diagnostics and treatment options are multidisciplinary, and there is generally a lack of evidence for the treatment options. The aims for this review are first to summarize the pathophysiology and describe possible and expected symptoms and complications.Further, we will try to supply the clinician with a straightforward tool for diagnostics, and then, we shall summarize established treatment options, including diet recommendations, pharmacological and non-pharmacological options. Finally, we will explore the multiple possibilities of novel treatment, looking at medications related to the pathophysiology of neuropathy, other manifestations of autonomic neuropathies, and symptomatic treatment for other gastrointestinal disorders, also including new knowledge of endosurgical and neuromodulatory treatment. The overall goal is to increase awareness and knowledge on this frequent diabetic complication and to provide better tools for diagnosis and treatment. Ultimately, we hope to encourage further research in this field, as there are clear shortcomings in terms of biomarkers, pathophysiology, as well as treatment possibilities. In conclusion, diagnosis and management of diabetic gastroenteropathy are challenging and often require multidisciplinary teams and multimodal therapies. Treatment options are sparse, but new pharmacological, endoscopic, and neuromodulatory techniques have shown promising results in initial studies.

A mechanism-based proof of concept study on the effects of duloxetine in patients with painful knee osteoarthritis.

BACKGROUND: The global burden of osteoarthritis (OA) is steadily increasing due to demographic and lifestyle changes. The nervous system can undergo peripheral and central neuroplastic changes (sensitization) in patients with OA impacting the options to manage the pain adequately. As a result of sensitization, patients with OA show lower pressure pain thresholds (PPTs), facilitated temporal summation of pain (TSP), and impaired conditioned pain modulation (CPM). As traditional analgesics (acetaminophen and non-steroidal anti-inflammatory drugs) are not recommended for long-term use in OA, more fundamental knowledge related to other possible management regimes are needed. Duloxetine is a serotonin-noradrenalin reuptake inhibitor, and analgesic effects are documented in patients with OA although the underlying fundamental mechanisms remain unclear. The descending pain inhibitory control system is believed to be dependent on serotonin and noradrenalin. We hypothesized that the analgesic effect of duloxetine could act through these pathways and consequently indirectly reduce pain and sensitization. The aim of this mechanistic study is to investigate if PPTs, TSP, CPM, and clinical pain parameters are modulated by duloxetine. METHODS: This proof of concept study is a randomized, placebo-controlled, double-blinded, crossover trial, which compares PPTs, TSP, and CPM before and after 18 weeks of duloxetine and placebo in forty patients with knee OA. The intervention periods include a titration period (2 weeks), treatment period (60 mg daily for 14 weeks), and a discontinuation period (2 weeks). Intervention periods are separated by 2 weeks. DISCUSSION: Duloxetine is recommended for the treatment of chronic pain, but the underlying mechanisms of the analgesic effects are currently unknown. This study will investigate if duloxetine can modify central pain mechanisms and thereby provide insights into the underlying mechanisms of the analgesic effect. TRIAL REGISTRATION: ClinicalTrials.gov NCT04224584 . Registered on January 6, 2020. EudraCT 2019-003437-42 . Registered on October 22, 2019. The North Denmark Region Committee on Health Research Ethics N-20190055. Registered on October 31, 2019.

Practical and clinical applications of pancreatic magnetic resonance elastography: a systematic review.

Magnetic resonance elastography (MRE) is a non-invasive technique suitable for assessing mechanical properties of tissues, i.e., stiffness. MRE of the pancreas is relatively new, but recently an increasing number of studies have successfully assessed pancreas diseases with MRE aiming to differentiate healthy from pathological pancreatic tissue with or without fibrosis. This review will systematically describe the practical and clinical applications of pancreatic MRE. We conducted a systematic literature search with a pre-specified search strategy using PubMed and Embase according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. English peer-reviewed articles applying MRE of the pancreas were included. Two independent reviewers assessed the studies. The literature search yielded 14 studies. The pancreatic stiffness for healthy volunteers ranged from 1.11. to 1.21 kPa at a driver frequency of 40 Hz. In benign tumors, the stiffness values were slightly higher or sometimes even lower (range 0.78 to 2.00 kPa), compared to the healthy pancreas parenchyma whereas, in malignant tumors, the stiffness values tended to be higher (1.42 to 6.06 kPa). The pancreatic stiffness was increased in both acute (median: 1.99 kPa) and chronic pancreatitis (> 1.50 kPa). MRE is a promising technique for detecting and quantifying pancreatic stiffness. It is related to fibrosis and seems to be useful in assessing treatment response and clinical follow-up of pancreatic diseases. However, most of the described practical settings were characterized by a lack of uniformity and inconsistency in reporting standards across studies. Harmonization between centers is necessary to achieve more consensus and optimization of pancreatic MRE protocols.

Assessment of Gastrointestinal Autonomic Dysfunction: Present and Future Perspectives.

The autonomic nervous system delicately regulates the function of several target organs, including the gastrointestinal tract. Thus, nerve lesions or other nerve pathologies may cause autonomic dysfunction (AD). Some of the most common causes of AD are diabetes mellitus and α-synucleinopathies such as Parkinson's disease. Widespread dysmotility throughout the gastrointestinal tract is a common finding in AD, but no commercially available method exists for direct verification of enteric dysfunction. Thus, assessing segmental enteric physiological function is recommended to aid diagnostics and guide treatment. Several established assessment methods exist, but disadvantages such as lack of standardization, exposure to radiation, advanced data interpretation, or high cost, limit their utility. Emerging methods, including high-resolution colonic manometry, 3D-transit, advanced imaging methods, analysis of gut biopsies, and microbiota, may all assist in the evaluation of gastroenteropathy related to AD. This review provides an overview of established and emerging assessment methods of physiological function within the gut and assessment methods of autonomic neuropathy outside the gut, especially in regards to clinical performance, strengths, and limitations for each method.

Study protocol for a multicentre, randomised, parallel group, sham-controlled clinical trial investigating the effect of transcutaneous vagal nerve stimulation on gastrointestinal symptoms in people with diabetes complicated with diabetic autonomic neuropathy: the DAN-VNS Study.

INTRODUCTION: A high proportion of people with diabetes experience gastrointestinal (GI) symptoms, which may be manifestations of diabetic autonomic neuropathy (DAN). The current treatment regime is ineffective and associated with major side effects. Transcutaneous vagal nerve stimulation (tVNS) is a new therapeutic option, which has been shown to increase GI motility and reduce inflammatory responses. As vagus is the main neuronal pathway for extrinsic coordination of GI secretion and motility, we hypothesise that tVNS will improve DAN-induced GI symptoms in subjects with diabetes. METHODS AND ANALYSIS: The DAN-VNS study is a randomised multicentre clinical trial investigating the effect of short-term, high intensity as well as long-term, medium-intensity tVNS on GI symptom alleviation in 120 subjects with diabetes. The primary outcome consists of changes from baseline in subjective ratings of symptom severity. Secondary outcomes include changes in gastric motility and GI transit time measured by MRI and wireless motility capsule. Moreover, cardiovascular and sudomotor function, glycaemic control, brain sensory processing and presence of low-grade inflammation will be investigated as secondary outcome measures. Lastly, 15 responders of tVNS treatment will be included in an explorative, randomised, cross-over study, in which the acute endocrine and metabolic response to short-term tVNS will be investigated. ETHICS AND DISSEMINATION: The study has been approved by the North Denmark Region Committee on Health Research Ethics (N-20190020). Results will be published in relevant international peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04143269.