Effect of Exercise and Surgical Weight Loss on Polyneuropathy

The Effect of High Intensity Interval Training and Surgical Weight Loss on Distal Symmetric Polyneuropathy Outcomes

The purpose of this research study is to evaluate how exercise and surgical weight loss affect how likely an individual is to develop peripheral neuropathy and other neurologic complications.

Study Overview

• Status: Completed
• Conditions: Obesity; Polyneuropathies; Bariatric Surgery Candidate
• Intervention / Treatment: Other: High Intensity Interval Training (HIIT); Procedure: Bariatric surgery; Other: Routine Exercise

Detailed Description

The length of this study, including screening is approximately 24 months. Patients at Bariatric Surgery Clinics will be recruited for this study. Both patients that decide to undergo bariatric surgery, and those that do not undergo surgery will be enrolled. Patients will be randomized to either a high intensity interval training (HIIT) or standard exercise regimen after eligibility is confirmed and the baseline visit is complete. All patients will complete follow-up appointments at 3 month, 12 months and 24 months. Patients that are randomized to the HIIT program will compete 2 supervised and 1 unsupervised training sessions a week for 24 months.

• Study Type: Interventional
• Enrollment (Actual): 140
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Attending a bariatric surgery clinic
• BMI > 35 with one comorbid condition present or BMI > 40 without comorbid conditions present
• Willing and capable to sign the Institutional Review Board (IRB) approved consent form and cooperate with the medical procedures for the study duration
• Willing to accept random treatment assignment to HIIT or routine exercise counseling

Exclusion Criteria:

• History of distal symmetric polyneuropathy (DSP) from causes other than diabetes and/or the metabolic syndrome as determined through medical history, family history, history of medications, occupational history, history of exposure to toxins, physical and neurological examinations;
• Use of warfarin, heparin, or other anticoagulants, which would increase the risk of complications from skin biopsy
• Contraindication to HIIT participation including a failed exercise stress test
• Participation in an experimental medication trial within 3 months of starting the study
• Undergoing therapy for malignant disease other than basal-cell or squamous-cell skin cancer
• Medical or psychiatric reason for not being a surgical candidate
• Requiring a walking assist device;
• Currently smoking

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Bariatric Surgery/HIIT; Patients who have undergone bariatric surgery will be randomized to this arm and will follow a high intensity interval training (HIIT) protocol for 24 months. Patients will complete 2 supervised HIIT sessions and 1 unsupervised HIIT session a week.	Other: High Intensity Interval Training (HIIT); Patients will complete a HIIT training protocol of a total of 10 x 1 min intervals at 90% heart rate (HR) max. They will continue this training protocol, 3 sessions a week (2 supervised and 1 unsupervised), for 24 months.; Procedure: Bariatric surgery; Patients will undergo bariatric surgery as part of their routine care
Active Comparator: Bariatric Surgery/Routine Exercise; Patients who have undergone bariatric surgery will be randomized to this arm and will follow a standard routine exercise regimen for 24 months.	Procedure: Bariatric surgery; Patients will undergo bariatric surgery as part of their routine care; Other: Routine Exercise; Patients will receive counseling regarding exercise as a routine part of their participation in the bariatric surgery clinic. Specifically, they are counseled to participate in 60 min of aerobic exercise daily in addition to 2-3 non-consecutive days of strength training workouts every wk. Patients are encouraged to contact the bariatric conditioning program, obtain a gym membership, purchase exercise equipment, join a walking group, and/or sign up for fitness classes (employer or city parks and recreation).
Active Comparator: No Bariatric Surgery/HIIT; Patients who have not undergone bariatric surgery will be randomized to this arm and will follow a high intensity interval training (HIIT) protocol for 24 months. Patients will complete 2 supervised HIIT sessions and 1 unsupervised HIIT session a week.	Other: High Intensity Interval Training (HIIT); Patients will complete a HIIT training protocol of a total of 10 x 1 min intervals at 90% heart rate (HR) max. They will continue this training protocol, 3 sessions a week (2 supervised and 1 unsupervised), for 24 months.
Active Comparator: No Bariatric Surgery/Routine Exercise; Patients who have not undergone bariatric surgery will be randomized to this arm and will follow a standard routine exercise regimen for 24 months.	Other: Routine Exercise; Patients will receive counseling regarding exercise as a routine part of their participation in the bariatric surgery clinic. Specifically, they are counseled to participate in 60 min of aerobic exercise daily in addition to 2-3 non-consecutive days of strength training workouts every wk. Patients are encouraged to contact the bariatric conditioning program, obtain a gym membership, purchase exercise equipment, join a walking group, and/or sign up for fitness classes (employer or city parks and recreation).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intraepidermal Nerve Fiber Density (IENFD) at the Proximal Thigh	Intraepidermal Nerve Fiber Density (IENFD) as assessed by 3mm skin biopsies at the proximal thigh.	Baseline, 3 months, 12 months and 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intraepidermal Nerve Fiber Density (IENFD) at Distal Leg.	Intraepidermal Nerve Fiber Density (IENFD) as assessed by 3mm skin biopsies at the distal leg.	Baseline, 3 months, 12 months and 24 months
Corneal Confocal Microscopy (CCM) - Fiber Density	Non-invasive imaging technique of the corneal nerves to quantify nerve density and morphology. Corneal Nerve Fiber Density are quantified by fibers/mm2, a higher number represents a higher density of fibers. Lower numbers indicate worse neuropathy.	Baseline, 3 month, 12 months and 24 months
Corneal Confocal Microscopy (CCM) - Branch Density	Non-invasive imaging technique of the corneal nerves to quantify nerve density and morphology. Corneal Nerve Branch Density are quantified by branches/mm2, a higher number represents a higher density of branches. Lower numbers indicate worse neuropathy.	Baseline, 3 month, 12 months and 24 months
Corneal Confocal Microscopy (CCM) - Fiber Length	Non-invasive imaging technique of the corneal nerves to quantify nerve density and morphology. Corneal Nerve Fiber Length are quantified by mm/mm2, a higher number represents a higher total length of fibers. Lower numbers indicate worse neuropathy .	Baseline, 3 month, 12 months and 24 months
Corneal Confocal Microscopy (CCM) - Tortuosity Coefficient	Non-invasive imaging technique of the corneal nerves to quantify nerve density and morphology. Tortuosity Coefficient represents the total tortuosity (twisting/bending of nerves). As a coefficient the value is unitless, a higher value represents greater tortuosity. Lower numbers indicate worse neuropathy.	Baseline, 3 month, 12 months and 24 months
24-2 Frequency Doubling Technology (FDT) - Mean Deviation	24-2 FDT was used to evaluate retinopathy using visual field deficits. Mean Deviation is presented below. Mean deviation is the average difference from normal expected value in the patients' particular age group. Lower values indicate more visual deficit. Higher values indicate fewer visual deficit.	Baseline, 3 month, 12 months and 24 months
24-2 Frequency Doubling Technology (FDT) - Foveal Sensitivity dB	24-2 FDT was used to evaluate retinopathy using visual field deficits. Foveal sensitivity is presented below. Foveal sensitivity is the measurement of the fovea's light detection ability. Lower values suggest visual field deficits.	Baseline, 3 month, 12 months and 24 months
24-2 Frequency Doubling Technology (FDT) - Pattern SD	24-2 FDT was used to evaluate retinopathy using visual field deficits. Pattern SD (PSD) is presented below. PSD provides information about localized loss. A higher PSD indicates a non-uniform sensitivity loss and visual field deficit.	Baseline, 3 month, 12 months and 24 months
Retinal Fundus Photography	As assessed by fundus photographs, participants were identified as either having retinopathy or not having retinopathy. Data is shown as number of people with retinopathy at a particular study visit.	Baseline, 3 month, 12 months and 24 months
Nerve Conduction Study (NCS) - Latency	Latency measures the time in millisecond between stimulation and the recording electrode. Was performed on sural, peroneal, and tibial nerves. No response and abnormal values indicate neuropathy.; Peroneal: 0 - No response, >6.5 - Abnormal; Sural: 0 - No response, >4.5 - Abnormal; Tibial: 0 - No response, >6.1 - Abnormal	Baseline and 24 months
Nerve Conduction Study (NCS) - Motor Amplitude	Amplitude measures the height of electrical signal (waveform) in millivolts produced by the stimulated motor nerve. Was performed on peroneal, and tibial nerves. No response and abnormal values indicate neuropathy.; Peroneal: 0 - No response, < 1.1 - Abnormal; Tibial: 0 - No response, <1.1 - Abnormal	Baseline and 24 months
Nerve Conduction Study (NCS) - Sensory Amplitude	Amplitude measures the height of electrical signal (waveform) in microvolts produced by the stimulated sensory nerve. Was performed on sural nerve. No response and abnormal values indicate neuropathy. * Sural: 0 - No response, <4 - Abnormal	Baseline and 24 months
Nerve Conduction Study (NCS) - CV	Conduction velocity (V) measures the speed (m/s) at which the electrical impulse travels along the nerve. Was performed on peroneal nerves. No response and abnormal values indicate neuropathy. Abnormal values are <36 or 39, depending on whether certain criteria applied to the participant. Data was not analyzed separately.	Baseline and 24 months
Nerve Conduction Study (NCS) - F Wave Index	F wave index measures the time in millisecond between stimulation at a distal (near the muscle) point and for the stimulus to travel to the spinal cord and back, allowing to assess the entire length of the nerve. Was performed on peroneal, and tibial nerves. No response and abnormal values indicate neuropathy.; Peroneal: 0 - No response, >55 - Abnormal; Tibial: 0 - No response, >55 - Abnormal	Baseline and 24 months
Cardiac Autonomic Neuropathy Testing-Deep Breathing/Exhalation to Inhalation (E:I) Ratio	Deep breathing/exhalation to inhalation (E:I) ratio were evaluated using PS monitor software. Values < 1 are abnormal, indicative of cardiovascular autonomic neuropathy	Baseline and 24 months
Cardiac Autonomic Neuropathy Testing (30:15 Ratio)	Postural change-30:15 ratio was evaluated using PS monitor software. Values < 1 are abnormal, indicative of cardiovascular autonomic neuropathy	Baseline and 24 months
Cardiac Autonomic Neuropathy Testing (Valsalva Ratio)	Valsalva ratio was evaluated using PS monitor software. Values <= 1.10 are abnormal, indicative of cardiovascular autonomic neuropathy	Baseline and 24 months
Participants With Probable Polyneuropathy as Defined by the Toronto Definition of Probable Neuropathy	Toronto definition of probable neuropathy is having at least 2 out of 3 of the following: abnormal sensory examination, reflexes, and patient-reported symptoms. Data is reported as number of participants who, under the Toronto definition, were identified as having probable polyneuropathy.	24 months
Michigan Neuropathy Screening Instrument (MNSI)	MNSI questionnaire is scored from 0-15, score > 4 indicate neuropathy, higher scores indicate worse neuropathy. A score of 1 point is given for answers of "yes" for questions 1-6, 8-12, 14, and 15 and "no" for questions 7 and 13.	Baseline, 3 month, 12 months and 24 months
Michigan Neuropathy Screening Instrument (MNSI) - Exam	MNSI exam is scored from 0-8, score >= 2.5 indicate neuropathy. Higher scores indicate worse neuropathy.	Baseline, 3 month, 12 months and 24 months
Michigan Neuropathy Screening Instrument (MNSI) - Index	The Michigan Neuropathy Screening Instrument (MNSI) index is a weighted composite score computed using the sum of the b-coefficients for all items within the MNSI questionnaire (15 questions) and MNSI exam (4 physical/visual exam). Range: -0.93, 7.39 Values > 2.5407 are indicative of clinical neuropathy	Baseline, 3 month, 12 months and 24 months
Utah Early Neuropathy Score (UENS)	UENS is a composite score with five sections measuring multiple clinical measures of nerve injury. Sections are scored separately for each side (Right vs Left), and the total score is the sum across everything. Range: 0-42, higher score represents more severe polyneuropathy.	Baseline, 3 month, 12 months and 24 months
Modified Toronto Neuropathy Score (mTNS)	mTNS is a scale of 0-33 that measures neuropathy symptoms and exam findings. Higher scores indicate more severe polyneuropathy.	Baseline, 3 month, 12 months and 24 months
Survey of Autonomic Symptoms (SAS)	SAS evaluates the presence and magnitude of autonomic symptoms. Total impact score ranges from 0-60 (or up to 55 for participants to whom certain criteria did not apply). Higher score indicates worse autonomic neuropathy	Baseline, 3 month, 12 months and 24 months
Diabetic Neuropathy Score (DNS)	DNS is a questionnaire of neuropathy symptoms. Score ranges 0-4, >/=1 indicates polyneuropathy. 0 indicates no polyneuropathy.	Baseline, 3 month, 12 months and 24 months
Short Form McGill Pain Questionnaire	Sum of the sensory score (0-30) and affective score (0-15) for a total score of 0-45. A higher score represents greater pain present.	Baseline, 3 months, 12 months, 24 months
Numerical Rating Scale for Pain	Participant reported pain scale with range 0-10, higher score indicates more pain.	Baseline, 3 months, 12 months, 24 months
Neuropathy Quality of Life (NeuroQOL)	Neuropathy Quality of Life (NeuroQOL) evaluates symptoms and function in regard to quality of life over the past four weeks. Range 1-15, higher score indicates neuropathy having a greater impact on quality of life.	Baseline, 3 months, 12 months, and 24 months
8 Foot Get Up and Go Test	This test measures in seconds how long it takes the participant to stand up from a seated position, walk around a cone places 8 feet away, and return to the chair and sit down. Less time indicates better speed, agility, and balance when moving.	Baseline, 3 months, 12 months, and 24 months
Berg Balance Scale	Berg Balance Scale measures participants' ability to balance and avoid falls. Scores range from 0-56, higher score indicates less likely to fall.	Baseline, 3 months, 12 months, and 24 months
Modified Falls Efficacy Scale - Fall Evaluation	Patient response indicating if they have fallen in the last year. Data is shown as number of people who have fallen in the last year.	Baseline, 3 months, 12 months, and 24 months
Neurothesiometer	Neurothesiometer is placed on the bottom of the great toe, and slowly increased until participant reports they can feel the vibration. The greater the microns, the less feeling the participant has, suggestive of worse sensory function. Value > 25 Microns is indicative of neuropathy. There is no known maximum range. Lower values indicate better sensory function.	Baseline, 3 months, 12 months, and 24 months
NIH Toolbox Cognitive Battery	NIH Toolbox Cognition Fluid (Range: 0-100) - Composite score derived as an average across five cognitive domains. It's a fully adjusted T-score comparing the participant to a nationally representative sample, stratified by age and other demographics. Individual domain scores are fully adjusted T score with range 0-100 and measures the following-; Inhibitory Control and Attention - executive function, attention .; Dimensional Change Card Sort - executive function; Picture Sequence Memory - episodic memory; List Sorting Working Memory - working memory; Pattern Comparison - processing speed A T-score of 50 represents the population mean. A score of 60 indicates that the participant is 1 SD above the national average for individuals with similar demographic characteristics Higher scores reflect better cognitive functionality. No set clinical threshold, scores above mean indicate above average cognition for a given age group.	Baseline and at 24 months
Rey Auditory Verbal Learning Test	Used to evaluate verbal learning and memory using a list of 15 unrelated words presented to the participant over repeat trial. Includes 3 independent scales: Auditory Learning (Total recall) - Measures memory and learning ability. Raw score range (0- 75); Delayed Recall - Measures long term memory retention. Raw score range (0-15); Recognition - Measures ability to recognize previously learned information. Raw score range (0-15).; Raw scores were converted to age-standardized Z-scores using 10-year age bands (e.g., 20-29, 30-39, 40-49, etc.), with a mean of 0 and standard deviation of 1.; A Z-score of 0 represents the population mean; For each scale, scores above 0 are better. Standard deviations above the mean indicates a better learning and memory ability for a given age group. No set clinical threshold, scores above mean indicate above average cognition for a given age group.	Baseline and at 24 months

Collaborators and Investigators

• Sponsor: University of Michigan
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Brian C Callaghan, MD, MS, University of Michigan, Department of Neurology

Publications and helpful links

General Publications

• Reynolds EL, Koenig F, Watanabe M, Kwiatek A, Elafros MA, Stino A, Henderson D, Herrmann DN, Feldman EL, Callaghan BC. Comparison of intraepidermal nerve fiber density and confocal corneal microscopy for neuropathy. Ann Clin Transl Neurol. 2024 Dec;11(12):3115-3124. doi: 10.1002/acn3.52218. Epub 2024 Oct 12.

Study record dates

Study Major Dates

• Study Start (Actual): July 27, 2018
• Primary Completion (Actual): August 1, 2024
• Study Completion (Actual): August 1, 2024

Study Registration Dates

• First Submitted: July 14, 2018
• First Submitted That Met QC Criteria: August 2, 2018
• First Posted (Actual): August 6, 2018

Study Record Updates

• Last Update Posted (Actual): February 24, 2026
• Last Update Submitted That Met QC Criteria: February 12, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Exercise; Metabolic syndrome
• Additional Relevant MeSH Terms: Nervous System Diseases; Nutrition Disorders; Neuromuscular Diseases; Metabolic Diseases; Overnutrition; Body Weight; Peripheral Nervous System Diseases; Glucose Metabolism Disorders; Insulin Resistance; Hyperinsulinism; Overweight; Pathological Conditions, Signs and Symptoms; Behavior; Nutritional and Metabolic Diseases; Signs and Symptoms; Obesity; Metabolic Syndrome; Polyneuropathies; Motor Activity; Motor Activity; Movement; Musculoskeletal Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena; Therapeutics; Surgical Procedures, Operative; Physical Conditioning, Human; Exercise; Bariatrics; Obesity Management; High-Intensity Interval Training; Bariatric Surgery
• Other Study ID Numbers: HUM00143541; 1R01DK115687-01A1 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No