Non-invasive transcutaneous vagus nerve stimulation applied by the GammaCore device (ElectroCore LLC)

Inactive sham vagus nerve stimulation applied by the GammaCore sham device (ElectroCore LLC)

Diabetes Mellitus, Type 2

Gastrointestinal Dysfunction

Bilateral stimulation 4 times per day for 7 days (period 1) and 2 times per day for 8 weeks (period 2). The two periods are separated by a 2 weeks wash-out period.

Non-invasive transcutaneous vagus nerve stimulation

Bilateral stimulation 4 times per day for 7 days (period 1) and 2 times per day for 8 weeks (period 2). The two periods are separated by a 2 weeks wash-out period.
The sham device produces a slight vibrating sensation, but do not provide any vagal nerve activation

Sham vagus nerve stimulation

Treatment of Complications to Diabetic Autonomic Neuropathy With Vagus Nerve Stimulation

Assessed as changes from baseline in scores from the validated questionnaire Gastroparesis Cardinal Symptom Index (GCSI). The GCSI-score ranges from 0 to 5 with a higher score indicating a higher amount of experienced symptoms

Assessed as changes from baseline in scores from the validated questionnaire Gastrointestinal Symptom Rating Scale (GSRS). The GSRS-score ranges from 1 to 7 with a higher score indicating a higher amount of experienced symptoms

A small patch sensor (ePatch) will be used to monitor the heart rate variability during a period of 5 days. Classical time (RR-interval, SDNN, SDNNi, SDANN, RMSSD) and frequency (VLF, LF, HF and LF/HF) domain heart rate variability parameters will be assessed

A three lead electrocardiography device (eMotion Faros) will record the cardiac vagal tone during a period of 5 minutes rest. Cardiac vagal tone is measured on a linear vagal scale with a low score indicating dysfunction of the vagal nerve

The VAGUS device, will be used to test three different standardised heart reflexes(Ewings battery). From these tests the device calculates a score from 0-3 indicating the degree of autonomic neuropathy, with 0 being no neuropathy and 3 being manifest neuropathy

Participants will swallow a indigestible wireless motility capsule (SmartPill) in order to assess the transit time of whole gut as well as individual segments.

40 electrodes will be used to record EEG during a period of 5 minutes rest. The results will be used to model connectivity between brain centres as well as the dominating centres of brain. EEG power will be assessed in the Delta, Theta, Alpha, Beta, and Gamma bands between 1 and 70 Hertz. Finally inverse modelling will be conducted to explore the dominating centres of brain activity.

Pressure will be applied to the tibial bone and the quadriceps muscle by a handheld pressure algometer. The pain tolerance threshold (measured in kPa) is reached when the participant reports the pain to be intolerable

The left hand of the participant is immersed in 2.0 degree (celsius) cold water for up to 2 minutes or until the pain becomes intolerable. The participant is asked to rate the pain on a 10-point Visual Analogue Scale (0 being no pain and 10 being worst imaginable pain) every 10 seconds during the test.

Continuous glucose monitoring (FreeStyle Libre)

Multiplex analysis of serum samples. Serum concentrations (pg/mL) of inflammatory biomarkers (TNF-alpha, IL-2, IL-4, IL-6 and IL-10) will be assessed.

Asbjørn Mohr Drewes

Professir, Chief Physician, MD, PhD, DMSc

Aalborg University Hospital

ElectroCore INC

The study consists of four different parts:
11C Donepezil PET/CT scan
3D-Transit
3D-Transit during treatment with pyridostigmine
3D-Transit after Malone appendicostomy (only diabetic patients who had a Malone-surgery for severe obstipation ordered during standard clinical practice)

The study consists of two different parts:
11C Donepezil PET/CT scan
3D-Transit

Diabetic Autonomic Neuropathy

Gastrointestinal Motility Disorder

Diabetes Mellitus

Change of Transit or Circulation

Donepezil binds with high affinity to acetylcholine esterase in the cholinergic synapses. The quantity of density of acetylcholine esterase in the abdominal organs including the intestinal wall are demonstrated by 11C Donepezil PET/CT scan. The PET-signal are measured as Standard-uptake values (SUV) in the internal organs. After 6 hours of fast CT- and PET-scans are performed after injection of iv. contrast and about 500MBq (megabecquerel) [11C]donepezil. The CT scan is used for anatomical location of the internal organs. The scan-field includes the heart and the abdominal organs. Total scan time is about 60 minutes.

11C Donepezil PET/CT scan

3D-Transit: 3D-Transit for minimal invasive and ambulant describing of regional transit times and contractions pattern of the bowel. The motility and the passage time is measured by 3D-Transit The description of location and rotation of the capsule is dynamic and very precise. It permits precise detailed description of the gastrointestinal contraction pattern and regional passage time. 3D-transit consist of three different parts:
A wireless electromagnetic capsule to be swallowed by the subject
A portable detector plate comprising four sensors worn in a belt around the waist
Specific software for visualizing and analyzing data

3D-Transit

3D-Transit and Pyridostigmine: The motility and the passage time is measured by 3D-Transit (as mentioned above) in diabetic patients during administration of Pyridostigmine 60 mg administrated 4 times with 4 hours between each administration. Pyridostigmine is increasing the amount of cholinergic neurotransmitter and is suggested to have a reversible effect on the cholinergic denervation. The mechanism of action of Pyridostigmine in the human body is well-known and the drug is used as a tool to determine if the disturbance in the guts are reversible in diabetic patients.

3D-Transit during treatment with Pyridostigmine

3D-Transit (as earlier described) is performed after Malone appendicostomy. The patients are suppose use the antegrade edema technic during the 3D-transit examination.

3D-Transit after Malone appendicostomy

Department of Hematology and Gastroenterology, Aarhus University Hospital

Gastrointestinal Motility Among Diabetes Patients

The PET signal is measured as standard-uptake values (SUV) in the internal organs. This simple value has earlier been validated as equivalent to more advanced PET kinetic parameters, were an arterial-needle is required. From the CT-scan volume-of-interests of the relevant organs are applied (bowel segments, heart, pancreas) and the SUV-values draw from the PET-scans. SUV in the small intestine are compared between healthy subjects and diabetic patients. SUV is a measure of in vivo quantification of cholinergic cells in the small bowel.

The following parameters are analyzed: Total gastrointestinal transit time (capsule number 1).
Data from capsule 1 in healthy subjects and diabetic patients will be used for: Comparison of total GI transit times and transit patterns in healthy individuals and diabetic patients.

If new software for analysis permits more detailed data analysis. Amplitudes of gastric contractions during awake and sleep will be analyzed.

If new software for analysis permits more detailed data analysis. Number of "fast movements" in the small intestine will be analyzed.

If new software for analysis permits more detailed data analysis. Number and distance covered by "mass-movements" in colorectum will be analyzed.

3D-Transit data from capsule 1 and 2 (only the diabetic patients): By comparing total GI transit times with and without administration of acetylcholine esterase inhibitor mechanistic data will be obtained to determine if neuropathy of acetylcholine containing neurons is the cause of physiological changes in GI transit times. The primary end-point is difference in total gastrointestinal passage time.

The following parameters are analyzed: Gastric emptying, small intestinal and colorectal transit time (capsule number 1).
Data from capsule 1 in healthy and patients will be used for: Comparison of regional GI transit times and transit patterns in healthy individuals and diabetic patients.

The following parameters are analyzed: Gastric emptying, small intestinal and colorectal transit time (capsule number 1 and 2, only in diabetic patients).
Data from capsule 1 and 2 will be used for: Comparison of regional GI transit times and transit patterns in diabetic patients with and without Pyridostigmine

The following parameters are analyzed: Gastric emptying, small intestinal and colorectal transit time (capsule number 1 and 3, only in diabetic patients with Malone Surgery).
Data from capsule 1 and 3 will be used for: Comparison of regional GI transit times and transit patterns in diabetic patients

University of Aarhus

Novo Nordisk A/S

Svend Faelding Humanitarian Foundation

Copenhagen University Foundation for Medical Students

Hoejmosegaard Foundation

Holger Rabitz og Hustru Doris Mary foedt Phillipps Mindelegat

Subjects in the DPAEP group will undergo a structured weight loss for approximately 6 months, followed by approximately 6 months of weight maintenance, as well as 12 months of aerobic exercise. This intervention stresses a personalized program emphasizing activities that are meaningful to and are tailored to individual participants; provides consistent contact between the participants and research staff; and allows monitoring of activity levels using questionnaires, actigraphy, monitoring of heart rate, direct and telephone contact. Participants dietary and physical activity goals as assessed by the dietician and trainer will be discussed at face-to face meetings to re-establish these goals. These programs will be tailored to meet the realistic goals of the individual participant. The program stresses aerobic exercise, rather than other types of exercise interventions, as aerobic exercise appears to correlate best with improved autonomic function.

The SC group will be assigned an interventionist assessor. This assessor will meet with the subjects during their orientation meeting and will be provided guidelines and a weight loss and physical activity target to achieve by the end of the program at their orientation meeting. Participants will contacted approximately weekly during the approximate 12 month period.

Diabetes

Neuropathy

Impaired Glucose Tolerance

Structured weight loss or weight maintenance and aerobic exercise intervention for 12 months or standard of care weight and exercise management

lifestyle modification

Baltimore VA Medical Center VA Maryland Health Care System, Baltimore, MD

Improving Autonomic Function and Balance in Diabetic Neuropathy

This is a cardiac autonomic measure that will be carried out using clinical equipment in the autonomic laboratory at the site. The measurement requires placing electrodes near the heart similar to an EKG.

This outcome measure assesses changes in trunk positioning using a standardized, validated test.

This outcome assesses sweat gland nerve fiber density, which is proposed as a sensitive neuropathy pathology biomarker.

diabetic neuropathies/caureja

Treatment of Complications to Diabetic Autonomic Neuropathy With Vagus Nerve Stimulation

Gastrointestinal Motility Among Diabetes Patients

Improving Autonomic Function and Balance in Diabetic Neuropathy

Nerve Conduction Velocity in Diabetic Children

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