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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Concurrent Training Group (CT) | Active Comparator | Participants will undergo a combined aerobic and resistance exercise program. |
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| Soleus Push-Up Group (SPU) | Experimental | Participants will perform seated plantar-flexion exercises targeting the soleus muscle, using a controlled movement protocol modeled after the soleus push-up method. |
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| Control Group | No Intervention | Participants will receive standard diabetes care and general lifestyle advice without structured exercise intervention. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Concurrent Training | Other | Combined aerobic and resistance exercise program. |
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| Measure | Description | Time Frame |
|---|---|---|
| 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. | From enrollment to 4 weeks and then to the end of treatment at 8 weeks. |
| 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. | From enrollement to 4 weeks and then after 8 weeks of intervention |
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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Inclusion Criteria:
Diagnosis is based on clinical evaluation and scoring tools such as:
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)
Vibration Pressure Threshold (≥25 Volts)(106)
Exclusion Criteria:
History of recent cardiovascular events Includes myocardial infarction, stroke, or any cardiac intervention within the past 6 months.
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Waqar Ahmed Awan, Ph.D | Contact | +923335348846 | waqar.ahmed@riphah.edu.pk | |
| Muhammad Ashar Rafi, MS-NMPT | Contact | +923083407837 | ashar.special51@gmail.com |
| Name | Affiliation | Role |
|---|---|---|
| Muhammad Ashar Rafi, MS-NMPT | Riphah International University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Pakistan Railways General Hospital and Mediplex Healthcare Center | Rawalpindi | 46210 | Pakistan |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32550216 | Background | Jamali A, Shahrbanian S, Morteza Tayebi S. The Effects of Exercise Training on the Brain-Derived Neurotrophic Factor (BDNF) in the Patients with Type 2 Diabetes: A Systematic Review of the Randomized Controlled Trials. J Diabetes Metab Disord. 2020 May 6;19(1):633-643. doi: 10.1007/s40200-020-00529-w. eCollection 2020 Jun. |
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Individual participant data collected during the trial will not be made publicly available. Study findings will be disseminated through peer-reviewed publications and conference presentations. All data will remain securely stored by the research team in accordance with institutional policies and ethical guidelines.
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP_ICF | Yes | Yes | Yes | Study Protocol, Statistical Analysis Plan, and Informed Consent Form | Jan 1, 2026 | Mar 15, 2026 | Prot_SAP_ICF_000.pdf |
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| ID | Term |
|---|---|
| D003929 | Diabetic Neuropathies |
| D003924 | Diabetes Mellitus, Type 2 |
| D009477 | Hereditary Sensory and Autonomic Neuropathies |
| ID | Term |
|---|---|
| D010523 | Peripheral Nervous System Diseases |
| D009468 | Neuromuscular Diseases |
| D009422 | Nervous System Diseases |
| D048909 | Diabetes Complications |
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| ID | Term |
|---|---|
| D015444 | Exercise |
| ID | Term |
|---|---|
| D009043 | Motor Activity |
| D009068 | Movement |
| D009142 | Musculoskeletal Physiological Phenomena |
| D055687 | Musculoskeletal and Neural Physiological Phenomena |
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| Soleus Push-ups | Other | Seated plantar-flexion exercises targeting the soleus muscle, using a controlled movement protocol |
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| From enrollment to 4 weeks and then after 8 weeks of intervention |
| From enrollment to 4 weeks and then to the end of treatment at 8 weeks. |
| 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. | From enrollment to 4 weeks and then to the end of treatment at 8 weeks. |
| 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. | From enrollment to 4 weeks and then to the end of treatment at 8 weeks. |
| 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. | From enrollment to 4 weeks and then to the end of treatment at 8 weeks. |
| Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) | Health-related quality of life will be assessed using the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire, a validated patient-reported outcome measure specifically designed to evaluate the impact of diabetic peripheral neuropathy on physical functioning and quality of life. The questionnaire assesses symptoms and functional limitations across multiple domains, including physical functioning/large-fiber neuropathy, activities of daily living, symptoms, small-fiber neuropathy, and autonomic neuropathy. Assessments will be conducted at baseline, 4 weeks, and 8 weeks. The Norfolk QOL-DN total score ranges from -4 to 136, with higher scores indicating poorer health-related quality of life and greater neuropathy-related impairment, whereas lower scores indicate better quality of life and reduced symptom burden. A decrease in the total score following the intervention will be interprete | From enrollment to 4 weeks and then to the end of treatment at 8 weeks. |
| Acceptability of Intervention Measure (AIM) | Acceptability of the exercise intervention will be assessed using the Acceptability of Intervention Measure (AIM), a validated implementation outcome instrument. The AIM consists of 4 items rated on a 5-point Likert scale ranging from 1 (Completely Disagree) to 5 (Completely Agree), yielding a total score of 4-20. Higher scores indicate greater participant-perceived acceptability of the intervention. The AIM will be administered at the completion of the 8-week intervention. | At the end of treatment at 8 weeks. |
| Intervention Appropriateness Measure (IAM) | Perceived appropriateness of the exercise intervention will be assessed using the Intervention Appropriateness Measure (IAM). The IAM consists of 4 items rated on a 5-point Likert scale ranging from 1 (Completely Disagree) to 5 (Completely Agree), resulting in a total score of 4-20. Higher scores indicate that participants perceive the intervention to be more appropriate and suitable for managing diabetic peripheral neuropathy. The IAM will be administered at the completion of the 8-week intervention. | At the end of treatment after 8 weeks of intervention |
| Feasibility of Intervention Measure (FIM) | Feasibility of the exercise intervention will be evaluated using the Feasibility of Intervention Measure (FIM). The FIM consists of 4 items rated on a 5-point Likert scale ranging from 1 (Completely Disagree) to 5 (Completely Agree), yielding a total score of 4-20. Higher scores indicate greater perceived feasibility of implementing the intervention in clinical practice. The FIM will be administered at the completion of the 8-week intervention. | At the end of treatment after 8 weeks of intervention. |
| D003920 | Diabetes Mellitus |
| D004700 | Endocrine System Diseases |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D009421 | Nervous System Malformations |
| D020271 | Heredodegenerative Disorders, Nervous System |
| D019636 | Neurodegenerative Diseases |
| D011115 | Polyneuropathies |
| D000013 | Congenital Abnormalities |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D030342 | Genetic Diseases, Inborn |