Diabetic Peripheral Neuropathy (DPN)
Conditions
Keywords
Diabetic Peripheral Neuropathy, Zuogui Jiangtang Shuluo Formula, DPN, Metabolomics, Lipidomics, Randomized Controlled Trial
Brief summary
Diabetic peripheral neuropathy (DPN) is a common complication of type 2 diabetes mellitus, affecting 35%-50% of diabetic patients. Its pathogenesis involves metabolic disorders induced by hyperglycemia and dyslipidemia, leading to irreversible damage to neurons and vascular endothelial cells. Distal symmetric polyneuropathy (DSPN) is the most representative form, characterized by distal pain, numbness, and sensory loss, which may progress to ulcers, gangrene, and even amputation in severe cases. Current modern medical treatments for DPN primarily focus on nutritional nerve support, antioxidative stress, and microcirculation improvement, but these approaches are limited in variety and may carry side effects. Traditional Chinese Medicine (TCM) offers advantages including higher safety and diverse therapeutic options. Based on long-term clinical observation, our research group proposes that the core pathogenesis of DPN is Qi-Yin deficiency with blood stasis obstructing collaterals. The treatment principle is to nourish Yin, supplement Qi, activate blood circulation, and unblock collaterals, with Zuogui Jiangtang Shuluo Formula (ZGJTSLF) as the primary prescription. Previous studies have shown that ZGJTSLF can improve TCSS scores and nerve conduction velocity in DPN patients compared with mecobalamin, but high-level evidence is still lacking. This randomized, parallel-controlled trial aims to evaluate the clinical efficacy of ZGJTSLF in treating DPN, with TCSS score and nerve conduction velocity as primary outcomes. Metabolomics and lipidomics will be employed to compare metabolic profiles between healthy controls and DPN patients before and after ZGJTSLF treatment, aiming to identify potential biomarkers and explore the underlying mechanisms.
Detailed description
This study is a single-center, randomized, parallel-controlled trial. A total of 74 patients with DPN (37 per group) will be recruited from the outpatient and inpatient departments of Endocrinology at The First Affiliated Hospital of Hunan University of Traditional Chinese Medicine between August 2026 and August 2027, along with 30 healthy volunteers as controls. This study is a single-center, randomized, parallel-controlled trial. It is prepared to recruit 74 patients with diabetic peripheral neuropathy (DPN) from the outpatient and inpatient departments of Endocrinology at The First Affiliated Hospital of Hunan University of Traditional Chinese Medicine between January 2026 and December 2026, along with 30 healthy volunteers as normal controls, based on clinical diagnostic criteria and screening criteria. Eligible DPN patients will be randomly assigned in a 1:1 ratio to either the Zuogui Jiangtang Shuluo Formula (ZGJTSLF) group or the mecobalamin control group using a random number generator in SPSS software with a fixed seed. This is an open-label trial for participants, care providers, and investigators; however, the outcomes assessor, specifically, the technician responsible for nerve conduction velocity measurements, will be blinded to group allocation. Patients in the ZGJTSLF group will receive Zuogui Jiangtang Shuluo Formula decoction, while those in the control group will receive mecobalamin tablets, both for 4 consecutive weeks. The primary outcomes include the Toronto Clinical Scoring System (TCSS) score and nerve conduction velocity (NCV), and secondary outcomes include TCM syndrome score, fasting plasma glucose, glycated hemoglobin, and lipid profile. Meanwhile, blood, urine, and fecal samples will be collected from all participants, including healthy volunteers, at baseline and after 4 weeks of treatment and frozen for further analysis. Plasma metabolomics and lipidomics profiling will be performed using UPLC-MS/MS technology to detect differential metabolites and lipids, analyze the differences among the groups, identify potential biomarkers, and explore the underlying mechanisms of ZGJTSLF in treating DPN. Correlation analysis between differential metabolites/lipids and clinical parameters will also be conducted. All statistical analyses will be performed using SPSS version 26.0, with a two-sided P \< 0.05 considered statistically significant. This study has been approved by the Ethics Committee of The First Affiliated Hospital of Hunan University of Traditional Chinese Medicine (Approval No. HN-LL-YJSLW-2026), and all participants will provide written informed consent.
Interventions
DRUGZuogui Jiangtang Shuluo Formula
Oral decoction, twice daily for 4 weeks.
DRUGMecobalamin
Tablet, 0.5 mg per dose, three times daily orally for 4 weeks.
Sponsors
The First Affiliated Hospital of Hunan University of Traditional Chinese Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
35 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
DSPN inclusion criteria: 1. Meet the diagnostic criteria for type 2 diabetes mellitus with distal symmetric polyneuropathy (DSPN) according to Western medicine standards. 2. Meet the TCM syndrome differentiation criteria for consumptive thirst complicated with arthromyodynia of the pattern of Qi-Yin deficiency with blood stasis. 3. Glycated hemoglobin (HbA1c) between 6.5% and 9.0% (inclusive). 4. Aged 35 to 75 years (inclusive) at the time of screening, regardless of gender. 5. Have not participated in any other clinical trial within 2 weeks prior to the start of treatment, and have not taken lipid-lowering agents, antibiotics, non-steroidal anti-inflammatory drugs (NSAIDs), antidepressants, immunosuppressants, or other traditional Chinese medicines that may affect metabolomic and lipidomic profiles. 6. Willing to voluntarily participate in the trial and adhere to the 4-week traditional Chinese medicine treatment regimen. 7. Right-handed. 8. Provide written informed consent and are able to understand and comply with the study protocol requirements, including dietary and exercise recommendations and blood glucose monitoring. DSPN
Exclusion criteria
1. Patients with type 1 diabetes mellitus or other specific types of diabetes mellitus. 2. Women who are pregnant, breastfeeding, planning pregnancy, or taking oral contraceptives long-term. 3. Neuropathies caused by other conditions, including but not limited to multiple sclerosis, Parkinson's disease, Guillain-Barré syndrome, epilepsy, spinal cord injury, cervical or lumbar spine lesions (nerve root compression, spinal stenosis, cervical or lumbar degenerative diseases), neuromuscular diseases, severe arterial or venous vascular diseases (venous thrombosis, lymphangitis, etc.), sequelae of cerebrovascular disease, or post-surgical status of lower extremity vasculature. 4. History of stroke, transient ischemic attack, unstable angina, or myocardial infarction within 3 months prior to study enrollment. 5. History of acute diabetic complications (diabetic ketoacidosis, lactic acidosis, or hyperosmolar hyperglycemic state) within 3 months prior to study enrollment. 6. Concomitant severe complications of diabetes, such as end-stage diabetic kidney disease, or proliferative diabetic retinopathy. 7. Concomitant severe diseases of the heart, liver, kidney, cerebrovascular system, or malignant tumors, defined as serum creatinine \>200 μmol/L, blood urea nitrogen \>1.5 times the upper limit of normal, or alanine aminotransferase or aspartate aminotransferase \>3 times the upper limit of normal. 8. Any infection that, in the investigator's opinion, makes the patient unsuitable for participation prior to study enrollment, including but not limited to urinary tract infection, respiratory infection, or diabetic foot with infection requiring further treatment. 9. Patients with psychiatric disorders, cognitive impairment, or inability to cooperate with the study procedures; or individuals with a history of alcohol abuse or drug addiction. Healthy volunteer inclusion criteria: 1. Aged 18 to 55 years (inclusive) at the time of screening, regardless of gender. 2. Body mass index (BMI) within the range of 19.0 to 26.0 kg/m² (inclusive). No severe diseases of the heart, liver, kidney, cerebrovascular system, or malignant tumors; routine laboratory tests, electrocardiogram, and chest X-ray are essentially within normal limits. 3. Have not participated in any other clinical trial within 2 weeks prior to the start of treatment, and have not taken lipid-lowering agents, antibiotics, non-steroidal anti-inflammatory drugs (NSAIDs), antidepressants, immunosuppressants, or other traditional Chinese medicines that may affect metabolomic and lipidomic profiles. 4. Voluntarily sign the informed consent form and are willing and able to cooperate with the investigators to complete the clinical study. Healthy volunteer
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Nerve Conduction Velocity (NCV) | Baseline and 4 weeks after treatment completion | NCV measurements include motor nerve conduction velocity of the median, ulnar, tibial, and common peroneal nerves, and sensory nerve conduction velocity of the median and sural nerves. |
| Change in Toronto Clinical Scoring System (TCSS) Score | Baseline and 4 weeks after treatment completion | The Toronto Clinical Scoring System (TCSS) assesses neuropathic symptoms, sensory function, and reflexes. Neuropathic symptoms include foot pain, numbness, tingling, and ataxia; each symptom is scored 1 if present and 0 if absent (maximum 4 points). Sensory function tests include light touch, pain, temperature, vibration, and position sense; each test is scored 1 if abnormal and 0 if normal (maximum 5 points). Reflexes include knee and ankle reflexes bilaterally; each reflex is scored 0 if normal, 1 if reduced, and 2 if absent (maximum 8 points). The total score ranges from 0 to 19, with higher scores indicating more severe neuropathy. |
| Change in Traditional Chinese Medicine (TCM) Syndrome Score | Baseline and 4 weeks after treatment completion | The TCM syndrome score assesses primary and secondary symptoms according to the Guiding Principles for Clinical Research of New Traditional Chinese Medicines and the Clinical Diagnosis and Treatment Guidelines for Diabetic Peripheral Neuropathy in TCM (2016 Edition). Primary symptoms (limb weakness, limb pain and/or numbness) are graded as none, mild, moderate, or severe, scored 0, 2, 4, or 6, respectively (maximum 12 points). Secondary symptoms (fatigue, shortness of breath, spontaneous sweating, night sweating, feverish sensation in palms and soles, soreness and weakness of waist and knees, localized stabbing pain aggravated at night, dry and scaly skin, and purplish lips) are graded as none, mild, moderate, or severe, scored 0, 1, 2, or 3, respectively (maximum 18 points). The total score ranges from 0 to 30, with higher scores indicating more severe symptoms. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Fasting Blood Glucose (FBG) | Baseline and 4 weeks after treatment completion | Venous blood will be collected after at least 8 hours of fasting. Fasting blood glucose (FBG) will be measured using an automated biochemical analyzer, with the unit expressed as mmol/L. |
| Change in Glycated Hemoglobin (HbA1c) | Baseline and 4 weeks after treatment completion | Fasting venous blood will be collected. Glycated hemoglobin (HbA1c) will be measured using high-performance liquid chromatography (HPLC) and expressed as a percentage (%), reflecting the average blood glucose level over the preceding 2-3 months. |
| Change in DN4 Questionnaire Score | Baseline and 4 weeks after treatment completion | The DN4 (Douleur Neuropathique 4) questionnaire is a validated screening tool for neuropathic pain, consisting of 10 items (7 related to symptom description and 3 related to clinical examination). The total score ranges from 0 to 10, with a score ≥4 indicating the presence of neuropathic pain. |
| Change in Visual Analog Scale (VAS) for Pain | Baseline and 4 weeks after treatment completion | The VAS consists of a 100-mm horizontal line, with the left end labeled "0" (no pain) and the right end labeled "100" (worst imaginable pain). Participants will mark the line according to their average pain intensity over the past 24 hours, and the distance in millimeters will be recorded as the pain score. |
| Change in Lipid Profile | Baseline and 4 weeks after treatment completion | Venous blood will be collected after at least 8 hours of fasting. Total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) will be measured using an automated biochemical analyzer. All parameters are expressed in mmol/L. |
| Changes in Serum Untargeted Metabolomic Profiles | Baseline and 4 weeks after treatment completion | Fasting peripheral venous blood samples will be collected. Serum will be separated and stored at -80°C. Untargeted metabolomics analysis will be performed using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Raw data will be processed through peak extraction, alignment, and normalization, then imported into SIMCA software for multivariate statistical analysis. Principal Component Analysis and Orthogonal Partial Least Squares Discrimination Analysis will be used to distinguish metabolic profile differences among groups. Differential metabolites will be selected based on Variable Importance in Projection \> 1, P \< 0.05, and False Discovery Rate \< 0.1. The aim is to identify potential metabolic biomarkers associated with DPN and ZGJTSLF intervention. |
| Changes in Serum Targeted Lipidomic Profiles | Baseline and 4 weeks after treatment completion | Fasting peripheral venous blood samples will be collected from all participants at baseline and after 4 weeks of treatment. Serum will be separated and stored at -80°C. Targeted lipidomics analysis will be performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS), covering major lipid classes including glycerophospholipids, sphingolipids, and glycerolipids. Lipid identification will be performed using the LIPIDBLAST database, and quantification will be conducted using MultiQuant software. Missing values will be estimated using the K-Nearest Neighbors algorithm, and data will be normalized using internal standards. Differential lipids will be identified by unpaired t-test with Benjamin-Hochberg adjustment; an adjusted P \< 0.05 will be considered statistically significant. The aim is to identify potential lipid biomarkers associated with DPN and ZGJTSLF intervention. |
Countries
China
Contacts
CONTACTWang Tao, Doctor
CONTACTXuerong Wu, Doctor
STUDY_DIRECTORRong Yu
The First Affiliated Hospital of Hunan University of Traditional Chinese Medicine
PRINCIPAL_INVESTIGATORJuan Huang
The First Affiliated Hospital of Hunan University of Traditional Chinese Medicine
Outcome results
None listed