An active polypeptide and its use in treating diabetic peripheral neuropathy

Abstract

The application discloses an active polypeptide and application thereof in treating diabetic peripheral neuropathy, and belongs to the technical field of biological polypeptide drugs. An amino acid sequence of the active polypeptide is QVWPDGFVGLAKLWI, which is obtained by step-by-step enzymatic extraction and purification from Morus alba L. which is a homology of medicine and food. The polypeptide can significantly inhibit oxidative stress, inflammatory infiltration and cell apoptosis of Schwann cells induced by a high-sugar environment, and repair the function of damaged nerve cells. Meanwhile, the polypeptide can effectively improve abnormal sciatic nerve conduction function of a diabetic model mouse. The active polypeptide can be used for preparing a drug for treating diabetic peripheral neuropathy, and provides a new candidate drug and research and development direction for the targeted treatment of diabetic peripheral neuropathy.

Description

Technical Field

[0001] This invention belongs to the field of biopeptide drug technology, specifically relating to a mulberry leaf-derived active polypeptide and its use in the preparation of drugs for treating diabetic peripheral neuropathy. Background Technology

[0002] Diabetic peripheral neuropathy (DPN) is the most common and prevalent chronic microvascular complication of diabetes, with a global incidence rate exceeding 60% among diabetic patients. Its main clinical manifestations include numbness, tingling, burning sensation, hyperalgesia, or hypoalgesia in the distal extremities. As the disease progresses, it can lead to nerve demyelination, axonal necrosis, and limb motor dysfunction. In severe cases, it can cause foot ulcers and gangrene. It is one of the core causes of disability and death in diabetic patients, placing a heavy burden on global public health systems.

[0003] The currently accepted core mechanism of DPN pathogenesis is excessive activation of oxidative stress mediated by high glucose toxicity, persistent activation of inflammatory pathways, and aggravated neuronal apoptosis. A high-glucose environment can induce the generation of large amounts of reactive oxygen species, damaging the structure and function of neuronal mitochondria, while simultaneously promoting the secretion of large amounts of pro-inflammatory factors such as TNF-α, IL-1β, and IL-6, continuously damaging the sciatic nerve and peripheral sensory nerves, ultimately leading to nerve conduction dysfunction and irreversible damage to neural tissue structure.

[0004] Currently, there are no specific drugs to cure diabetic neuropathic neuropathy (DPN) in clinical practice. Conventional treatments mainly consist of neurotrophic drugs, antioxidants, and drugs that improve microcirculation, including mecobalamin, alpha-lipoic acid, and epalrestat. These drugs can only slightly relieve clinical symptoms and cannot fundamentally inhibit oxidative stress and the inflammatory cascade, making it difficult to reverse existing neuropathological damage. Furthermore, long-term use has drawbacks such as increasing the metabolic burden on the liver and kidneys and significant individual variability in efficacy. Therefore, developing a novel treatment drug with definite efficacy, high safety, and the ability to repair nerve damage is currently a key focus of DPN drug research.

[0005] Mulberry leaves are a traditional Chinese medicinal herb used in both food and medicine. They are abundant and extremely safe. Modern pharmacological studies have confirmed that mulberry leaves possess various biological activities, including hypoglycemic, antioxidant, anti-inflammatory, and neuroprotective effects. Compared to chemically synthesized drugs, natural plant-derived peptides have advantages such as small molecular weight, good water solubility, easy absorption by the body, no immunogenicity, and extremely low toxicity, making them ideal candidate raw materials for novel chronic disease treatments. Currently, there are no studies or reports on the use of specific mulberry leaf active peptides for the treatment of diabetic peripheral neuropathy. Summary of the Invention

[0006] The purpose of this invention is to overcome the shortcomings of existing drugs for treating diabetic peripheral neuropathy (DPN), such as limited efficacy, inability to reverse nerve damage, and insufficient safety. This invention provides an active polypeptide derived from mulberry leaves and its application in the treatment of DPN. The invention utilizes a three-step enzymatic hydrolysis technique combined with high-performance liquid chromatography (HPLC) purification to isolate a specific active polypeptide from mulberry leaves. Experimental verification has shown that this polypeptide can target multiple sites to intervene in the core pathogenesis of DPN, significantly protecting nerve cells and repairing nerve structure and function, demonstrating significant advantages as a finished drug.

[0007] To achieve the above objectives, the present invention adopts the following technical solution: The present invention provides an active polypeptide, the amino acid sequence of which is shown in SEQ ID NO:1.

[0008] Furthermore, the amino acid sequence of the active polypeptide of the present invention is: Gln-Val-Trp-Pro-Asp-Gly-Phe-Val-Gly-Leu-Ala-Lys-Leu-Trp-Ile.

[0009] Furthermore, the active polypeptide is extracted from mulberry leaves.

[0010] The present invention also provides a method for preparing the active polypeptide, comprising the following steps: using mulberry leaves as raw material, crushing and extracting to obtain crude mulberry leaf extract, sequentially passing it through pepsin, trypsin and papain for stepwise enzymatic hydrolysis, followed by enzyme inactivation, centrifugation, ultrafiltration, RP-HPLC purification and freeze drying to obtain high-purity active polypeptide.

[0011] Furthermore, the pepsin has an enzyme activity ≥3000 U / mg, and the enzymatic hydrolysis conditions are pH 2.0, temperature 37℃, hydrolysis time 2-4h, and enzyme dosage of 0.5-2% of substrate mass.

[0012] Furthermore, the enzymatic hydrolysis time was 2 hours and the amount of enzyme added was 1% of the substrate mass.

[0013] Furthermore, the trypsin has an enzyme activity ≥2500 U / mg, and the enzymatic hydrolysis conditions are pH 7.5, temperature 37℃, hydrolysis time 2-4h, and enzyme dosage of 0.5-2% of substrate mass.

[0014] Furthermore, the enzymatic hydrolysis time was 2 hours and the amount of enzyme added was 0.5% of the substrate mass.

[0015] Furthermore, the papain has an enzyme activity ≥800 U / mg, and the enzymatic hydrolysis conditions are pH 6.0, temperature 55℃, hydrolysis time 2-4h, and enzyme dosage of 0.5-2% of substrate mass.

[0016] Furthermore, the enzymatic hydrolysis time was 4 hours and the amount of enzyme added was 2% of the substrate mass.

[0017] The present invention also provides a pharmaceutical composition comprising the active polypeptide and pharmaceutically acceptable excipients.

[0018] Furthermore, the pharmaceutically acceptable excipients include at least one of fillers, disintegrants, binders, solvents, cosolvents, antioxidants, and antibacterial agents.

[0019] Furthermore, the dosage form of the pharmaceutical composition is an injection, a lyophilized powder for injection, a tablet, a capsule, or a granule.

[0020] The present invention further provides the use of the described active polypeptide or the pharmaceutical composition in the preparation of a medicament for treating diabetic peripheral neuropathy.

[0021] The present invention also provides a product for treating diabetic peripheral neuropathy.

[0022] Furthermore, the product may contain the active polypeptide or the pharmaceutical composition.

[0023] Compared with the prior art, the present invention has the following advantages and beneficial effects: This invention uses natural mulberry leaves, a food and medicine source, as raw material. Through stepwise enzymatic hydrolysis with pepsin, trypsin, and papain, combined with RP-HPLC gradient purification, a high-purity target active polypeptide (QVWPDGFVGLAKLWI) can be stably and efficiently prepared. The preparation process exhibits good reproducibility and strong controllability, making it suitable for large-scale industrial production. Furthermore, this active polypeptide demonstrates excellent drug-like properties and can be prepared into various commonly used clinical dosage forms. In vitro cell experiments and in vivo animal experiments have verified that it can effectively improve nerve cell damage, abnormal nerve conduction, and pathological structural damage caused by diabetic peripheral neuropathy. This effectively compensates for the current limitations of DPN treatment drugs in terms of limited efficacy and inability to reverse nerve damage, demonstrating extremely high clinical translational value and application prospects. Detailed Implementation

[0024] To illustrate the possible application scenarios, technical principles, implementable specific solutions, and achievable objectives and effects of this application in detail, the following description is provided in conjunction with the specific embodiments listed. The embodiments described herein are merely illustrative of the technical solutions of this application and are therefore intended only as examples, not as limiting the scope of protection of this application.

[0025] In this document, the term "embodiment" means that a specific feature, structure, or characteristic described in connection with an embodiment may be included in at least one embodiment of this application. The term "embodiment" appearing in various places throughout the specification does not necessarily refer to the same embodiment, nor does it specifically limit its independence or connection with other embodiments. In principle, in this application, as long as there are no technical contradictions or conflicts, the technical features mentioned in each embodiment can be combined in any way to form corresponding implementable technical solutions.

[0026] Unless otherwise specified, the raw materials, reagents or devices used in the following examples are available from conventional commercial sources or can be obtained by existing known methods.

[0027] Example 1: Preparation of mulberry leaf-derived active polypeptide (QVWPDGFVGLAKLWI) A method for preparing an active polypeptide includes the following steps: (1) Raw material pretreatment: Dry mulberry leaves (purchased from Changchun Traditional Chinese Medicine Wholesale Market, Yatai Street, Kuancheng District, Changchun City) were crushed in a pulverizer and passed through an 80-mesh standard sieve to collect mulberry leaf powder; purified water was added at a material-liquid mass-volume ratio of 1:20 (g:mL), stirred evenly, and then extracted at a constant temperature of 50℃ for 2 hours. The mixture was filtered through four layers of gauze to remove residue and collect the crude mulberry leaf extract.

[0028] (2) First step of enzymatic hydrolysis: Adjust the pH of the crude mulberry leaf extract to 2.0, add pepsin with an enzyme activity of ≥3000 U / mg (product number P7000, Sigma-Aldrich USA) at 1% of the substrate mass, mix well and then hydrolyze at a constant temperature of 37℃ with low speed for 2 hours.

[0029] (3) Second step of enzymatic hydrolysis: After the first step of enzymatic hydrolysis, adjust the pH of the system to 7.5, add trypsin with an enzyme activity of ≥2500 U / mg (product number T7409, Sigma-Aldrich USA) at 0.5% of the substrate mass, and continuously stir at 37℃ for 2 hours for enzymatic hydrolysis.

[0030] (4) Third step of enzymatic hydrolysis: After the second enzymatic hydrolysis is completed, adjust the pH of the system to 6.0, add papain (product number P3250, Sigma-Aldrich USA) with an enzyme activity ≥800 U / mg at 2% of the substrate mass, and heat to 55℃ and stir for 4 hours for enzymatic hydrolysis.

[0031] (5) High temperature enzyme inactivation: After the enzyme hydrolysis is completed, the enzyme hydrolysate is placed in a boiling water bath at 100℃ and heated for 15 minutes to completely inactivate the residual enzyme activity, and then cooled naturally at room temperature.

[0032] (6) Centrifugation and ultrafiltration: The cooled enzymatic hydrolysate was placed in a high-speed refrigerated centrifuge and centrifuged at 8000 r / min for 15 min. The supernatant was collected. Ultrafiltration was performed using a 2 kDa ultrafiltration membrane, and the permeate of small molecule peptides was collected.

[0033] (7) RP-HPLC purification: A C18 reverse-phase column (4.6 mm × 250 mm, 5 μm) was used. Mobile phase A was 0.1% trifluoroacetic acid-water solution, and mobile phase B was 0.1% trifluoroacetic acid-acetonitrile solution. The gradient elution program was set as follows: 0~5 min, 5% mobile phase B; 5~25 min, 5%~35% mobile phase B linear gradient elution; 25~30 min, 35%~90% mobile phase B; 30~35 min, equilibration with 90% mobile phase B; flow rate 1.0 mL / min, detection wavelength 220 nm, column temperature 30 ℃, and injection volume 20 μL. Based on the peak time and peak shape of the peptide standard, the target characteristic elution peak components were accurately collected, and the eluent was enriched and combined multiple times.

[0034] (8) Purification and freeze-drying: The collected target peptide eluent was concentrated under reduced pressure and freeze-dried in a vacuum freeze dryer to obtain a white powder of high-purity active peptide. The amino acid sequence was verified to be QVWPDGFVGLAKLWI (SEQ ID NO:1). The peptide purity was ≥98.5%. It was stored in a refrigerator for later use.

[0035] Example 2: Protective experiment of active peptides against high glucose-induced RSC96 Schwann cell damage Cell grouping and treatment: Logarithmically growing RSC96 rat Schwann cells (Shanghai Cell Bank, Chinese Academy of Sciences, catalog number SCSP-523) were seeded in 96-well and 6-well cell culture plates and cultured routinely until the cells reached 80% adherence and confluence. The cells were then divided into 6 groups, with 6 replicates per group to eliminate experimental error. (1) Blank control group: routine culture in DMEM medium with normal glucose concentration of 5.5 mmol / L; (2) Model control group: cultured in 150 mmol / L high glucose DMEM medium to construct a high glucose neuronal injury model; (3) Positive control group: 10 μmol / L α-lipoic acid (product number L8130, Sigma-Aldrich, USA) was added under high glucose environment for drug intervention; (4) Low-dose peptide group (LP): 50 μmol / L of the active peptide of this invention was added under high glucose conditions for intervention; (5) Medium dose group of peptide (MP): 100 μmol / L of the active peptide of the present invention was added under high glucose environment for intervention; (6) High-dose peptide group (HP): 200 μmol / L of the active peptide of this invention was added under high glucose conditions for intervention; All cells were placed in a 37°C, 5% CO2 incubator for 48 hours for continuous intervention and culture, after which the culture was terminated and various indicators were detected.

[0036] Detection kits: CCK-8 cell viability kit (Catalog No. CK04, Dojindo Japan), ROS reactive oxygen species detection kit (Catalog No. S0033S, Beyotime China), MDA detection kit (Catalog No. A003-1, Nanjing Jiancheng Biotechnology), SOD detection kit (Catalog No. A001-1, Nanjing Jiancheng Biotechnology), GSH-Px detection kit (Catalog No. A005-1, Nanjing Jiancheng Biotechnology), TNF-α / IL-1β / IL-6 ELISA kit (Catalog Nos. EK286 / 3-96, EK201B-96, EK206-96, Bioswamp China), Annexin V-FITC / PI cell apoptosis detection kit (Catalog No. CA1020, Solarbio China).

[0037] Detection methods: Cell viability assay: The CCK-8 colorimetric method was used. 10 μL of CCK-8 reagent was added to each well, and the cells were incubated in the dark for 2 hours. The absorbance at 450 nm was measured using a microplate reader, and the relative cell viability of each group was calculated. Oxidative stress index assay: ROS fluorescence intensity was detected using a fluorescent probe method, strictly following the kit instructions. MDA content, SOD, and GSH-Px antioxidant enzyme activity were measured. Inflammatory factor assay: Cell culture supernatant was collected, and the concentrations of TNF-α, IL-1β, and IL-6 were detected using an ELISA double-antibody sandwich method. Apoptosis assay: The total apoptosis rate was detected by flow cytometry using Annexin V-FITC / PI double staining. All experiments were independently repeated three times. Data are expressed as mean ± standard deviation (x±s). One-way ANOVA was performed using SPSS 26.0. P < 0.05 was considered statistically significant.

[0038] Experimental results and analysis: as shown in Table 1-2.

[0039] Table 1. Cell viability test results

[0040] Note: Compared with the blank control group, ##P<0.01; compared with the model group, *P<0.05, **P<0.01.

[0041] Table 2 Results of inflammatory factor detection

[0042] Note: Compared with the blank control group, ##P<0.01; compared with the model group, *P<0.05, **P<0.01.

[0043] Schwann cells in the model group after high glucose intervention showed significant damage, with substantially decreased cell viability, over-activated oxidative stress pathways, significantly increased levels of oxidative damage markers ROS and MDA (P<0.01), and significantly decreased activities of antioxidant enzymes SOD and GSH-Px (P<0.01). Meanwhile, a large amount of inflammatory factors were released and the cell apoptosis rate increased sharply (P<0.01), confirming that the high glucose-induced nerve injury model was successfully constructed.

[0044] After intervention with different doses of active polypeptide, the injury state of Schwann cells was significantly improved, and showed obvious dose-dependent characteristics: low-dose polypeptide could mildly alleviate cellular oxidative stress, inflammatory response and apoptotic injury, and improve cell viability; the intervention effect of medium- and high-dose polypeptide was greatly improved, and could significantly reverse the abnormality of various indicators caused by high glucose (P<0.01 or P<0.05). Among them, the cell viability, antioxidant level, anti-inflammatory effect and anti-apoptotic effect of the high-dose polypeptide group were all better than those of the clinical positive drug α-lipoic acid group, proving that the active polypeptide of the present invention can exert excellent in vitro neuroprotective effect by inhibiting oxidative stress, blocking inflammatory cascade, and reducing neuronal apoptosis, and its efficacy is superior to existing clinical antioxidant neuroprotective drugs.

[0045] Example 3 In vivo therapeutic experiment of active polypeptide on peripheral neuropathy in diabetic mice Experimental animals: SPF-grade male C57BL / 6 mice, 8 weeks old, body weight 20±2g, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd., animal license number: SCXK (Jing) 2022-0004. The mice were acclimatized for 1 week with free access to food and water, the ambient temperature was 22±2°C, the humidity was 50%±5%, and the饲养 was carried out with 12h light-dark alternation. All animal experimental procedures complied with animal ethics regulations.

[0046] Model construction and grouped administration: Except for the blank group, the remaining mice were intraperitoneally injected with 55mg / kg streptozotocin (STZ, Cat. No. S0130, Sigma, USA) for 5 consecutive days. 72h later, blood was collected from the tail vein to detect fasting blood glucose, and mice with blood glucose ≥16.7mmol / L were judged as successfully modeled with diabetes. They were continuously fed with high-fat diet for 4 weeks to construct a stable diabetic peripheral neuropathy model. The successfully modeled mice were randomly divided into 4 groups, and a blank control group was additionally set, with 10 mice in each group. There was no statistical difference in body weight and blood glucose of mice among groups: (1) Blank control group (Control): normally reared, intragastric administration with equal volume of normal saline daily; (2) Model control group (Model): DPN model, intragastric administration with equal volume of normal saline daily; (3) Positive control group: DPN model, daily intraperitoneal injection of 0.5 mg / kg mecobalamin (catalog number M9756, Sigma-Aldrich, USA). (4) Low-dose polypeptide group (LP): DPN model, 50 mg / kg of active polypeptide was administered by gavage daily; (5) High-dose polypeptide group (HP): DPN model, 100 mg / kg of active polypeptide was administered by gavage daily; Each group was given the medication once a day at a fixed time for 8 consecutive weeks. During the medication period, the group maintained normal diet and water intake. Various indicators were tested 24 hours after the last dose.

[0047] Detection method: (1) Mechanical pain threshold detection: The Von Frey fiber mechanical pain instrument was used. Mice were placed in a transparent isolation cage for 30 minutes to adapt. The soles of the mice were vertically stimulated with fiber filaments of different strengths. The positive reaction was the rapid lifting and licking of the mouse's foot. The 50% foot retraction threshold of the mouse was determined by the lifting and lowering method, which is the mechanical pain threshold. Each group of mice was tested 5 times with an interval of 5 minutes. The extreme values ​​were removed and the average value was taken.

[0048] (2) Thermal pain threshold detection: Using a thermal pain instrument, mice were placed on a constant temperature hot plate (55℃). The time from when the mouse's foot came into contact with the hot plate to when it raised or withdrew its foot was recorded as the thermal pain threshold. Each test should not exceed 30 seconds to avoid burns. Each group was tested 3 times with an interval of 10 minutes, and the average value was taken.

[0049] (3) Sciatic nerve conduction velocity detection: Mice were anesthetized by intraperitoneal injection of sodium pentobarbital, and bilateral sciatic nerves were exposed. Stimulating electrodes were placed at the proximal end of the sciatic nerve and recording electrodes were placed at the distal end. A single pulse stimulation was given, and the latency and amplitude of the nerve action potential were recorded. Motor conduction velocity (MNCV) and sensory conduction velocity (SNCV) were calculated. Each group was tested three times and the average value was taken.

[0050] (4) Neuropathological examination: After the examination, the mice were euthanized, the bilateral sciatic nerves were quickly separated, fixed with 4% paraformaldehyde, dehydrated in a gradient, embedded in paraffin, serially sectioned, stained with HE, dehydrated and cleared, mounted with neutral resin, and observed under an optical microscope for the myelin sheath structure, axonal morphology and inflammatory cell infiltration of the sciatic nerve. The degree of pathological damage was analyzed by taking pictures.

[0051] Experimental results and analysis: as shown in Table 3.

[0052] Table 3. Behavioral and electrophysiological test results

[0053] Note: Compared with the blank control group, ##P<0.01; compared with the model group, *P<0.05, **P<0.01.

[0054] Behavioral and electrophysiological results showed that, compared with the control group, the DPN model group mice had significantly lower mechanical and thermal pain thresholds (P<0.01), exhibited obvious hyperalgesia and paresthesia, and significantly slowed sciatic nerve motor and sensory conduction velocities, indicating typical peripheral nerve dysfunction in diabetic mice, thus successfully modeling the disease. Peptide intervention significantly improved the neurological function of mice. Low-dose peptides slightly increased the pain threshold and restored nerve conduction velocity (P<0.05); high-dose peptide intervention significantly restored pain sensitivity and nerve conduction velocity (P<0.01), with a significantly better improvement effect than the methylcobalamin positive drug group, demonstrating that the peptide can effectively improve the core symptoms of limb sensory abnormalities and nerve conduction disorders in DPN mice. Furthermore, the pathological results detailed that the sciatic nerve tissue structure of mice in the blank control group was intact, with dense, smooth, and uniformly thick myelin sheaths, and neatly and tightly arranged axons, without inflammatory cell infiltration or tissue edema. In contrast, the sciatic nerve of mice in the DPN model group showed severe pathological damage, characterized by loose, layered, and detached myelin sheaths, vacuolar degeneration, axonal atrophy, disordered arrangement, extensive interstitial inflammatory cell infiltration, and severe tissue edema. All peptide dosage groups could repair nerve damage to varying degrees. In the high-dose peptide group, the sciatic nerve myelin sheath structure was intact, the axons were neatly arranged, inflammatory infiltration was largely resolved, and the nerve tissue structure was close to normal. This confirms that the active peptide of this invention can effectively repair organic nerve damage caused by DPN and reverse neuropathological lesions.

[0055] The above description, in conjunction with specific preferred embodiments, provides a further detailed explanation of the present invention. It should not be construed that the specific implementation of the present invention is limited to these descriptions. For those skilled in the art, various simple deductions or substitutions can be made without departing from the concept of the present invention, and all such modifications and substitutions should be considered within the scope of protection of the present invention.

Claims

1. An active polypeptide, characterized in that, The amino acid sequence of the active polypeptide is shown in SEQ ID NO:1: Gln-Val-Trp-Pro-Asp-Gly-Phe-Val-Gly-Leu-Ala-Lys-Leu-Trp-Ile.

2. A method for preparing the active polypeptide according to claim 1, characterized in that, Includes the following steps: Using mulberry leaves as raw material, a crude mulberry leaf extract was obtained by crushing and soaking. The extract was then subjected to stepwise enzymatic hydrolysis by pepsin, trypsin, and papain. The extract was then purified by enzyme inactivation, centrifugation, ultrafiltration, RP-HPLC, and freeze-drying to obtain the active polypeptide.

3. The preparation method according to claim 2, characterized in that, The pepsin has an enzyme activity ≥3000 U / mg, and the enzymatic hydrolysis conditions are pH 2.0, temperature 37℃, hydrolysis time 2-4h, and enzyme dosage 0.5-2% of substrate mass.

4. The preparation method according to claim 2, characterized in that, The trypsin has an enzyme activity ≥2500 U / mg, and the enzymatic hydrolysis conditions are pH 7.5, temperature 37℃, hydrolysis time 2-4h, and enzyme dosage 0.5-2% of substrate mass.

5. The preparation method according to claim 2, characterized in that, The papain has an enzyme activity ≥800 U / mg, and the enzymatic hydrolysis conditions are pH 6.0, temperature 55℃, hydrolysis time 2-4h, and enzyme dosage of 0.5-2% of substrate mass.

6. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises the active polypeptide of claim 1 and pharmaceutically acceptable excipients.

7. The pharmaceutical composition according to claim 6, characterized in that, Pharmaceutically acceptable excipients include at least one of fillers, disintegrants, binders, solvents, cosolvents, antioxidants, and antibacterial agents.

8. The pharmaceutical composition according to claim 6, characterized in that, The dosage form of the pharmaceutical composition is injection, lyophilized powder for injection, tablet, capsule or granule.

9. The use of the active polypeptide of claim 1 or the pharmaceutical composition of any one of claims 6-8 in the preparation of a medicament for treating diabetic peripheral neuropathy.

10. A product for treating diabetic peripheral neuropathy, characterized in that, The product comprises the active polypeptide of claim 1 or the pharmaceutical composition of any one of claims 6-8.

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