Biomarker composition for early diagnosis of diabetic neuropathy

Abstract

The present invention relates to: a biomarker composition for early diagnosis of diabetic neuropathy, comprising an agent for measuring the level of CA 15-3; a kit; and a method for providing information for early diagnosis of diabetic neuropathy, and can be effectively used for early prediction and diagnosis of diabetic neuropathy.

Description

Biomarker composition for early diagnosis of diabetic neuropathy

[0001] The present invention relates to a biomarker composition for early diagnosis of diabetic neuropathy, and more particularly, to a CA 15-3 biomarker composition, kit, and method for providing information for early diagnosis of diabetic neuropathy for prediction and diagnosis of diabetic neuropathy.

[0002] Diabetes mellitus is a metabolic disease characterized by hyperglycemia due to defects in insulin secretion or action. It is a chronic, degenerative condition often accompanied by complications such as renal failure. Type 2 diabetes, in particular, occurs when insulin secretion is well-regulated but insulin malfunctions, resulting in a failure to control blood sugar levels, due to acquired factors such as lack of exercise, obesity, or stress.

[0003] Secondary diabetic complications, which arise from diabetes, include diabetic neuropathy, diabetic retinopathy, and diabetic nephropathy. Diagnosing diabetic neuropathy relies primarily on subjective symptoms, but a clinical diagnosis can also be made based on neurological examinations. More detailed testing can include monofilament testing, quantitative sensory nerve testing, nerve conduction studies, electromyography, and autonomic nerve testing.

[0004] As a prior art, according to Patent Document 1 (Korean Patent Publication No. 10-2021-0088053), a composition for diagnosing diabetic neuropathy containing miRNA is disclosed, but research on a method for early diagnosis of diabetic complications by measuring the level of CA 15-3, a cancer antigen, is insufficient.

[0005] Against this backdrop, the inventors of the present invention have made efforts to discover a blood protein marker with high sensitivity and specificity for diagnosing diabetic neuropathy, and as a result, selected CA 15-3 (Cancer Antigen 15-3) as a biomarker. In the case of CA 15-3, a pattern in which its expression significantly increases in a diabetic neuropathy patient group compared to a normal group or a diabetic patient group without complications was confirmed, thereby completing the present invention.

[0006] [Patent Document]

[0007] (Patent Document 0001) Republic of Korea Patent Publication No. 10-2021-0088053 (July 14, 2021)

[0008] The purpose of the present invention is to provide a biomarker composition for early diagnosis of diabetic neuropathy.

[0009] Accordingly, an object of the present invention is to provide a biomarker composition for early diagnosis of diabetic neuropathy, comprising a preparation for measuring the level of CA 15-3 (Cancer Antigen 15-3).

[0010] Another object of the present invention is to provide a kit for early diagnosis of diabetic neuropathy, comprising a preparation for measuring the level of CA 15-3 (Cancer Antigen 15-3).

[0011] Another object of the present invention is to provide a method for providing information for early diagnosis of diabetic neuropathy, comprising the steps of (a) measuring the CA 15-3 level from a biological sample isolated from a diabetic neuropathy patient; and (b) comparing the CA 15-3 level with a control sample.

[0012] Another object of the present invention is to provide a method for early diagnosis of diabetic neuropathy, comprising the steps of (a) measuring the CA 15-3 level from a biological sample isolated from a diabetic neuropathy patient; and (b) comparing the CA 15-3 level with a control sample.

[0013] To achieve the above purpose, the present invention provides a biomarker composition for early diagnosis of diabetic neuropathy, comprising a preparation for measuring the level of CA 15-3 (Cancer Antigen 15-3).

[0014] The present invention also provides a kit for early diagnosis of diabetic neuropathy, comprising a preparation for measuring the level of CA 15-3 (Cancer Antigen 15-3).

[0015] The present invention also provides a method for providing information for early diagnosis of diabetic neuropathy, comprising the steps of: (a) measuring a CA 15-3 level from a biological sample isolated from a diabetic neuropathy patient; and (b) comparing the CA 15-3 level with a control sample.

[0016] The present invention also provides a method for early diagnosis of diabetic neuropathy, comprising the steps of (a) measuring a CA 15-3 level from a biological sample isolated from a diabetic neuropathy patient; and (b) comparing the CA 15-3 level with a control sample.

[0017] The CA 15-3 biomarker composition for early diagnosis of diabetic neuropathy of the present invention can be usefully utilized for prediction and early diagnosis of diabetic neuropathy by confirming a pattern in which there is no significant difference between diabetic subjects without complications and normal subjects, and CA 15-3 expression is significantly increased in subjects with diabetic neuropathy, a diabetic complication, compared to normal subjects or diabetic subjects without complications.

[0018] Figure 1 shows the results of cytokine analysis performed on the blood of normal subjects, diabetic patients without diabetic complications, and diabetic neuropathy patients, visualized as clusters and heatmaps for cytokines that showed a change of 1.5 times or more between groups.

[0019] Figure 2 is a bar graph showing the expression levels of cytokines among normal subjects, diabetic patients without diabetic complications, and diabetic neuropathy patients.

[0020] Figure 2 is a comparative data of the level of blood CA 15-3 expression selected through cytokine analysis between a group of normal diabetic patients without diabetic complications and patients with diabetic neuropathy.

[0021] Figure 3 shows data statistically analyzing significant changes between groups by measuring the blood concentrations of CA 15-3, interleukin 2 receptor subunit alpha (IL2 RA), transforming growth factor beta (TGF-β), L-selectin, platelet factor 4 (PF4), and beta-2 microglobulin (B2M) quantitatively by performing immunoradiometric assay on the blood of normal subjects, diabetic patients without diabetic complications, and diabetic neuropathy patients.

[0022] Hereinafter, the present invention will be described in detail.

[0023] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Generally, the nomenclature used herein is well known and commonly used in the art.

[0024] In the present invention, when it is said that a component or a step “includes”, this does not mean that other components or other steps are excluded, but rather that other components or other steps may be further included, unless specifically stated otherwise.

[0025] In the present invention, the term "diagnosis" refers to confirming the presence or characteristics of a pathological condition. For the purposes of the present invention, diagnosis refers to early diagnosis of diabetes or the onset of diabetic neuropathy.

[0026] In the present invention, the term "diagnostic biomarker" includes organic biomolecules such as polypeptides or nucleic acids (e.g., mRNA, etc.), lipids, glycolipids, glycoproteins, sugars (monosaccharides, disaccharides, oligosaccharides, etc.), etc., which show a significant increase or decrease in gene expression level or protein expression level in individuals with diabetic neuropathy compared to a normal control group (individuals without diabetes or diabetic complications) or individuals with diabetes without diabetic complications, and may preferably be CA 15-3, but is not limited thereto.

[0027] In the present invention, the term "measurement" encompasses both detecting and confirming the presence or expression of a target substance, or detecting and confirming changes in the presence or expression level of a target substance. The measurement can be performed without limitation, including both qualitative and quantitative methods.

[0028] In the present invention, the term "measuring protein expression levels" refers to the process of confirming the presence and expression level of a protein expressed from a biomarker for early prediction or diagnosis of diabetic neuropathy through a biological sample from a patient with diabetic neuropathy. The amount of protein can be determined using antibodies, interacting proteins, ligands, nanoparticles, or aptamers that specifically bind to the protein or peptide fragment of the gene.

[0029] In the present invention, the term "antibody" is a term known in the art and refers to a specific protein molecule directed against an antigenic site. For the purposes of the present invention, the antibody refers to an antibody that specifically binds to the aforementioned biomarker, and such an antibody can be produced by cloning each gene into an expression vector according to a conventional method to obtain a protein encoded by the biomarker gene, and then producing the obtained protein by a conventional method. This may also include a partial peptide that can be produced from the protein. The form of the antibody of the present invention is not particularly limited, and a polyclonal antibody, a monoclonal antibody, or a portion thereof that has antigen binding properties is included in the antibody of the present invention, and all immunoglobulin antibodies are included. Furthermore, the antibody of the present invention also includes special antibodies such as humanized antibodies. The antibody against the protein encoded by the biomarker gene of the present invention may be any antibody that can be produced by a method known in the art. For example, the antibody used for detection of the aforementioned biomarker may include a complete form having two full-length light chains and two full-length heavy chains, as well as a functional fragment of the antibody molecule. The functional fragment of the antibody molecule means a fragment that possesses at least an antigen-binding function, and may be, but is not particularly limited to, Fab, F(ab'), F(ab')2, Fv, etc.

[0030] In the present invention, the term "aptamer" refers to a single-stranded oligonucleotide, which has a function similar to an antibody and is also called a chemical antibody, and refers to a nucleic acid molecule having binding activity to a predetermined target molecule. The aptamer may have various three-dimensional structures depending on its base sequence, and may have high affinity for a specific substance, such as an antigen-antibody reaction. An aptamer can inhibit the activity of a predetermined target molecule by binding to the predetermined target molecule.

[0031] The above aptamer may be RNA, DNA, modified nucleic acid, or a mixture thereof, and may be linear or cyclic in shape, but is not limited thereto. An aptamer having binding activity to each of the three types of biomarker proteins can be easily produced by a person skilled in the art using a known method with reference to each base sequence.

[0032] The present invention provides a biomarker composition for early diagnosis of diabetic neuropathy, comprising a preparation for measuring the level of CA 15-3 (Cancer Antigen 15-3).

[0033] The above diabetic neuropathy is also called diabetic peripheral neuropathy or diabetic neuropathy, and is one of the three major complications of diabetes. It is caused by metabolic abnormalities in nerve cells or nutrient blood vessels that accompany hyperglycemia.

[0034] The above diabetic neuropathy can be classified into symmetric peripheral polyneuropathy, diabetic amyotrophy, mononeuropathy, autonomic neuropathy, painless myocardial ischemia, asymptomatic hypoglycemia, and movement disorders.

[0035] The above CA 15-3 is part of a large protein called Mucin 1 (MUC 1) that mainly appears in epithelial cells, and is a type of cancer antigen (CA) and a type of tumor marker.

[0036] The level of CA 15-3 can be measured in one or more biological samples selected from the group consisting of tissues, cells, whole blood, blood, serum, plasma, and urine, and preferably, one or more biological samples selected from the group consisting of blood, serum, and plasma, but is not limited thereto. In addition, one or more of the above samples can be mixed and used. Such biological samples can be directly obtained from a patient immediately before the test using a conventional sample obtaining method, or can be previously separated and stored.

[0037] The above formulation may be, but is not limited to, an antibody, an interacting protein, a ligand, a nanoparticle, or an aptamer that specifically binds to the CA 15-3 or a fragment thereof.

[0038] The above CA 15-3 level measurement is performed by protein chip analysis, immunoassay, ligand binding assay, MALDI-TOF (Matrix Desorption / Ionization Time of Flight Mass Spectrometry) analysis, SELDITOF (Sulface Enhanced Laser Desorption / Ionization Time of Flight Mass Spectrometry) analysis, radioimmunoassay, radioimmunodiffusion, immunoradiometric assay, Ouchterlony immunodiffusion, rocket immunoelectrophoresis, tissue immunostaining, complement fixation assay, two-dimensional electrophoresis analysis, liquid chromatography-mass spectrometry (LC-MS), liquid chromatography-mass spectrometry / mass spectrometry (LCMS / MS), Western blot, enzyme linked immunosorbent assay (ELISA), multiple reaction monitoring (MRM), and parallel reaction monitoring. The method may be performed by at least one method selected from the group consisting of sequential windowed data independent acquisition of the total high-resolution (SWATH), selected reaction monitoring (SRM), and immuno multiple reaction monitoring (iMRM), and preferably, but not limited to, immunoradiometric assay.

[0039] The present invention also provides a kit for early diagnosis of diabetic neuropathy, comprising a preparation for measuring the level of CA 15-3 (Cancer Antigen 15-3).

[0040] The above kit may be, but is not limited to, an RT-PCR (Reverse transcription polymerase chain reaction) kit, a DNA chip kit, an ELISA (Enzymelinked immunosorbent assay) kit, a protein chip kit, a rapid kit, or an MRM (Multiple reaction monitoring) kit.

[0041] The present invention also provides a method for providing information for early diagnosis of diabetic neuropathy, comprising the steps of: (a) measuring a CA 15-3 level from a biological sample isolated from a diabetic neuropathy patient; and (b) comparing the CA 15-3 level with a control sample.

[0042] The control group may be, but is not limited to, a normal patient group or a diabetic patient group without complications.

[0043] The biological sample may be measured from one or more biological samples selected from the group consisting of tissues, cells, whole blood, blood, serum, plasma, and urine, and preferably, at least one selected from the group consisting of blood, serum, and plasma, but is not limited thereto. In addition, one or more of the above samples may be mixed and used. The biological sample may be obtained directly from the patient immediately before the test using a conventional sample acquisition method, or may be previously separated and stored.

[0044] If the CA 15-3 level increases compared to the control group in the above step (b), the subject can be diagnosed with diabetic neuropathy. According to one embodiment of the present invention, if the CA 15-3 level increases by 1.5 to 2 times or more, the subject can be diagnosed with diabetic neuropathy.

[0045] The comparison in step (b) above can be performed by a statistical analysis method.

[0046] The above statistical analysis method may be performed by any one or more analysis methods selected from the group consisting of linear or nonlinear regression analysis, linear or nonlinear classification analysis, logistic regression analysis, Analysis of Variance (ANOVA), neural network analysis, genetic analysis, support vector machine analysis, hierarchical analysis or clustering analysis, hierarchical algorithm using decision tree or kernel principal component analysis, Markov Blanket analysis, recursive feature elimination or entropy-based regression feature elimination analysis, forward floating search or backward floating search analysis, and combinations thereof, but is not limited thereto.

[0047] The present invention also provides a method for early diagnosis of diabetic neuropathy, comprising the steps of (a) measuring a CA 15-3 level from a biological sample isolated from a diabetic neuropathy patient; and (b) comparing the CA 15-3 level with a control sample.

[0048] The above biomarker composition and kit can be used together with existing biomarkers and / or diagnostic methods.

[0049]

[0050] Hereinafter, to aid understanding of the present invention, examples will be given in detail. However, the following examples are intended only to illustrate the scope of the present invention and are not intended to limit its scope. These examples are provided to more fully explain the present invention to those of average skill in the art.

[0051]

[0052] Example 1: Preliminary study of biomarker screening for early diagnosis of diabetic neuropathy.

[0053]

[0054] 1-1: Patient selection and blood collection

[0055] In the present invention, in order to discover predictive and diagnostic markers for type 2 diabetic neuropathy, a small group of 10 normal individuals, 20 type 2 diabetic patients (patients without diabetic complications), and 13 diabetic neuropathy patients were selected as a preliminary study, and blood samples were collected from the patients (Table 1).

[0056]

[0057] Normal (10) Type 2 diabetes without complications (20) Type 2 diabetes with neuropathy (13) Age 54.00±4.32 56.70±7.07 59.23±7.36 Height 162.02±9.06 161.77±7.69 160.02±9.41 Weight 57.99±8.18 61.85±10.12 66.48±9.64 BMI 22.04±1.93 23.48±2.62 25.92±2.95 Waist circumference 74.10±6.99 82.50±7.13 66.48±9.64 Fasting blood sugar Value 79.60±6.38 138.35±34.56 90.08±6.53 HbA1c 5.29±0.17 7.48±1.24 7.32±1.39 M / C ratio 2.88±1.50 9.94±7.57 11.91±8.75 eGFR(MDRD) 102.57±19.03 101.29±19.22 95.97±19.17 Duration of diabetes 04.80±5.18 12.85±5.76 Hypertension 0 / 10 12 / 2011 / 13 Hyperlipidemia 0 / 10 17 / 2011 / 13 Smoking [1 / 0] 0 / 10 4 / 20 1 / 13 Drinking [1 / 0] 0 / 10 6 / 20 2 / 13 M / C ratio: microalbumin / creatinine ratioeGFR: Estimated glomerular filtration rateMDRD: modification of diet in renal disease

[0058]

[0059] 1-2: Antibody Array Data Collection and Analysis

[0060] Antibody array experiments using patient blood were performed as follows. Slide scanning was performed using a GenePix 4100A scanner (Axon Instrument, USA). Slides were completely dried before scanning and scanned within 24–48 hours. Slides were scanned at 10 μm resolution, with optimal laser power and photomask (PMT). After obtaining scanned images, they were gridded and quantified using GenePix 7.0 software (Axon Instrument, USA). Numerical data were analyzed using Genowiz 4.0™ (Ocimum Biosolutions, India), and protein information was annotated using the UniProt database.

[0061]

[0062] 1-3: Clustering Heatmap Visualization

[0063] Sample and gene clustering was performed using MeV 4.9.0. Hierarchical clustering analysis was performed using Euclidean distance correlation as a distance measure via average linkage. Clusters and heatmaps were visualized using MeV 4.9.0 (Fig. 1).

[0064]

[0065] 1-4: Biomarker screening

[0066] Through cytokine analysis, the expression levels of 310 cytokines were confirmed in the patients' blood. Based on the normalized data as above, the fold change value was calculated by comparing normal subjects, patients with type 2 diabetes (diabetes without complications), and patients with diabetic neuropathy, and among the 310 cytokines, 12 cytokines that showed a 1.5-fold or greater increase or decrease between the groups were identified. Among them, CA 15-3 showed the most prominent difference between the groups, and thus was selected as a biomarker of diabetic neuropathy (Fig. 2, P=0.0003).

[0067]

[0068] 1-5: Confirmation of the diagnostic ability of CA 15-3 for diabetic neuropathy

[0069] In the present invention, based on normalized data comparing antibody-based expression levels of CA 15-3 in the blood in Example 1, a comparative analysis was conducted based on the fold change in expression of CA 15-3 between normal subjects, patients with type 2 diabetes without complications, and patients with diabetic neuropathy (Table 2).

[0070]

[0071] Gene symbol fold change Type 2 diabetes with neuropathy / normal Type 2 diabetes without complications / normal Type 2 diabetes with neuropathy / type 2 diabetes without complications CA 15-3-1.903-6.0483.178

[0072]

[0073] As a result, it was confirmed that the expression of CA 15-3 was increased 3- to 4-fold in patients with diabetic neuropathy compared to patients with type 2 diabetes without complications.

[0074] Therefore, the CA 15-3 biomarker of the present invention can be used to diagnose diabetic neuropathy.

[0075]

[0076] Example 2: Quantitative validation study on selected biomarkers

[0077]

[0078] 2-1: Patient selection and blood collection

[0079] In a previous small study, CA 15-3 was identified as a biomarker for the prediction and diagnosis of diabetic neuropathy through non-quantitative cytokine analysis. To quantitatively validate the validity of the identified CA 15-3, blood samples were collected from a large cohort of 100 healthy individuals, 125 patients with type 2 diabetes (without diabetic complications), and 69 patients with diabetic neuropathy (Table 3).

[0080]

[0081] Normal (N=100)Type 2 diabetes without complications (N=125)Type 2 diabetes with neuropathy (N=69)Age 49.68±6.7155.30±8.8659.77±9.83Height 167.29±7.91163.57±8.98162.18±8.63Weight 63.05±7.4567.98±13.7568.45±13.05BMI 22.54±1.5225.21±3.6625.90±4.26Fasting blood sugar Value 88.35±5.00 128.02±28.50 123.30±17.76 HbA1c 5.28±0.18 7.08±1.10 7.45±1.21 M / C ratio 8.09±6.34 9.99±8.55 eGFR (MDRD) 100.63±19.86 102.37±83.42 92.40±18.04 Duration of diabetes 03.59±5.33 7.75±5.55 Hypertension 1 / 100 35 / 125 37 / 69 Hyperlipidemia 0 / 100 35 / 125 7 / 69 M / C ratio: microalbumin / creatinine ratio eGFR: Estimated glomerular filtration rate MDRD: modification of diet in renal disease

[0082]

[0083] 2-2: Immunoradiometric assay

[0084] 200 μl of antisera was added to 10 μl of the standard solution, control solution, and sample, fixed on a rack, sealed with foil, and incubated at room temperature for 1 hour while shaking at a shaker speed of 600 rpm to ensure that the reagents are well dissolved.

[0085] After adding 2 ml of diluted washing solution, the supernatant was discarded and the remaining reagent was removed by shaking the rack up and down. The above washing process was repeated at least twice.

[0086] 200 μl of tracer (marker) was added to each tube, fixed on a rack, sealed with foil, and incubated at room temperature for 1 hour while shaking at 600 rpm to ensure good aggregation of the reagent. After adding 2 ml of diluted washing solution, the supernatant was discarded, and the remaining reagent was removed by shaking the rack up and down. The above washing process was repeated at least twice.

[0087] The radiation dose of each tube was measured using a gamma meter for at least 60 seconds, and the CA 15-3 concentration in the sample was calculated from the standard curve.

[0088] The expression level of CA 15-3 in the blood of each patient group was quantitatively confirmed using immunoradiometric analysis (Table 4). As shown in Figure 3, CA 15-3 did not significantly differ between the normal group and the type 2 diabetes patient group without complications. In contrast, the diabetic neuropathy group showed a significant increase compared to the normal group or the type 2 diabetes (diabetic patients without diabetic complications) group (P=0.003, ANOVA).

[0089]

[0090] Normal (N=100)Type 2 diabetes without complications (N=125)Type 2 diabetes with neuropathy (N=69)pCA 15-39.45 ± 2.939.77 ± 3.3111.37 ± 5.020.003

[0091]

[0092] 2-3: Confirmation of the diagnostic ability of CA 15-3 for diabetic neuropathy

[0093] In the present invention, based on data quantitatively measuring the antibody-based expression level of CA 15-3 in the blood in Example 2, the quantitative blood expression values ​​of CA 15-3 between patients with type 2 diabetes without complications and patients with diabetic neuropathy were compared and analyzed using a student t-test.

[0094] As a result, the blood CA 15-3 concentration showed a significant increase in the diabetic neuropathy group compared to the type 2 diabetes patient group without complications (P=0.012, t-test), and also showed a significant increase compared to the normal group (P=0.003, t-test).

[0095] In summary, the present invention confirmed through the above examples that the level of CA 15-3 significantly increased in type 2 diabetic patients with diabetic neuropathy compared to the normal group and type 2 diabetic patients without diabetic complications, thereby elucidating that CA 15-3 can be utilized for early prediction and diagnosis of diabetic neuropathy.

[0096]

[0097] The present invention is an invention carried out through the following tasks.

[0098]

[0099] [National Research and Development Project Supporting This Invention]

[0100] [Project ID]1465039959

[0101] [Task Number]HR18C0012 (HR18C0012040023)

[0102] [Ministry Name] Ministry of Health and Welfare

[0103] [Name of Project Management (Specialist) Institution] Korea Health Industry Development Institute

[0104] [Research Project Name] Research-Oriented Hospital Development

[0105] [Research Project Name] Open Module-Based Metabolic Disease Diagnosis and Treatment Practicalization System

[0106] Development (Development of a multi-diagnostic chip-based diabetes and diabetes complication progression prediction model)

[0107] [Contribution rate] 1 / 1

[0108] [Name of Project Performing Organization] Keimyung University Dongsan Medical Center

[0109] [Research Period] July 26, 2018 - December 31, 2026

Claims

1. A biomarker composition for early diagnosis of diabetic neuropathy, comprising a preparation for measuring the level of CA 15-3 (Cancer Antigen 15-3).

2. A biomarker composition according to claim 1, wherein the level of CA 15-3 is measured in one or more biological samples selected from the group consisting of tissue, cells, whole blood, blood, serum, and urine.

3. A biomarker composition according to claim 1, wherein the preparation is an antibody, interacting protein, ligand, nanoparticle or aptamer that specifically binds to CA 15-3 or a fragment thereof.

4. In the first paragraph, the CA 15-3 level measurement is performed by protein chip analysis, immunoassay, ligand binding assay, MALDI-TOF (Matrix Desorption / Ionization Time of Flight Mass Spectrometry) analysis, SELDITOF (Sulface Enhanced Laser Desorption / Ionization Time of Flight Mass Spectrometry) analysis, radioimmunoassay (RIA), radioimmunodiffusion (RID), immunoradiometric assay, Ouchterlony immunodiffusion, rocket immunoelectrophoresis, tissue immunostaining, complement fixation assay, two-dimensional electrophoresis analysis, liquid chromatography-mass spectrometry (LC-MS), liquid chromatography-mass spectrometry / mass spectrometry (LCMS / MS), western blot, A biomarker composition performed by at least one method selected from the group consisting of enzyme linked immunosorbent assay (ELISA), multiple reaction monitoring (MRM), parallel reaction monitoring (PRM), sequential windowed data independent acquisition of the total high-resolution (SWATH), selected reaction monitoring (SRM), and immuno multiple reaction monitoring (iMRM).

5. A kit for early diagnosis of diabetic neuropathy, comprising a preparation for measuring the level of CA 15-3 (Cancer Antigen 15-3). 6.(a) measuring the CA 15-3 level from a biological sample isolated from a patient with diabetic neuropathy; and (b) A method for providing information for early diagnosis of diabetic neuropathy, comprising a step of comparing the CA 15-3 level with a control sample.

7. A method for providing information in paragraph 6, wherein the control group is a normal patient group or a diabetic patient group without complications.

8. A method for providing information in paragraph 6, wherein the biological sample is at least one selected from the group consisting of tissue, cell, whole blood, blood, serum, and urine.

9. A method for providing information, wherein in the 6th paragraph, if the CA 15-3 level increases compared to the control group in the step (b), the subject is diagnosed with diabetic neuropathy. 10.(a) measuring the CA 15-3 level from a biological sample isolated from a patient with diabetic neuropathy; and (b) A method for early diagnosis of diabetic neuropathy, comprising a step of comparing the CA 15-3 level with a control sample.

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