Exercise-facilitated Neurorehabilitation in Diabetic Neuropathy

This study will determine the type and combination of exercise needed to rehabilitate the neuro-compromised diabetic Veteran. Guided exercise protocols may prove to be practical therapeutic options for the prophylactic management of diabetic subjects with neuropathy.

Purpose: A single-site, randomized, blinded, prospective clinical trial is proposed to determine the significance of a combined isokinetic strength and aerobic exercise training program on the rehabilitation of peripheral nerve function in Type 2 diabetic veterans and non-veterans with neuropathy. Background and Significance: Obesity is a major factor in the increasing rates of diabetes and its related complications. Diabetes affects greater than 7% of the population. Veterans are at even greater risk, with approximately 16% currently receiving treatment at Department of Veterans Affairs Medical Centers for diabetes. More than half of affected veterans experience debilitating complications of diabetes, including peripheral neuropathy (PN). Exercise training, in combination with pharmacologic intervention, is now recognized as a cornerstone of management for diabetes. Therapeutic interventions currently available for the treatment of PN in diabetic patients are limited, however, to pain management and stringent glycemic control. Exercise is reported to significantly decrease peripheral nerve microvascular complications common among chronic diabetics. Our preliminary findings demonstrate that exercise intervention improves peripheral nerve function in the diabetic veteran with PN. Intervention strategies, such as proposed in this application, offer a unique and novel therapeutic option for the rehabilitation of the neuro-compromised Type 2 diabetic veterans and non-veterans. Methods & Research Plan: One-hundred subjects will be recruited for this 24-week study. Subjects each will be randomly assigned to aerobic, isokinetic strength training, combined aerobic and strength training, or non-exercise (control) intervention groups. Isokinetic strength training (Biodex System 3), aerobic exercise training (treadmill), or the combination of strength and aerobic training will be administered 3x per week for the initial 12 weeks. Control subjects will receive 12 clinical visits over the course of the initial 12 weeks. The effects of exercise training type, compared with control subjects, on recovery of peripheral nerve function will be rigorously determined from baseline, 12- and 24-week testing using electrodiagnostic primary outcome measures, Quantitative Sensory Testing, and a battery of validated qualitative and quantitative secondary outcome measures that include an incremental symptom-limited treadmill test, peak torque, Total Neuropathy Score, visual analogue pain scale, and quality of life SF-36V Health Survey. Sustainability of effect will be determined at 24-weeks.The individual effects of exercise training type, compared with control subjects, on tissue oxygenation will be determined from baseline, 12- and 24-week testing by non-invasive quantitated infrared spectroscopy using an InSpectraTM Tissue Spectrometer. Expected Outcomes: This study will objectively and critically determine the type and combination of exercise needed to rehabilitate the neuro-compromised diabetic Veteran. Guided exercise protocols may prove to be practical therapeutic options for the prophylactic management of diabetic subjects with neuropathy.

diabetes mellitus, diabetic neuropathies, Aerobic Exercise, Exercise Therapy, electromyography, United States Veterans

Maximal responses were obtained using percutaneous electrical stimuli. Sensory nerve action potentials were recorded from sural (antidromic), median (antidromic to second digit), and ulnar nerves (antidromic to fifth digit).To minimize inter-examiner variability and maximize neurophysiologic test/retest reliability, the same experienced neurologist conducted all nerve conduction studies on days separate from all other testing activities. A dedicated TECA Synergy electromyograph system was used for all nerve conduction studies. The patients dominant side was chosen. In patients with definable differences between the two sides, the side with the most prominent clinical findings was chosen. In all cases, the same limb was used for all three (baseline, 12-weeks, 24-weeks) conduction studies.

Maximal responses were obtained using percutaneous electrical stimuli. Sensory nerve action potentials were recorded from sural (antidromic), median (antidromic to second digit), and ulnar nerves (antidromic to fifth digit).To minimize inter-examiner variability and maximize neurophysiologic test/retest reliability, the same experienced neurologist conducted all nerve conduction studies on days separate from all other testing activities. A dedicated TECA Synergy electromyograph system was used for all nerve conduction studies. The patients dominant side was chosen. In patients with definable differences between the two sides, the side with the most prominent clinical findings was chosen. In all cases, the same limb was used for all three (baseline, 12-weeks, 24-weeks) conduction studies.

Maximal responses were obtained using percutaneous electrical stimuli. Sensory nerve action potentials were recorded from sural (antidromic), median (antidromic to second digit), and ulnar nerves (antidromic to fifth digit).To minimize inter-examiner variability and maximize neurophysiologic test/retest reliability, the same experienced neurologist conducted all nerve conduction studies on days separate from all other testing activities. A dedicated TECA Synergy electromyograph system was used for all nerve conduction studies. The patients dominant side was chosen. In patients with definable differences between the two sides, the side with the most prominent clinical findings was chosen. In all cases, the same limb was used for all three (baseline, 12-weeks, 24-weeks) conduction studies.

Maximal responses were obtained using percutaneous electrical stimuli. Distal motor nerve evoked compound muscle action potential (CMAP) potentials were recorded from tibial and peroneal nerves.To minimize inter-examiner variability and maximize neurophysiologic test/retest reliability, the same experienced neurologist conducted all nerve conduction studies on days separate from all other testing activities. A dedicated TECA Synergy electromyograph system was used for all nerve conduction studies. The patients dominant side was chosen. In patients with definable differences between the two sides, the side with the most prominent clinical findings was chosen. In all cases, the same limb was used for all three (baseline, 12-weeks, 24-weeks) conduction studies.

Maximal responses were obtained using percutaneous electrical stimuli. Distal motor nerve evoked compound muscle action potential (CMAP) potentials were recorded from tibial and peroneal nerves.To minimize inter-examiner variability and maximize neurophysiologic test/retest reliability, the same experienced neurologist conducted all nerve conduction studies on days separate from all other testing activities. A dedicated TECA Synergy electromyograph system was used for all nerve conduction studies. The patients dominant side was chosen. In patients with definable differences between the two sides, the side with the most prominent clinical findings was chosen. In all cases, the same limb was used for all three (baseline, 12-weeks, 24-weeks) conduction studies.

Maximal responses were obtained using percutaneous electrical stimuli. Distal motor nerve evoked compound muscle action potential (CMAP) potentials were recorded from tibial and peroneal nerves.To minimize inter-examiner variability and maximize neurophysiologic test/retest reliability, the same experienced neurologist conducted all nerve conduction studies on days separate from all other testing activities. A dedicated TECA Synergy electromyograph system was used for all nerve conduction studies. The patients dominant side was chosen. In patients with definable differences between the two sides, the side with the most prominent clinical findings was chosen. In all cases, the same limb was used for all three (baseline, 12-weeks, 24-weeks) conduction studies.

Maximal responses were obtained using percutaneous electrical stimuli. Sensory nerve action potentials were recorded from sural (antidromic), median (antidromic to second digit), and ulnar nerves (antidromic to fifth digit).To minimize inter-examiner variability and maximize neurophysiologic test/retest reliability, the same experienced neurologist conducted all nerve conduction studies on days separate from all other testing activities. A dedicated TECA Synergy electromyograph system was used for all nerve conduction studies. The patients dominant side was chosen. In patients with definable differences between the two sides, the side with the most prominent clinical findings was chosen. In all cases, the same limb was used for all three (baseline, 12-weeks, 24-weeks) conduction studies.

Maximal responses were obtained using percutaneous electrical stimuli. Sensory nerve action potentials were recorded from sural (antidromic), median (antidromic to second digit), and ulnar nerves (antidromic to fifth digit).To minimize inter-examiner variability and maximize neurophysiologic test/retest reliability, the same experienced neurologist conducted all nerve conduction studies on days separate from all other testing activities. A dedicated TECA Synergy electromyograph system was used for all nerve conduction studies. The patients dominant side was chosen. In patients with definable differences between the two sides, the side with the most prominent clinical findings was chosen. In all cases, the same limb was used for all three (baseline, 12-weeks, 24-weeks) conduction studies.

Maximal responses were obtained using percutaneous electrical stimuli. Sensory nerve action potentials were recorded from sural (antidromic), median (antidromic to second digit), and ulnar nerves (antidromic to fifth digit).To minimize inter-examiner variability and maximize neurophysiologic test/retest reliability, the same experienced neurologist conducted all nerve conduction studies on days separate from all other testing activities. A dedicated TECA Synergy electromyograph system was used for all nerve conduction studies. The patients dominant side was chosen. In patients with definable differences between the two sides, the side with the most prominent clinical findings was chosen. In all cases, the same limb was used for all three (baseline, 12-weeks, 24-weeks) conduction studies.

Maximal responses were obtained using percutaneous electrical stimuli. Sensory nerve action potentials were recorded from sural (antidromic), median (antidromic to second digit), and ulnar nerves (antidromic to fifth digit).To minimize inter-examiner variability and maximize neurophysiologic test/retest reliability, the same experienced neurologist conducted all nerve conduction studies on days separate from all other testing activities. A dedicated TECA Synergy electromyograph system was used for all nerve conduction studies. The patients dominant side was chosen. In patients with definable differences between the two sides, the side with the most prominent clinical findings was chosen. In all cases, the same limb was used for all three (baseline, 12-weeks, 24-weeks) conduction studies.

Maximal responses were obtained using percutaneous electrical stimuli. Sensory nerve action potentials were recorded from sural (antidromic), median (antidromic to second digit), and ulnar nerves (antidromic to fifth digit).To minimize inter-examiner variability and maximize neurophysiologic test/retest reliability, the same experienced neurologist conducted all nerve conduction studies on days separate from all other testing activities. A dedicated TECA Synergy electromyograph system was used for all nerve conduction studies. The patients dominant side was chosen. In patients with definable differences between the two sides, the side with the most prominent clinical findings was chosen. In all cases, the same limb was used for all three (baseline, 12-weeks, 24-weeks) conduction studies.

Maximal responses were obtained using percutaneous electrical stimuli. Sensory nerve action potentials were recorded from sural (antidromic), median (antidromic to second digit), and ulnar nerves (antidromic to fifth digit).To minimize inter-examiner variability and maximize neurophysiologic test/retest reliability, the same experienced neurologist conducted all nerve conduction studies on days separate from all other testing activities. A dedicated TECA Synergy electromyograph system was used for all nerve conduction studies. The patients dominant side was chosen. In patients with definable differences between the two sides, the side with the most prominent clinical findings was chosen. In all cases, the same limb was used for all three (baseline, 12-weeks, 24-weeks) conduction studies.

Maximal responses were obtained using percutaneous electrical stimuli. Distal motor nerve evoked compound muscle action potential (CMAP) potentials were recorded from tibial and peroneal nerves.To minimize inter-examiner variability and maximize neurophysiologic test/retest reliability, the same experienced neurologist conducted all nerve conduction studies on days separate from all other testing activities. A dedicated TECA Synergy electromyograph system was used for all nerve conduction studies. The patients dominant side was chosen. In patients with definable differences between the two sides, the side with the most prominent clinical findings was chosen. In all cases, the same limb was used for all three (baseline, 12-weeks, 24-weeks) conduction studies.

Maximal responses were obtained using percutaneous electrical stimuli. Distal motor nerve evoked compound muscle action potential (CMAP) potentials were recorded from tibial and peroneal nerves.To minimize inter-examiner variability and maximize neurophysiologic test/retest reliability, the same experienced neurologist conducted all nerve conduction studies on days separate from all other testing activities. A dedicated TECA Synergy electromyograph system was used for all nerve conduction studies. The patients dominant side was chosen. In patients with definable differences between the two sides, the side with the most prominent clinical findings was chosen. In all cases, the same limb was used for all three (baseline, 12-weeks, 24-weeks) conduction studies.

Maximal responses were obtained using percutaneous electrical stimuli. Distal motor nerve evoked compound muscle action potential (CMAP) potentials were recorded from tibial and peroneal nerves.To minimize inter-examiner variability and maximize neurophysiologic test/retest reliability, the same experienced neurologist conducted all nerve conduction studies on days separate from all other testing activities. A dedicated TECA Synergy electromyograph system was used for all nerve conduction studies. The patients dominant side was chosen. In patients with definable differences between the two sides, the side with the most prominent clinical findings was chosen. In all cases, the same limb was used for all three (baseline, 12-weeks, 24-weeks) conduction studies.

The short form-36Veterans (SF-36V) health survey questionnaire was used to measure health-related quality of life. This survey is comprised of eight subscales and two overall component scores, all of which have demonstrated high levels of internal consistency and discriminate validity when administered to groups of medically stable individuals. Patient aggregate responses for the eight distinct summary subscales and two component scores were compiled as a percentage of total points possible using the RAND 36-item health survey table. Data shown are expressed as a percentage of total possible score ranging from 0%-100% with 100% considered relatively good health and 0% considered poor health. Physical Component scores reflect perceived changes in physical health relative to the previous year.

Total time subjects voluntarily exercised while undergoing a modified Bruce Protocol treadmill test (TMT)

Peak volume of air exchanged per minute achieved while undergoing a modified Bruce Protocol treadmill test (TMT)

Peak RER achieved while undergoing a modified Bruce Protocol treadmill test (TMT). This is a mathematical ratio of maximally achieved (peak) VCO2 divided by maximally achieved (peak) VO2.

Peak Carbon Dioxide expelled achieved while undergoing a modified Bruce Protocol treadmill test (TMT)

Peak metabolic rate equivalents (METS) achieved while undergoing a modified Bruce Protocol treadmill test (TMT). One MET is defined as the metabolic rate observed at rest, quantified as resting oxygen consumption of 250 ml/min (Male) or 200 ml /min (female). A value of 5 METS would represent a metabolic rate that is 5x that at rest and is considered an indicator of how hard a given individual is exercising. Data shown are expressed as a ratio at peak of exercise of oxygen consumed relative to normalized values for men or women at rest.

The short form-36Veterans (SF-36V) health survey questionnaire was used to measure health-related quality of life. This survey is comprised of eight subscales and two overall component scores, all of which have demonstrated high levels of internal consistency and discriminate validity when administered to groups of medically stable individuals. Patient aggregate responses for the eight distinct summary subscales and two component scores were compiled as a percentage of total points possible using the RAND 36-item health survey table. Data shown are expressed as a percentage of total possible score ranging from 0%-100% with 100% considered relatively good health and 0% considered poor health. Mental Component scores reflect perceived changes in emotional health relative to the previous year.

Laboratory total cholesterol, HDL-cholesterol, and LDL-cholesterol levels at baseline entry into study

Inclusion Criteria: Clinical diagnosis of type 2 diabetes mellitus stable blood glucose control clinical findings consistent with length-dependent sensorimotor polyneuropathy, stage N2a Exclusion Criteria: foot ulceration unstable heart disease co-morbid conditions limiting exercise disorders of the central nervous system causing weakness or sensory loss received treatment with medications known to have neuropathy as a prominent side effect including vincristine, vinblastine, cis-platin, and paclitaxel medical conditions that may be associated with neuropathies such as alcoholism, liver disease, kidney disease, toxic exposure, vitamin deficiency, autoimmune disorders, cancer, or hypothyroidism

Stubbs EB Jr, Fisher MA, Miller CM, Jelinek C, Butler J, McBurney C, Collins EG. Randomized Controlled Trial of Physical Exercise in Diabetic Veterans With Length-Dependent Distal Symmetric Polyneuropathy. Front Neurosci. 2019 Feb 11;13:51. doi: 10.3389/fnins.2019.00051. eCollection 2019.