This study will examine how two types of exercise programs affect nerve health in people with diabetic peripheral neuropathy. Diabetic peripheral neuropathy is a common complication of type 2 diabetes that can cause numbness, pain, balance problems, and reduced quality of life. Exercise is often recommended for people with diabetes, but it is not yet clear which types of exercise are most effective for improving nerve function.
In this randomized controlled trial, participants with type 2 diabetes and confirmed peripheral neuropathy will be assigned to one of three groups. One group will perform a combined program of aerobic and resistance exercises (concurrent training). Another group will perform soleus push-up exercises, a seated ankle movement designed to activate the soleus muscle and improve glucose metabolism. The third group will continue with standard diabetes care and general lifestyle advice without a structured exercise program.
The study will evaluate whether these exercise interventions influence biological markers related to nerve repair and neuroplasticity, including brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and the Schwann cell marker S100B. In addition, the study will assess changes in neuropathy symptoms, balance and postural stability, blood sugar control, and quality of life.
Participants will complete assessments before the intervention and again during follow-up after the exercise program. The findings of this study may help identify effective and feasible exercise strategies to support nerve health, improve physical function, and reduce the impact of diabetic peripheral neuropathy.
Age 40-65 years
Diagnosed Type 2 Diabetes Mellitus (T2DM) Confirmed diagnosis of T2DM for at least 5 years.
Confirmed Diabetic Peripheral Neuropathy (DPN)
Michigan Neuropathy Screening Instrument (MNSI) Cut-off value of ≥4 for Part A (History)(104) Cut-off value of ≥2 from Part B (Examination)(105)
History of recent cardiovascular events Includes myocardial infarction, stroke, or any cardiac intervention within the past 6 months.
Uncontrolled hypertension Blood pressure ≥160/100 mmHg at rest.
Severe musculoskeletal disorders or physical disability Including joint deformities, fractures, or amputation that limit the ability to perform exercise.
Severe diabetic foot ulcers or active lower limb infection Increases risk during lower limb activity or exercise.
Parallel
Concurrent Training
Other interventionCombined aerobic and resistance exercise program.
Soleus Push-ups
Other interventionSeated plantar-flexion exercises targeting the soleus muscle, using a controlled movement protocol
BDNF (Brain-Derived Neurotrophic Factor)
Serum Brain-Derived Neurotrophic Factor (BDNF) concentration will be measured quantitatively using a commercially available enzyme-linked immunosorbent assay (ELISA) kit at baseline, 4 weeks, and 8 weeks. BDNF is a neurotrophic factor involved in neuronal survival, synaptic plasticity, and exercise-induced neuroplasticity. Changes in circulating BDNF levels will be used as a primary biomarker of exercise-induced neuroplasticity and neurogenesis-related biological activity. Higher serum BDNF concentrations are considered indicative of greater neurotrophic activity and potential enhancement of neuroplastic processes.
NGF (Nerve Growth Factor)
Serum Nerve Growth Factor (NGF) concentration will be measured quantitatively using a commercially available enzyme-linked immunosorbent assay (ELISA) kit at baseline, 4 weeks, and 8 weeks. NGF is a key neurotrophic factor involved in the survival, maintenance, and regeneration of peripheral neurons. It plays a fundamental role in peripheral nerve repair and axonal regeneration following nerve injury. Changes in circulating NGF levels will be used as a primary biomarker of peripheral nerve regeneration and neuroregeneration-related biological activity. Higher serum NGF concentrations are considered indicative of enhanced neurotrophic support and regenerative potential of peripheral nerves.
S100B (Schwann Cell Marker)
Serum S100 Calcium-Binding Protein B (S100B) concentration will be measured quantitatively using a commercially available enzyme-linked immunosorbent assay (ELISA) kit at baseline, 4 weeks, and 8 weeks. S100B is a calcium-binding protein that is expressed by Schwann cells in the peripheral nervous system and plays an important role in peripheral nerve repair, remyelination, and axonal regeneration. Changes in circulating S100B levels will be used as a primary biomarker of Schwann cell activity and peripheral nerve regeneration. Higher serum S100B concentrations are considered indicative of increased Schwann cell-mediated neuroregenerative activity.
Michigan Neuropathy Screening Instrument (MNSI)
Neuropathy severity will be assessed using the Michigan Neuropathy Screening Instrument (MNSI), a validated instrument for screening and evaluating diabetic peripheral neuropathy. The MNSI consists of two components: (1) a 15-item patient-reported symptom questionnaire (History; Part A) and (2) a standardized physical examination (Part B) that assesses foot appearance, ulceration, ankle reflexes, and vibration sensation. Assessments will be performed at baseline, 4 weeks, and 8 weeks. The MNSI History score ranges from 0 to 13, with a score of ≥4 indicating the presence of diabetic peripheral neuropathy. The MNSI Examination score ranges from 0 to 8, with a score of ≥2 considered diagnostic of diabetic peripheral neuropathy. Higher scores on both components indicate greater neuropathy severity, whereas lower scores following the intervention indicate improvement in peripheral nerve function and neuropathic symptoms.
Vibration perception threshold (VPT)
Vibration perception threshold will be assessed using a digital biothesiometer to evaluate large-fiber peripheral nerve function in participants with diabetic peripheral neuropathy. The biothesiometer measures the minimum vibration intensity perceived by the participant and is recorded in volts (V). Assessments will be performed at baseline, 4 weeks, and 8 weeks. The VPT score ranges from 0 to 50 volts, with higher values indicating poorer vibration perception and more severe peripheral nerve dysfunction. A VPT value of ≥25 volts will be used as the diagnostic threshold for diabetic peripheral neuropathy. A reduction in VPT values following the intervention indicates improved sensory nerve function and reduced neuropathy severity.
Balance and Gait Mobile Application
Balance and gait performance will be assessed using the validated Balance and Gait mobile application. The application utilizes the smartphone's built-in inertial sensors (accelerometer and gyroscope) to objectively evaluate postural stability and gait performance. Assessments will be conducted at baseline, 4 weeks, and 8 weeks. The application provides quantitative measures of balance and gait, including postural sway, gait stability, walking speed, cadence, stride characteristics, and an overall balance/gait performance score, depending on the application outputs. Higher balance and gait scores (or improved gait parameters, such as increased gait speed and reduced postural sway) indicate better functional mobility and postural stability, whereas poorer scores indicate greater balance impairment and increased risk of falls.
Glycated Hemoglobin (HbA1c)
Glycated hemoglobin (HbA1c) will be measured using a standardized laboratory assay to assess long-term glycemic control. HbA1c reflects the average blood glucose concentration over the preceding 2-3 months and is reported as a percentage (%) of total hemoglobin. Assessments will be performed at baseline, 4 weeks, and 8 weeks. HbA1c values range from approximately 4% to 14% or higher, with lower values indicating better glycemic control. In accordance with the American Diabetes Association (ADA) criteria, an HbA1c level of \<5.7% is considered normal, 5.7%-6.4% indicates prediabetes, and ≥6.5% is diagnostic of diabetes mellitus. Participants eligible for this study will have baseline HbA1c values between 6.5% and 9.0%. A reduction in HbA1c following the intervention will indicate improved long-term glycemic control.
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