Traditional Chinese medicine composition for treating or improving abnormal glucose tolerance as well as preparation method and application of traditional Chinese medicine composition

Abstract

The invention discloses a traditional Chinese medicine composition for treating or improving abnormal glucose tolerance as well as a preparation method and application of the traditional Chinese medicine composition. The traditional Chinese medicine composition is prepared from the following components in parts by weight: 5 to 20 parts of wine-processed rhizoma polygonati, 1 to 10 parts of rhizoma dioscoreae, 1 to 10 parts of raw fructus crataegi, 1 to 10 parts of radix angelicae sinensis, 1 to 10 parts of radix polygonati officinalis, 1 to 10 parts of folium mori, 1 to 5 parts of radix puerariae, 1 to 5 parts of rhizoma phragmitis and 1 to 5 parts of fried fructus gardeniae. On the other hand, the invention discloses an extract of the traditional Chinese medicine composition, and the extract is obtained through water decoction extraction. The traditional Chinese medicine composition provided by the invention can be used for people with abnormal sugar tolerance caused by phlegm-dampness constitution, and can tonify qi and yin, clear heat and promote salivation, and disperse blood stasis and reduce blood sugar. The traditional Chinese medicine composition provided by the invention can be used for carrying out quality standard detection through content determination by taking polygonatum polysaccharide and trigonelline in polygonatum as detection indexes.

Description

Technical Field

[0001] The present invention relates to the technical field of traditional Chinese medicines, and in particular to a traditional Chinese medicine composition for treating or improving impaired glucose tolerance, and a preparation method and application thereof. Background Art

[0002] The 10th edition of the Global Diabetes Atlas released by IDF in 2021 shows that 9% of global health expenditures are spent on diabetes, totaling $966 billion. Diabetes-related health expenditures are expected to increase by more than $206 billion by 2045. The direct costs of diabetes are expected to continue to grow in the future, with the United States having the highest diabetes-related health expenditures ($379.5 billion), followed by China and Brazil ($165.3 billion and $42.9 billion, respectively).

[0003] Glucose tolerance refers to the body's ability to tolerate glucose. Blood sugar 2 hours after a meal exceeds the normal 7.8mmol / L, but still does not reach the diabetes diagnostic standard of 11.1mmol / L (or fasting blood sugar rises but does not reach the diabetes diagnostic standard, that is, fasting blood sugar is between 6.2 and 7.0) is called impaired glucose tolerance (or impaired fasting glucose).

[0004] Impaired glucose tolerance is a stage in the development of diabetes. Before 1999, WHO diagnosed impaired glucose tolerance as early diabetes. Since 1999, WHO's newly revised diabetes diagnosis and classification scheme divides the development stages of diabetes into normal blood sugar and hyperglycemia stages. The hyperglycemia stage is further divided into two periods, impaired fasting glucose (IFG) and impaired glucose tolerance (IGT). Since patients with impaired glucose tolerance do not have typical symptoms of diabetes and their fasting blood sugar is normal, it has not attracted people's attention. However, if patients in the stage of impaired glucose tolerance are allowed to develop naturally, 1 / 3 of them will develop diabetes every year. Therefore, it is very necessary to intervene and treat during the period of impaired glucose tolerance.

[0005] Due to the rapid development of my country's economy and the improvement of living standards, the dietary structure has changed. The sources of calories, protein and fat in the diet have shifted from mainly plants to mainly animals, resulting in excess total calories. At the same time, the lifestyle is unhealthy and unscientific, including ignorance of diabetes, excessive calorie intake and reduced physical activity. These factors have jointly led to an increase in the incidence of diabetes. Therefore, diet therapy and exercise therapy are the premise and basis of all intervention treatments. Intervention treatment includes Western medicine intervention and Chinese medicine intervention. Impaired glucose tolerance is the result of the combined effect of multiple factors. Modern medicine has unique advantages in the treatment of diseases caused by single factors, but it is temporarily unable to treat complex multi-factor and multi-system diseases, which is the strength of traditional Chinese medicine. Starting from the holistic concept, traditional Chinese medicine treats the disease based on syndrome differentiation, effectively regulates the body's functional disorders from multiple systems, multiple organs and multiple targets, plays a role in preventing and treating diseases and improving the quality of life of patients, and has unique therapeutic effects. Western medicine has significant therapeutic effects on patients with impaired glucose tolerance, but the side effects of the drugs cannot be ignored during the treatment process. Traditional Chinese medicine has fewer side effects, focuses on overall regulation, tends to be individualized, has flexible additions and subtractions, has many comprehensive benefits, and is suitable for long-term treatment. Summary of the invention

[0006] In view of the above technical problems, the present invention provides a traditional Chinese medicine composition for treating or improving impaired glucose tolerance, and a preparation method and application thereof.

[0007] To achieve the above object, the technical solution adopted by the present invention is:

[0008] On the one hand, the present invention provides a traditional Chinese medicine composition for treating or improving impaired glucose tolerance, comprising, by weight, 5-20 parts of polygonatum odoratum, 1-10 parts of yam, 1-10 parts of raw hawthorn, 1-10 parts of angelica, 1-10 parts of polygonatum odoratum, 1-10 parts of mulberry leaves, 1-5 parts of kudzu root, 1-5 parts of reed root and 1-5 parts of stir-fried gardenia.

[0009] As a preferred embodiment, the Chinese medicine composition comprises, by weight, 6-15 parts of Polygonatum odoratum, 3-9 parts of Chinese yam, 3-9 parts of raw hawthorn, 3-6 parts of Chinese angelica, 3-6 parts of Polygonatum odoratum, 3-6 parts of mulberry leaves, 2-5 parts of Pueraria root, 2-5 parts of Phragmites australis and 1-3 parts of stir-fried Gardenia jasminoides;

[0010] Preferably, in parts by weight, the Chinese medicine composition comprises 10 parts of Polygonatum odoratum, 5 parts of yam, 5 parts of raw hawthorn, 4.5 parts of angelica, 4.5 parts of polygonatum odoratum, 4.5 parts of mulberry leaves, 3 parts of kudzu root, 3 parts of reed root and 2 parts of stir-fried gardenia.

[0011] On the other hand, the present invention provides a traditional Chinese medicine composition for treating or improving impaired glucose tolerance, comprising, by weight, 5-20 parts of Polygonatum sibiricum extract, 1-10 parts of yam extract, 1-10 parts of raw hawthorn extract, 1-10 parts of angelica extract, 1-10 parts of polygonatum odoratum extract, 1-10 parts of mulberry leaf extract, 1-5 parts of kudzu root extract, 1-5 parts of reed root extract and 1-5 parts of stir-fried gardenia extract.

[0012] As a preferred embodiment, the Chinese medicine composition comprises, by weight, 6-15 parts of Polygonatum sibiricum extract, 3-9 parts of yam extract, 3-9 parts of raw hawthorn extract, 3-6 parts of angelica extract, 3-6 parts of polygonatum odoratum extract, 3-6 parts of mulberry leaf extract, 2-5 parts of kudzu root extract, 2-5 parts of reed root extract and 1-3 parts of stir-fried gardenia extract;

[0013] Preferably, in parts by weight, the Chinese medicine composition includes 10 parts of Polygonatum odoratum extract, 5 parts of yam extract, 5 parts of raw hawthorn extract, 4.5 parts of angelica extract, 4.5 parts of polygonatum odoratum extract, 4.5 parts of mulberry leaf extract, 3 parts of kudzu root extract, 3 parts of reed root extract and 2 parts of stir-fried gardenia extract.

[0014] As a preferred embodiment, the extract is a decoction extract.

[0015] As a preferred embodiment, the dosage form of the Chinese medicine composition is an oral dosage form, preferably granules, oral liquid, tablets, syrup or paste.

[0016] In certain specific embodiments, the dosage form of the Chinese medicine composition is a granule, and the granule further comprises dextrin, xylitol and a flavor corrector;

[0017] Preferably, the mass ratio of dextrin to xylitol is 10:1 to 2:1, more preferably 6.5:1;

[0018] Preferably, the flavor corrector comprises at least one of a sweetener and a sour agent;

[0019] Preferably, the flavor corrector is a mixture of steviol glycoside and citric acid.

[0020] In the technical solution of the present invention, the dextrin and xylitol are used as excipients.

[0021] As a preferred embodiment, the granules are prepared by wet granulation, wherein the wet granulation uses an ethanol solution with a mass fraction of 70% to 95% as a wetting agent, preferably an ethanol solution with a mass fraction of 90% to 95%;

[0022] In another aspect, the present invention provides a method for preparing the above-mentioned Chinese medicine composition for treating or improving impaired glucose tolerance, comprising the following steps:

[0023] According to the proportion, Polygonatum sibiricum, Chinese yam, raw hawthorn, Chinese angelica, Polygonatum odoratum, mulberry leaf, Pueraria root, Phragmites australis and stir-fried Gardenia jasminoides are extracted by decocting in water, and the medicinal liquids are combined, filtered and concentrated.

[0024] As a preferred embodiment, the water decoction extraction is performed 1 to 2 times; the first time, 8 to 12 times the amount of water is added and boiled for 1 to 2 hours; the second time, 6 to 10 times the amount of water is added and boiled for 1 to 2 hours;

[0025] Preferably, the concentration is reduced pressure concentration;

[0026] Preferably, the concentration is to concentrate to obtain a clear paste with a relative density of 1.25-1.30. In the technical solution of the present invention, the relative density is the relative density measured at 60°C;

[0027] Preferably, the filtration is performed by centrifugal filtration or plate and frame filter press.

[0028] As a preferred embodiment, the cream yield of the clear cream is in the range of 20-25%.

[0029] In another aspect, the present invention provides use of the above-mentioned Chinese medicine composition in preparing a medicament for treating or improving impaired glucose tolerance.

[0030] The above technical solution has the following advantages or beneficial effects:

[0031] The present invention provides a Chinese medicine composition, which can be obtained by water decoction and extraction, and is mainly used for people with impaired glucose tolerance caused by phlegm-damp constitution, and can invigorate qi and nourish yin, clear away heat and promote the production of body fluid, and remove blood stasis and reduce blood sugar. The Chinese medicine composition provided by the present invention can be tested for quality standards by content determination using polygonatum polysaccharide and trigonelline in polygonatum as detection indicators.

[0032] The Chinese medicine composition comprises:

[0033] Huangjing and Chinese yam are both monarch drugs. Among them, Huangjing is recorded in Compendium of Materia Medica as "replenishing all deficiencies and filling the essence and marrow". It can replenish qi and nourish yin, benefit the kidney, strengthen the spleen, moisten the lungs, nourish the five internal organs, and is good at nourishing yin and kidney, filling the essence and benefiting the marrow; Chinese yam can balance and replenish the yin of the lungs, spleen, and kidneys. The two drugs replenish qi and nourish yin.

[0034] Polygonatum odoratum, reed root, mulberry leaf and gardenia are all ministerial drugs, among which: Polygonatum odoratum nourishes yin and moistens dryness, produces body fluid and quenches thirst; reed root clears heat and produces body fluid, relieves restlessness; mulberry leaf clears the lungs and moistens dryness, clears the liver and improves eyesight. Modern medicine has found that mulberry leaf has the effect of lowering blood sugar; gardenia clears heat and purges fire, cools blood and detoxifies;

[0035] Angelica, hawthorn and kudzu root are adjuvants. Angelica can nourish blood and invigorate blood circulation; hawthorn can help digestion, relieve stagnation, invigorate blood circulation and remove blood stasis, and is good at removing meat accumulation and has the effect of lowering blood lipids. When combined with mulberry leaves, it can reduce both sugar and lipids and prevent vascular diseases; kudzu root can promote body fluid and quench thirst, and can also raise clear yang. Modern medical research shows that kudzu root has the effect of lowering blood sugar. The three drugs are adjuvants.

[0036] The Chinese medicine composition provided by the invention is combined with various medicines to achieve the effects of invigorating qi and nourishing yin, clearing away heat and promoting body fluid, and removing blood stasis and lowering blood sugar. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 This is a graph showing the clinical efficacy of Xiaokeyin + auricular acupoint pressing pills in the intervention of impaired glucose tolerance in an embodiment of the present invention.

[0038] Figure 2 This is a graph showing the results of Xiaokeyin + auricular acupoint pressing pills in an embodiment of the present invention regulating abnormal glucose tolerance by intervening intestinal flora.

[0039] Figure 3 This is a graph showing the changes in the plasma metabolome in the treatment of impaired glucose tolerance using Xiaokeyin + auricular acupoint pressing pills in an embodiment of the present invention.

[0040] Figure 4 It is a graph of potential target genes and their PPI network results for treating impaired glucose tolerance with Xiaokeyin+Auricular acupoint pressing pills in an embodiment of the present invention.

[0041] Figure 5 This is a diagram showing the safety evaluation results of Xiaokeyin+Auricular acupoint pressing pills in the intervention of impaired glucose tolerance in an embodiment of the present invention. DETAILED DESCRIPTION

[0042] The following embodiments are only some embodiments of the present invention, rather than all embodiments. Therefore, the detailed description in the embodiments of the present invention provided below is not intended to limit the scope of the present invention claimed for protection, but merely represents selected embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without making creative work belong to the protection scope of the present invention.

[0043] In the present invention, unless otherwise specified, all equipment and raw materials can be purchased from the market or are commonly used in the industry. The methods in the following embodiments are all conventional methods in the art unless otherwise specified.

[0044] Embodiment 1:

[0045] 1. Research Plan

[0046] (1) Ethical Review

[0047] On November 11, 2020, the ethics review was passed by the Ethics Committee of Beijing University of Chinese Medicine (2020BZYLL0608). From February 4, 2021 to January 27, 2022, the present invention conducted this multicenter, randomized, placebo-controlled clinical trial (registration on the website httP: / / www.chictr.org.cn / has been completed, registration number (ChiCTR2000040574).

[0048] (2) Research subjects

[0049] The cases came from physical examination populations in eight tertiary hospitals, including Beijing University of Chinese Medicine Dongzhimen Hospital, Beijing University of Chinese Medicine Oriental Hospital, the Third Affiliated Hospital of Beijing University of Chinese Medicine, Beijing University of Chinese Medicine Zaozhuang Hospital, Beijing University of Chinese Medicine Shenzhen Hospital, Beijing University of Chinese Medicine Sun Simiao Hospital, Xiamen Traditional Chinese Medicine Hospital, and China Academy of Chinese Medical Sciences Ophthalmology Hospital.

[0050] (3) Diagnostic criteria

[0051] In this study, the diagnosis of impaired glucose tolerance was based on the WHO 1999 classification standard for glucose metabolism status, and the following venous plasma glucose test was used: fasting blood glucose <7.0mmol / L and 7.8mmol / L≤2h blood glucose after glucose load <11.1mmol / L.

[0052] (4) Inclusion and exclusion criteria

[0053] 1) Inclusion criteria

[0054] Age 18 to 65 years old; oral glucose tolerance test (venous plasma glucose): the following two conditions are met at the same time: fasting blood sugar <7.0mmol / L, 2-hour postprandial blood sugar: 7.8mmol / L≤2hOGTT blood sugar <11.1mmol / L; no use of Western medicine, Chinese medicine, or acupuncture to control blood sugar (or the treatment method has been stopped for 2 weeks); willing to be randomly assigned to the active and passive intervention technology group and the control group; voluntarily participate in the trial and sign the informed consent form.

[0055] 2) Exclusion criteria

[0056] Patients diagnosed with diabetes; pregnant or lactating women; patients taking benzodiazepines or antipsychotics and receiving corticosteroids or other immunosuppressants; patients with severe primary diseases of the heart, brain, and hematopoietic system, severe liver and kidney damage, malignant tumors, lung infections, and other diseases that may affect this study; patients with ear ulcers, clear ear diseases, and skin allergies to adhesive tape; patients undergoing auricular acupuncture treatment within the past 3 months; patients with cognitive dysfunction and inability to communicate; patients deemed unsuitable for clinical trials by doctors; and patients currently participating in clinical trials of other drugs or external treatments.

[0057] (5) Exit criteria

[0058] Target patients with impaired glucose tolerance who have developed diabetes and require western medicine control; patients who have adverse reactions to auricular acupoint pressure pills; patients who have adverse reactions to Xiaoke Drink; those who withdraw consent; those who are lost to follow-up; those who have serious adverse events; and those who become pregnant during the trial.

[0059] (6) Elimination criteria

[0060] Those with extremely poor compliance who do not accept the intervention treatment as required; those who use other related drugs or treatments on their own and regularly use other means of treatment during the intervention period; those who should not be included in the group but have been included should be excluded, including: those who are mistakenly included, misdiagnosed, or have no scale assessment records; those who actively request to withdraw and refuse to provide relevant information required by the project. Those who meet any of the above items will have their data excluded.

[0061] (7) Patient information collection process

[0062] Fasting and postprandial blood glucose levels should be measured at each visit. Oral glucose tolerance test (OGTT) is used for testing. Starting from 7 to 9 am, the subjects take 75g of anhydrous glucose powder dissolved in 300ml of water after fasting (8 to 10 hours). If 1 molecule of water glucose is used, it is 82.5g. The sugar solution should be consumed within 5 minutes. The time starts from the first sip of sugar, and blood glucose is measured on the forearm before and 2 hours after taking sugar. During the test, the subjects do not drink tea or coffee, do not smoke, and do not do strenuous exercise, but they do not need to stay in bed absolutely. Blood samples should be sent for testing as soon as possible. Within 3 days before the test, the daily carbohydrate intake should be no less than 150g. Drugs that may affect OGTT, such as contraceptives, diuretics, or phenytoin sodium, should be discontinued for 3 to 7 days before the test. The determination of TCM constitution refers to the standard of "Classification and Determination of TCM Constitution" (ZYYXH / T157-2009) formulated and promulgated by the Chinese Association of Traditional Chinese Medicine in 2009, including 9 types of constitutions, including peaceful constitution and partial constitution (Qi deficiency constitution, Yang deficiency constitution, Yin deficiency constitution, phlegm-damp constitution, damp-heat constitution, blood stasis constitution, Qi stagnation constitution, and special constitution). The diabetes symptom grading and quantitative table includes 24 items, and each symptom is graded into four categories: none, mild, moderate, and severe. The Hamilton Depression Rating Scale has 17 items, each with a score of 0-4. A total score of <8 points is considered normal, a total score of 8-20 points is considered possible depression, a total score of 20-35 points is considered certain depression, and a total score of >35 points is considered severe depression. The Hamilton Anxiety Rating Scale has 14 items, each with a score of 0-4. The total score can better reflect the severity of the disease. According to the data provided by the National Scale Collaboration Group, a total score of more than 29 points may indicate severe anxiety; more than 21 points indicates obvious anxiety; more than 14 points indicates anxiety; more than 7 points indicates possible anxiety; and if the score is less than 6 points, the patient has no anxiety symptoms. The general cut-off score is 14 points for the 14-item HAMA.

[0063] (8) Sample size calculation

[0064] Referring to the sample size requirements for Phase III clinical trials in the Drug Registration Management Measures, 360 cases were included in the trial group and 120 cases in the control group according to a 3:1 ratio. Taking into account the 20% dropout rate, it was finally determined that 500 cases would be included.

[0065] (9) Random setting method

[0066] The central randomization system (CRS) is a computer information system used for random allocation, subject management, drug management and other services in multicenter clinical trials. At present, randomization has become one of the basic principles that must be followed in clinical trials. In clinical research, the correct implementation of true random allocation is the key to clinical trials, and the correct use of random grouping is the guarantee for obtaining initial comparability between comparison groups and avoiding selective bias. The fundamental purpose of dynamic randomization is to adjust the grouping of enrolled individuals by considering the number and weight of factors (factors that need to be controlled) and the distribution of enrolled individuals on these stratification factors, so as to ensure that the intervention group and the control group are balanced on these stratification factors.

[0067] This study is based on a self-developed technology platform. With the support of smartphones and computer network technology, a one-click dynamic random algorithm based on the linkage between the smartphone operation terminal and the Internet management terminal was developed to achieve real-time one-click grouping of subjects under the random principle. That is, during the clinical trial, the probability of each patient being assigned to each group is not fixed, but adjusted according to certain conditions. The platform-based dynamic random grouping algorithm can effectively ensure that the number of cases and some important non-treatment factors between the experimental groups are close to the same. When it is necessary to limit random grouping by certain factors to ensure balance, the purpose of stratified randomization is to ensure the balance between the experimental group and the stratification based on covariate factors, and before the start of the trial, a randomization list is generated in each stratum.

[0068] (10) Active and Passive Intervention Schemes

[0069] The control group of 137 cases was given health education + placebo; the experimental group of 395 cases was given health education + Xiaokeyin (the Chinese medicine composition of the present invention)

[0070] 1) Health education: ①Diet plan: even distribution of staple and non-staple food, regular and quantitative, coarse and fine food, whole grains and beans account for 1 / 3; eat more vegetables and fruits in moderation, with a variety of colors; eat fish, poultry, eggs, livestock and lean meat in moderation, do not eat processed meat, avoid frying, grilling, and pickling, use less oil, steaming, stir-frying, and stewing, and do not use starch to thicken; have dairy products and beans every day, and choose snacks and meals reasonably; eat a light diet, drink as much water as possible, limit tobacco and alcohol, and do not drink beverages; order of meals: eat vegetables first, then meat, and finally staple food. Do not eat too fast, it is recommended to chew slowly. ②Healthy exercise: Goal: For overweight or obese people, make the BMI reach or approach 24kg / m 2 Or reduce initial body weight by at least 5% within 3 to 6 months and maintain it at a healthy level for a long time. Exercise time: 30 minutes after each meal and 30 minutes of activity.

[0071] 2) Chinese herbal medicine for conditioning body (Xiao Ke Yin): Produced uniformly by Jiangxi Baoli Pharmaceutical Co., Ltd., made into granules, 1 packet / time (each packet contains 10g of Xiao Ke Yin granules), 2 times / day.

[0072] The specific preparation process of the thirst-quenching drink is as follows:

[0073] (1) By weight, 10 parts of wine polygonatum, 5 parts of yam, 5 parts of raw hawthorn, 4.5 parts of angelica, 4.5 parts of polygonatum, 4.5 parts of mulberry leaves, 3 parts of kudzu root, 3 parts of reed root and 2 parts of stir-fried gardenia are decocted in water for extraction twice, 10 times the amount of water is added for the first time, and the decoction is performed for 1.5 hours, and 8 times the amount of water is added for the second time, and the decoction is performed for 1 hour, and then the filtrates are combined; the filtrate is centrifuged and filtered through a 300-mesh polyester cloth or a plate and frame filter, and the filtrate is concentrated under reduced pressure to a clear paste with a relative density of 1.25-1.30 (60° C.);

[0074] (2) adding dextrin and xylitol in a mass ratio of 6.5:1 as excipients, wherein the mass ratio of dextrin to the clear paste obtained in step (1) is 1:1-1:1.2, using stevioside and citric acid as flavor correctors, and using 90%-95% ethanol solution as a wetting agent to perform wet granulation to obtain Xiaoke Drink.

[0075] 3) Placebo: provided by Jiangxi Poly Pharmaceutical Co., Ltd. based on the taste and color of Xiaoke Drink.

[0076] (11) Efficacy evaluation criteria

[0077] The main efficacy indicators were blood glucose 2 hours after the oral glucose tolerance test, the conversion rate of the number of people who turned into diabetes after the oral glucose tolerance test, and the conversion rate of the number of people who turned into impaired fasting blood glucose and normal blood glucose after the oral glucose tolerance test. Glycated hemoglobin and four blood lipids were secondary efficacy indicators. Other indicators included the physical fitness score table, the diabetes symptom grading and quantification table, the Hamilton Depression Rating Scale (HAMD), and the Hamilton Anxiety Rating Scale (HAMA) (see Table 26).

[0078] Table 26 Observation time points of clinical research indicators of impaired glucose tolerance

[0079]

[0080] (12) Safety evaluation indicators

[0081] Measure and record vital signs and clinical laboratory data at baseline (before the first treatment) and after 12 weeks of treatment. Collect fasting blood samples at baseline and 12 weeks. All events that are not related to the purpose of treatment in clinical trials, including symptoms, laboratory or special examination abnormalities, should be accurately recorded and followed up. Safety evaluation indicators (blood and urine routine, liver and kidney function, electrocardiogram, adverse drug events, etc.)

[0082] Adverse events refer to all adverse medical events that occur after the subjects receive the trial drug. They can be manifested as symptoms, signs, diseases or laboratory test abnormalities, but they may not necessarily be inferred to have a clear causal relationship with the trial drug. All adverse events or other symptoms and signs that occur during the study should be recorded in the adverse event page of the case report form, regardless of whether it is related to the clinical trial.

[0083] (13) Clinical research quality control plan

[0084] Register with the China Clinical Trial Registry, establish a Clinical Event Review Committee (CEC) and a Data Safety Monitoring Committee (DSMB) independent of the study, hire clinical monitors, and ensure that the study is conducted in strict accordance with the requirements of Good Clinical Practice (GCP). During the study, a standardized operating procedure (SOP) was developed, and researchers from each center were trained uniformly to ensure homogeneity among different researchers. During each visit, the observing doctor recorded in detail whether the patient took the medicine on time, and recovered the remaining medicine from the patient to determine the patient's compliance with the medication. Medication compliance = actual total amount of medication / total amount of medication required by the protocol × 100%. Researchers should adopt standard operating procedures to ensure the quality control of clinical trials and the implementation of quality assurance systems. Before and during the trial, participating units should train their respective staff participating in the trial to make them familiar with and proficient in standard operating procedures.

[0085] (14) Data Statistical Methods

[0086] For the primary efficacy indicators, this embodiment performed full analyses set (FAS) and per-protocol analyses (PPS) analyses. The FAS set is defined as all randomized participants with a baseline and at least one efficacy assessment, and the per-protocol set includes all subjects who successfully completed the entire trial according to the study protocol. Based on previous experience, for missing data, this embodiment uses the last observation carryforward method to supplement. Safety analysis includes all participants who were randomized and received at least one dose of the designated study drug. Continuous data were compared by t-test or non-parametric test, and categorical data were compared by χ2 test or Fisher's exact test.

[0087] 2. Research Results

[0088] (1) Basic characteristics of the baseline population

[0089] A total of 532 subjects were screened for the study, of which 4 did not meet the inclusion criteria, 45 had incomplete data, and 483 were included in the FAS set and randomly assigned to the treatment group (Xiao Ke Yin + Ear Point Pressing Pills, n = 363) or the control group (placebo group, n = 120). During the follow-up, 40 people dropped out, and 443 people were included in the PPS set, including 328 in the experimental group and 115 in the control group. Specifically, there were 185 males and 298 females in the FAS set. The average age was 47.99 ± 11.34 years old, and the average body mass index was 24.43 ± 3.67 kg / m 2 The average fasting blood glucose was 5.83±0.64mmol / L, the average 2-hour postprandial blood glucose was 9.06±1.0mmol / L, and the average glycosylated hemoglobin was 5.64±0.58%. There was no difference in the baseline between the experimental group and the control group, and the baseline was comparable (see Table 27 for details).

[0090] A total of 443 subjects were included in the study group, including 328 subjects in the experimental group and 115 subjects in the control group, including 171 males and 272 females. The average age was 47.95±11.39 years old, and the average body mass index was 24.42±3.59 kg / m 2 , the average fasting blood glucose was 5.84±0.64mmol / L, the average 2-hour postprandial blood glucose was 9.06±0.99mmol / L, and the average glycosylated hemoglobin was 5.65±0.57. There was no difference in the baseline between the experimental group and the control group, and the baseline was comparable (see Table 27 and Table 28).

[0091] Table 27 FAS baseline status of impaired glucose tolerance

[0092]

[0093] *P<0.05, ** P<0.01

[0094] Table 28 PPS baseline status of impaired glucose tolerance

[0095]

[0096]

[0097] * P<0.05, ** P<0.01

[0098] (2) Center effect analysis

[0099] 1) Analysis of effectiveness of main efficacy indicators

[0100] Since the subjects of this study were subjects with impaired glucose tolerance, fasting blood glucose <7.0mmol / L and 7.8mmol / L≤2h blood glucose after sugar load <11.1mmol / L, the range of blood glucose fluctuation was small, and the clinical evaluation of the effectiveness of impaired glucose tolerance was not unified. Combined with clinical experience, this study used a drop in postprandial blood glucose of more than 1mmol / L as the effective evaluation standard. FAS set analysis showed that there was no difference in samples from different experimental groups (P>0.05). However, PPS set analysis showed that the effectiveness of samples from different experimental groups was significant (chi=4.931, P=0.026<0.05). By comparing the difference in percentage, it can be seen that the proportion of ineffectiveness in the control group was 62.50%, which was significantly higher than the proportion of ineffectiveness in the experimental group of 54.30%. The effective proportion of the experimental group was 45.73%, which was significantly higher than the proportion of 37.50% in the control group (see Table 29 and Table 30).

[0101] Table 29 Main efficacy indicators of FSA set for impaired glucose tolerance

[0102]

[0103] *P<0.05, **P<0.01

[0104] Table 30 Main efficacy indicators of PPS set for impaired glucose tolerance

[0105]

[0106] *P<0.05, **P<0.01

[0107] 2) Center effect test

[0108] The present invention respectively counts the number of effective hypoglycemic patients in each sub-center, and the effective rate of the test group of Dongzhimen Hospital is 40.38%, and the effective rate of the control group is 37.50%, the effective rate of the test group of Dongfang Hospital is 36.00%, and the effective rate of the control group is 31.25%, the effective rate of the test group of the Third Affiliated Hospital of Beijing University of Chinese Medicine is 45.65%, and the effective rate of the control group is 14.29%, the effective rate of the test group of Zaozhuang Hospital of Beijing University of Chinese Medicine is 40.00%, and the effective rate of the control group is 29.17%, the effective rate of the test group of Shenzhen Hospital of Beijing University of Chinese Medicine is 33.33%, and the effective rate of the control group is 33.33%, the effective rate of the test group of Xiamen Traditional Chinese Medicine Hospital is 42.86%, and the effective rate of the control group is 50.00%, the effective rate of the test group of Sun Simiao Hospital of Beijing University of Chinese Medicine is 57.61%, and the effective rate of the control group is 48.48%, the effective rate of the test group of Ophthalmology Hospital of China Academy of Chinese Medical Sciences is 50.00%, and the effective rate of the control group is 75.00%. The results of the Breslow-Day odds ratio homogeneity test showed that the Breslow-Day odds ratio homogeneity test did not show significance (chi=5.105, P=0.647>0.05), which means that the relationships between the layers are homogeneous and there is no confounding effect between the stratification factors. The results of the Cochran-Mantel-Haenszel conditional independence test showed that the Cochran-Mantel-Haenszel conditional independence test did not show significance (chi=2.037, P=0.154>0.05), which means that after considering the interference factors, there is no significant difference between the test groups and the effectiveness (see Table 31, Table 32, Table 33).

[0109] The results of the per-protocol analysis showed that the Breslow-Day odds homogeneity test did not show significance, there was no confounding effect between the stratification factors (centers), and the Cochran-Mantel-Haenszel conditional independence test showed significance (chi=5.000, P=0.025<0.05), which means that after considering the interference factor of center stratification, there was still a significant difference in effectiveness between the experimental group and the control group (see Table 34, Table 35, Table 36).

[0110] Table 31 Comparison of the efficacy of each center in the FAS set for impaired glucose tolerance

[0111]

[0112] Table 32 Impaired glucose tolerance FAS set odds ratio homogeneity test (Breslow-Day-Tarone)

[0113] χ2 df P 5.1050 7 0.6472

[0114] Table 33 Cochran-Mantel-Haenszel conditional independence test for impaired glucose tolerance FAS set

[0115] OR value (Mantel-Haenszel Common) 95% CI χ2 df P 0.7136 0.4645～1.0963 2.0370 1 0.1535

[0116] * P<0.05, ** P<0.01

[0117] Table 34 Comparison of effective rates of PPS for impaired glucose tolerance in each center

[0118]

[0119] Table 35 PPS set odds homogeneity test for impaired glucose tolerance (Breslow-Day-Tarone)

[0120] χ2 df P 4.7332 7 0.6925

[0121] * P<0.05, ** P<0.01

[0122] Table 36 Cochran-Mantel-Haenszel conditional independence test for impaired glucose tolerance PPS set

[0123] OR value (Mantel-Haenszel Common) 95% CI χ2 df P 0.5871 0.3767～0.9152 4.9995 1 0.0254

[0124] * P<0.05, ** P<0.01

[0125] (3) Analysis of efficacy indicators

[0126] 1) Outcome indicators

[0127] For the efficacy indicators of fasting blood glucose, 2h postprandial blood glucose, and glycosylated hemoglobin, the FAS set analysis before and after the intervention showed that there was no significant difference in the indicators between the groups (P>0.05). The statistical analysis within the experimental group showed that there were differences in the data of 2h postprandial blood glucose and glycosylated hemoglobin (P<0.05). The specific analysis showed that the baseline 2h postprandial blood glucose and the 12-week 2h postprandial blood glucose showed a significant difference at the 0.01 level (P=0.000), and the average value of the baseline 2h postprandial blood glucose was 9.01mmol / L, which was significantly higher than the average value of 8.59mmol / L of the 12-week 2h postprandial blood glucose. The baseline glycosylated hemoglobin and the 12-week glycosylated hemoglobin showed a significant difference at the 0.01 level (P=0.002), and the average value of the baseline glycosylated hemoglobin was 5.66%, which was significantly higher than the average value of 5.60% of the 12-week glycosylated hemoglobin. Intra-group analysis of the control group showed that there was a significant difference at the 0.05 level between baseline 2h postprandial blood glucose and 12-week 2h postprandial blood glucose (P=0.031). The average baseline 2h postprandial blood glucose was 9.21mmol / L, which was significantly higher than the average 12-week 2h postprandial blood glucose of 8.79mmol / L.

[0128] After the intervention, the analysis of the number of people with blood sugar recovery showed that 165 people (44.6%) in the experimental group recovered normal glucose tolerance, and 53 people (14.6%) progressed to diabetes, while 45 people (37.5%) in the control group recovered normal glucose tolerance, and 20 people (16.7%) progressed to diabetes. There was no significant difference between the groups (P>0.05) (see Table 37).

[0129] Table 37 FAS outcome indicators for impaired glucose tolerance

[0130]

[0131] * P<0.05, ** P<0.01

[0132] At the same time, the per-protocol analysis was performed, and there was no significant difference between the groups (P>0.05). The intra-group analysis of the experimental group showed that there were differences in the 2h postprandial blood glucose and glycosylated hemoglobin data (P<0.05). The baseline 2h postprandial blood glucose and the 12-week 2h postprandial blood glucose showed a significant difference at the 0.01 level (P=0.000), and the average value of the baseline 2h postprandial blood glucose was 9.01mmol / L, which was significantly higher than the average value of 8.52mmol / L of the 12-week 2h postprandial blood glucose. The baseline glycosylated hemoglobin and the 12-week glycosylated hemoglobin showed a significant difference at the 0.01 level (P=0.003), and the average value of the baseline glycosylated hemoglobin was 5.66%, which was significantly higher than the average value of 5.60% of the 12-week glycosylated hemoglobin. The intra-group analysis of the control group showed that there was no difference (P>0.05).

[0133] After the intervention, the analysis of the number of people with blood sugar recovery showed that the proportion of people in the experimental group who recovered normal glucose tolerance was 48.2%, which was significantly higher than the proportion of people in the control group who recovered normal glucose tolerance was 36.7% (P=0.03). The proportion of people in the experimental group who developed diabetes was 15.5%, which was not significantly different from the proportion of people in the control group who developed diabetes was 17.4% (P=0.643) (see Table 38).

[0134] Table 38 PPS outcome indicators for impaired glucose tolerance

[0135]

[0136] * P<0.05, ** P<0.01

[0137] 2) Individual blood sugar changes

[0138] This example further analyzes the changes in individual blood sugar after meals. The proportion of people whose blood sugar after meals dropped by more than 1mmol / L in the test group (45.73%) was higher than the proportion of people whose blood sugar did not drop (38.6%); while the proportion of people whose blood sugar after meals dropped by more than 1mmol / L in the control group (37.50%) was much lower than the proportion of people whose blood sugar did not drop (46.7%). The PPS set analysis of individual postprandial blood sugar changes obtained similar results, and the proportion of people whose blood sugar dropped by more than 1mmol / L in the test group was significantly higher than that in the control group (P=0.020), and the proportion of people whose blood sugar did not drop in the test group was significantly lower than that in the control group (P=0.016) (see Table 39, Table 40).

[0139] Table 39 Postprandial blood glucose changes in individuals with impaired glucose tolerance FAS group

[0140]

[0141] * P<0.05, ** P<0.01

[0142] Table 40 Postprandial blood glucose changes in individuals with impaired glucose tolerance PPS group

[0143]

[0144] * P<0.05, ** P<0.01

[0145] (4) Other indicators

[0146] 1) Determination of TCM constitution

[0147] TCM constitution was determined for 483 subjects. Among the 483 subjects, phlegm-damp constitution, including combined constitution, appeared 253 times, qi deficiency constitution, 205 cases, yang deficiency constitution, 175 cases, yin deficiency constitution, 151 cases, blood stasis constitution, 140 cases, damp-heat constitution, 112 cases, special constitution, and 74 cases. Among them, 66 cases were basically peaceful constitution, 417 cases were biased constitution, 129 cases were simple biased constitution, and 288 cases had a complex constitution with two or more biased constitutions (see Table 41, Table 42, Table 43).

[0148] Table 41 Frequency distribution of abnormal glucose tolerance

[0149] name Frequency percentage(%) Phlegm-damp constitution 253 52.38 Peaceful 74 15.32 Qi deficiency 205 42.44 Yin deficiency constitution 175 36.23 Yang deficiency constitution 200 41.41 Blood Stasis 140 28.99 Qi stagnation constitution 151 31.26 Moisture and heat 112 23.19 Special qualities 95 19.67

[0150] Table 42 Frequency distribution of single constitution of abnormal glucose tolerance

[0151]

[0152]

[0153] Table 43 Frequency distribution of abnormal glucose tolerance and physical constitution

[0154]

[0155] 2) Symptom analysis

[0156] The frequency statistics of the symptoms of abnormal glucose tolerance in FAS patients showed that, ranked by frequency, the first was forgetfulness, which occurred 338 times, accounting for 69.98%; the second was thirst, which occurred 312 times, accounting for 64.60%; the third was irritability, which occurred 307 times, accounting for 63.56%; the fourth was fatigue, which occurred 293 times, accounting for 60.66%; the fifth was low back pain, which occurred 274 times, accounting for 56.73% (see Table 44).

[0157] Table 44 Frequency statistics of symptoms of impaired glucose tolerance

[0158]

[0159]

[0160] 3) Analysis of anxiety and depression

[0161] The frequency statistics of anxiety and depression in 483 subjects were conducted. The Hamilton Anxiety Rating Scale showed that 71.22% of the subjects had no anxiety, 18.63% had possible anxiety, 0.62% had possible severe anxiety, 7.25% had definitely anxiety, and 2.28% had definitely significant anxiety. The Hamilton Depression Rating Scale showed that 82.19% of the subjects had no depression, 16.15% had possible depression, and 1.66% had definitely depression (see Table 45).

[0162] Table 45 Frequency statistics of Hamilton Anxiety and Depression Rating Scale for Impaired Glucose Tolerance

[0163]

[0164] (5) Safety analysis

[0165] Of the 532 subjects, 483 had taken the study drug and were included in the safety analysis. During this clinical trial, no serious adverse events occurred in all patients. There was no statistical difference between the treatment group and the control group in terms of blood routine, liver function, and blood lipid changes before and after treatment, but there were statistical differences in uric acid and urea nitrogen (see Table 46).

[0166] Table 46 Analysis of safety indicators of impaired glucose tolerance

[0167]

[0168]

[0169] * P<0.05, ** P<0.01

[0170] 3. Analysis and Discussion

[0171] Compared with health education (control group), after 12 weeks of intervention with TCM body-regulating food Xiaokeyin combined with ear acupuncture pills (experimental group) on the basis of health education, there was no significant difference in the FAS group indexes. The intra-group analysis of the experimental group showed that the average value of 2h postprandial blood glucose was 8.59mmol / L in 12 weeks, which was lower than the average value of 2h postprandial blood glucose at baseline of 9.01mmol / L; the average value of glycosylated hemoglobin was 5.60% in 12 weeks, which was lower than the average value of glycosylated hemoglobin at baseline of 5.66%. The intra-group analysis of the control group also showed that the average value of 2h postprandial blood glucose at 12 weeks was 8.79mmol / L, which was significantly lower than the average value of 2h postprandial blood glucose at baseline of 9.21mmol / L. At the same time, the per-protocol analysis was performed, and there was no significant difference between the groups. The intra-group analysis of the experimental group showed that the average 2h postprandial blood glucose of 8.52mmol / L in the 12th week was significantly lower than the average 2h postprandial blood glucose of 9.01mmol / L at the baseline, and the average 12-week glycosylated hemoglobin of 5.60% was lower than the average 5.66% of glycosylated hemoglobin at the baseline. In general, both groups can reduce postprandial blood glucose, and the experimental group is more obvious.

[0172] FAS set analysis showed that the proportion of people who recovered normal glucose tolerance in the experimental group was higher than that in the control group, but there was no significant statistical difference. PPS set analysis showed that the proportion of people who recovered normal glucose tolerance in the experimental group was 48.2%, which was significantly higher than the proportion of people who recovered normal glucose tolerance in the control group (36.7%) (P=0.03). At present, the clinical efficacy evaluation of diabetes is based on the effective standard of fasting and 2h postprandial blood glucose reduction exceeding 20% ​​before treatment. The subjects of this study were subjects with abnormal glucose tolerance, with fasting blood glucose <7.0mmol / L and 7.8mmol / L≤2h blood glucose after sugar load <11.1mmol / L. The range of blood glucose fluctuation was small, and the clinical evaluation of the effectiveness of abnormal glucose tolerance was not unified. Combined with clinical experience, this study used a postprandial blood glucose reduction of more than 1mmol / L as an effective evaluation standard. The FAS set statistical results showed that the proportion of people in the experimental group whose postprandial blood glucose decreased by more than 1mmol / L was higher than the proportion of people whose blood glucose did not decrease, but there was no statistical difference; while the proportion of people in the control group whose postprandial blood glucose decreased by more than 1mmol / L was much lower than the proportion of people whose blood glucose did not decrease. Similar results were obtained in the analysis of the protocol set, and the proportion of people whose blood sugar dropped by more than 1mmol / L in the experimental group was significantly higher than that in the control group (P=0.02), and the proportion of people whose blood sugar did not drop in the experimental group was significantly lower than that in the control group (P=0.016). At the same time, no serious adverse events occurred during the implementation of this study.

[0173] The study of the present invention is the first study to use TCM body-regulating foods combined with TCM characteristic technologies to intervene in impaired glucose tolerance. TCM diet therapy and TCM characteristic technologies are important components of TCM, and are also methods often recommended by TCM clinics for patients with mild hyperglycemia to reduce symptoms related to hyperglycemia, but their specific efficacy and safety in lowering blood sugar still need to be clarified. This study is the first placebo-controlled clinical trial to explore the hypoglycemic efficacy and safety of Xiaokeyin, a food-modulating food with the same origin as medicine. The results show that for people with impaired glucose tolerance, on the basis of health education, the application of Xiaokeyin combined with auricular acupuncture pills has the effect of lowering postprandial blood sugar, and no adverse events occurred during the 12-week treatment period. The applicant observed that compared with the ordinary health education group, the postprandial blood sugar level of subjects with impaired glucose tolerance decreased when the combined intervention scheme was used for treatment, but there was no significant difference in fasting blood sugar between the two groups. The baseline analysis showed that fasting blood sugar was roughly around 5-6mmol / L, and the fluctuation range of fasting blood sugar was small, so there was no significant difference in fasting blood sugar changes. At the same time, the applicant also found that no hypoglycemia occurred during the study, indicating that the use of the combined scheme is safe and effective for the initial treatment of people with impaired glucose tolerance.

[0174] Chinese Herbal Medicine Tianqi Reduces Progression From ImPairedGlucose Tolerance to Diabetes: A Double-Blind, Randomized, Placebo-Controlled, Multicenter Trial is a double-blind, randomized, placebo-controlled, multicenter trial. IGT patients were randomly assigned to receive the trial group (n=210) or placebo (n=210) in a double-blind manner, and an oral glucose tolerance test was performed every 3 months to evaluate the development of diabetes or recovery to normal glucose tolerance. All subjects received the same lifestyle education, and the primary endpoint was the transformation of IGT to T2DM. The results showed that after the 12-month trial, 389 of the 420 IGT subjects completed the trial (198 in the trial group and 191 in the placebo group), 36 subjects in the trial group (18.18%) and 56 subjects in the placebo group (29.32%) developed diabetes (P=0.01), and there was a significant difference in the number of subjects with normal glucose tolerance between the trial group and the placebo group (n=125, 63.13% and n=89, 46.60%, respectively; P=0.001). The results of the present invention show that it is feasible to start hypoglycemic treatment for people with impaired glucose tolerance using a simple and inexpensive method of traditional Chinese medicine, which can help people with impaired glucose tolerance restore normal glucose tolerance. It is necessary to further implement clinical trials on hypoglycemic treatment for people with impaired glucose tolerance.

[0175] Analysis of subjective scale indicators showed that among 483 subjects with glucose tolerance, including those with combined constitutions, phlegm-damp constitution appeared 253 times, indicating that patients with abnormal glucose tolerance have phlegm-damp constitution in the biased constitution, which is consistent with the research results of Sun Hongfeng, Meng Xianghe, etc. As for the clinical symptoms of abnormal glucose tolerance, the results showed that the top ten symptoms were forgetfulness, thirst and love of drinking, irritability, fatigue, back pain, sweating, heavy head and body, insomnia, uncomfortable bowel movements, and frequent urination at night. Among them, forgetfulness symptom appeared most frequently, which is consistent with the research results of Song Xiaoqin, Chai Kefu, etc. Clinical observations also found that people with abnormal glucose tolerance often have manifestations of phlegm-damp constitution such as obesity, poor appetite, sticky mouth, abdominal distension and loose stools. Regarding the pathological mechanisms of impaired glucose tolerance and phlegm-dampness constitution, Pang Guoming et al. found that the insulin secretion function of people with phlegm-dampness constitution is still good, but the insulin resistance is more obvious. One of the main causes of impaired glucose tolerance is insulin resistance, which shows that phlegm-dampness constitution and impaired glucose tolerance have a common modern pathological basis, namely insulin resistance. Tan Chaojian et al. used acupuncture to regulate patients with phlegm-dampness constitution and impaired glucose tolerance. The results also showed that fasting and postprandial blood sugar and insulin were significantly improved compared with before treatment. After treatment, the improvement of phlegm-dampness constitution in the treatment group was more obvious than that in the control group.

[0176] The results of the Hamilton Anxiety and Depression Rating Scale analysis showed that most patients with impaired glucose tolerance were not accompanied by anxiety and depression, which was inconsistent with the research results of Tang Lei, Xu Jianping, He Jiandong, etc., and was considered to be related to the different scales used in clinical research. The Hamilton Depression and Anxiety Rating Scale is a professional tool for doctors to assess the degree of depression and anxiety. It uses peer evaluation to objectively evaluate the overall condition of the patient, and the score can better reflect the severity of the disease. The self-rating depression scale and the self-rating anxiety scale are scored by patients based on the frequency and degree of their own symptoms, and the score can reflect the severity of the patient's subjective symptoms. The two types of scales evaluate depression and anxiety from a subjective and objective perspective.

[0177] This study shows that, based on health education, the application of traditional Chinese medicine and food homology regulating food Xiaokeyin as an intervention method for patients with impaired glucose tolerance can reduce postprandial blood sugar to a certain extent, restore normal glucose tolerance, slow down the transition from pre-disease state to clinical disease, and reduce medical costs and the economic burden of patients. In addition, ear acupoint pressure pills are easy to operate, green and safe, simple and inexpensive, not limited by time, location and other conditions, easy for subjects to adhere to for a long time, and suitable for large-scale promotion.

[0178] This study has the following advantages: In terms of intervention scheme, the formulation and standardized operation of the comprehensive TCM intervention scheme under the guidance of TCM constitution was completed. Through multi-center, randomized, placebo-controlled clinical trials, it was proved that the TCM food-to-body conditioning food Xiaokeyin combined with ear acupoint pressing pills as an intervention method for patients with impaired glucose tolerance can reduce postprandial blood sugar to a certain extent and restore normal glucose tolerance, providing evidence-based medical evidence for clinical practice. This study also has the following limitations: Although this study was implemented in multiple centers, due to the impact of the epidemic, the number of subjects included in each center was uneven, and the treatment lasted only 12 weeks, the follow-up period was extended, and the follow-up data were incomplete. This study applied a combined scheme, designed 2 groups, and the ear acupoint pressing pill intervention could not be blinded. Therefore, the feasibility of the combined scheme for hypoglycemic treatment of people with impaired glucose tolerance still needs to be further confirmed in future larger-scale, long-term, multi-center, double-blind clinical trials.

[0179] 4. Xiaokeyin + auricular acupoint pressing pills to intervene in impaired glucose tolerance

[0180] (1) Research subjects

[0181] A total of 27 healthy controls (HC), 34 patients with impaired glucose tolerance before treatment (IGTP), and 36 subjects with impaired glucose tolerance after treatment (IGTT) were included in this study. They were recruited from Beijing University of Chinese Medicine, Beijing University of Chinese Medicine Dongzhimen Hospital, Beijing University of Chinese Medicine Oriental Hospital, the Third Affiliated Hospital of Beijing University of Chinese Medicine, and the Eye Hospital of China Academy of Chinese Medical Sciences; the Ethics Committee of Beijing University of Chinese Medicine was entrusted to conduct ethical review and supervision (ethics number: 2021BZYLL0302).

[0182] (2) Observation indicators

[0183] 1) Basic Information

[0184] Including the subject's name, gender, age, ethnicity, blood pressure, blood sugar levels, etc.

[0185] 2) Medical history

[0186] ① History of impaired glucose tolerance (mainly including course of disease, diagnosis and previous treatment, medication, laboratory tests and disease control of the subjects during screening);

[0187] ② History of dry mouth, thirst, sticky mouth, obesity, and emaciation (mainly including duration, associated symptoms, previous treatment, and the subject's disease control during screening);

[0188] ③ Past medical history (including major organs such as the heart, liver, spleen, lungs, and kidneys, as well as history of epilepsy and mental illness; major surgeries must indicate when, where, and what type of surgery was performed, and the current condition);

[0189] ④History of allergy;

[0190] ⑤ History of smoking and drinking;

[0191] ⑥Menstrual and reproductive history.

[0192] 3) Laboratory examination and index determination

[0193] ①OGTT tests fasting blood sugar and blood sugar changes 2 hours after a meal;

[0194] ②OGTT was used to detect fasting insulin and C-peptide levels, and changes in pancreatic islet and C-peptide levels 2 hours after a meal;

[0195] ③Biochemistry, electrocardiogram, glycosylated hemoglobin, four blood lipids, BMI, blood, urine and stool routine tests;

[0196] ⑤16s rDNA sequencing;

[0197] ⑥ Plasma metabolomics;

[0198] ⑦ Plasma proteomics;

[0199] ⑧Peripheral leukocyte mRNA sequencing.

[0200] 4) Scale evaluation

[0201] ① Diabetes symptom grading and quantification table;

[0202] ②Hamilton Depression Rating Scale (HAMD), Hamilton Anxiety Rating Scale (HAMA).

[0203] (3) Research results

[0204] 1) Macro-efficacy indicators

[0205] Xiaokeyin plus auricular acupoint pressing pills can significantly reduce the blood sugar and glycosylated hemoglobin levels 2 hours after meal in patients with impaired glucose tolerance (see Figure 1 ), in the figure, the left side of each index is IGTP, and the right side is IGTT. IGTP is before the intervention of impaired glucose tolerance; IGTT is after the intervention of impaired glucose tolerance. ** P<0.01.

[0206] 2) Micro-efficacy indicators

[0207] ①16S rDNA sequencing

[0208] Xiaokeyin plus auricular acupoint pressing pills can significantly improve the intestinal flora disorder in patients with impaired glucose tolerance, mainly manifested in the changes in α diversity, β diversity and relative abundance of species; with the help of Wilcoxon rank-sum test and MetagenomeSeq analysis, a total of 2 core genera were screened, including Dorae and Butyricicoccus, which can be used as potential genera for the clinical efficacy evaluation of Xiaokeyin plus auricular acupoint pressing pills for impaired glucose tolerance (see Figure 2 ). Figure 2 middle, Figure 2 (A) is α diversity; Figure 2 (B) is β diversity; Figure 2 (C) Cluster heat map of ToP 50Genera abundance; Figure 2 (D) Venn diagram for differential Genera screening; Figure 2 (E) shows the core differential species, HC, IGTP, and IGTT from top to bottom in Dorae and Butyricicoccus. In each group of figures, HC: healthy control; IGTP: before treatment of impaired glucose tolerance; IGTT: after treatment of impaired glucose tolerance. * P<0.05, *** P<0.001.

[0209] ② Plasma metabolomics

[0210] There are 84 potential target metabolites for Xiaokeyin + auricular acupoint pressure pills in the intervention of impaired glucose tolerance, and the functional enrichment involves TCA cycle and NF-kaPPa B signaling pathway (see Figure 3 ). Figure 3 middle, Figure 3 (A) 84 target metabolites of Xiaokeyin + auricular acupoint pressing pills in the treatment of impaired glucose tolerance. Figure 3 (B) Cluster analysis of target metabolites in the treatment of impaired glucose tolerance with Xiaokeyin + auricular acupoint pressing pills. Figure 3 (C) KEGG pathway enrichment analysis of target metabolites of impaired glucose tolerance treated with Xiaokeyin + auricular pressure pills (ToP 20). In each group, HC, healthy control group; IGTP, before treatment of impaired glucose tolerance; IGTT, after treatment of impaired glucose tolerance.

[0211] ③ Peripheral leukocyte mRNA sequencing

[0212] There are 90 potential therapeutic target genes for impaired glucose tolerance treated with Xiaokeyin + auricular acupoint pressing pills. The PPI network suggests that MATN4, COMP, and SDC1 are the core genes for intervention (see Figure 4 ). Figure 4 middle, Figure 4(A) 90 potential target genes for Xiaokeyin + auricular acupoint pressing pills in the treatment of impaired glucose tolerance. Figure 4 (B) PPI network of potential target genes in the treatment of impaired glucose tolerance by Xiaokeyin + auricular pressure pills. HC, healthy control group; IGTP, before treatment of impaired glucose tolerance; IGTT, after treatment of impaired glucose tolerance.

[0213] 3) Safety evaluation

[0214] Xiaokeyin + auricular acupoint pressing pills had no significant effect on blood routine, liver and kidney function, and blood lipid status in patients with impaired glucose tolerance, and the intervention measures were safe (see Figure 5 ). Figure 5 In the figure, the left side of each index is IGTP, and the right side is IGTT. IGTP, before intervention for impaired glucose tolerance; IGTT, after intervention for impaired glucose tolerance.

[0215] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A Chinese medicine composition for treating or improving impaired glucose tolerance, It is characterized in that Calculated by weight, it includes 5-20 parts of wine polygonatum, 1-10 parts of yam, 1-10 parts of raw hawthorn, 1-10 parts of angelica, 1-10 parts of polygonatum, 1-10 parts of mulberry leaves, 1-5 parts of kudzu root, 1-5 parts of reed root and 1-5 parts of stir-fried gardenia.

2. The Chinese medicine composition according to claim 1, It is characterized in that In parts by weight, the Chinese medicine composition comprises 6-15 parts of wine polygonatum, 3-9 parts of yam, 3-9 parts of raw hawthorn, 3-6 parts of angelica, 3-6 parts of polygonatum, 3-6 parts of mulberry leaves, 2-5 parts of kudzu root, 2-5 parts of reed root and 1-3 parts of stir-fried gardenia; Preferably, in parts by weight, the Chinese medicine composition comprises 10 parts of Polygonatum odoratum, 5 parts of yam, 5 parts of raw hawthorn, 4.5 parts of angelica, 4.5 parts of polygonatum odoratum, 4.5 parts of mulberry leaves, 3 parts of kudzu root, 3 parts of reed root and 2 parts of stir-fried gardenia.

3. A Chinese medicine composition for treating or improving impaired glucose tolerance, It is characterized in that Calculated by weight, it includes 5-20 parts of polygonatum sibiricum extract, 1-10 parts of yam extract, 1-10 parts of raw hawthorn extract, 1-10 parts of angelica extract, 1-10 parts of polygonatum odoratum extract, 1-10 parts of mulberry leaf extract, 1-5 parts of kudzu root extract, 1-5 parts of reed root extract and 1-5 parts of stir-fried gardenia extract.

4. The Chinese medicine composition according to claim 3, It is characterized in that In parts by weight, the Chinese medicine composition comprises 6-15 parts of Polygonatum odoratum extract, 3-9 parts of yam extract, 3-9 parts of raw hawthorn extract, 3-6 parts of angelica extract, 3-6 parts of polygonatum odoratum extract, 3-6 parts of mulberry leaf extract, 2-5 parts of kudzu root extract, 2-5 parts of reed root extract and 1-3 parts of stir-fried gardenia extract; Preferably, in parts by weight, the Chinese medicine composition includes 10 parts of Polygonatum odoratum extract, 5 parts of yam extract, 5 parts of raw hawthorn extract, 4.5 parts of angelica extract, 4.5 parts of polygonatum odoratum extract, 4.5 parts of mulberry leaf extract, 3 parts of kudzu root extract, 3 parts of reed root extract and 2 parts of stir-fried gardenia extract.

5. The Chinese medicine composition according to claim 3, It is characterized in that The extract is a decoction extract.

6. The Chinese medicine composition according to claim 3, It is characterized in that The dosage form of the Chinese medicine composition is an oral dosage form, preferably a granule, an oral liquid, a tablet, a syrup or a paste; Preferably, the granules are prepared by wet granulation, wherein the wet granulation uses an ethanol solution with a mass fraction of 70-95% as a wetting agent, preferably an ethanol solution with a mass fraction of 90%-95%.

7. A method for preparing the Chinese medicine composition for treating or improving impaired glucose tolerance according to any one of claims 3 to 6, It is characterized in that The steps include: According to the proportion, wine polygonatum, Chinese yam, raw hawthorn, Chinese angelica, polygonatum odoratum, mulberry leaf, kudzu root, reed root and fried gardenia are extracted by decocting in water, and the medicinal liquids are combined, filtered and concentrated.

8. The preparation method according to claim 7, It is characterized in that The water decoction extraction is performed 1 to 2 times; the first time, 8 to 12 times the amount of water is added and the decoction is performed for 1 to 2 hours; the second time, 6 to 10 times the amount of water is added and the decoction is performed for 1 to 2 hours; Preferably, the concentration is reduced pressure concentration; Preferably, the concentration is to obtain a clear paste with a relative density of 1.25-1.30; Preferably, the filtration is centrifugal filtration or plate and frame filtration.

9. The preparation method according to claim 8, It is characterized in that The cream yield of the clear cream is in the range of 20-25%.

10. Use of the Chinese medicine composition according to claim 1 or claim 3 in the preparation of a medicament for treating or improving impaired glucose tolerance.

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