CN115281345A - Application of composite probiotic composition in combination with dimethylguanidine to treatment of type II diabetes - Google Patents

Application of composite probiotic composition in combination with dimethylguanidine to treatment of type II diabetes Download PDF

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CN115281345A
CN115281345A CN202210368569.8A CN202210368569A CN115281345A CN 115281345 A CN115281345 A CN 115281345A CN 202210368569 A CN202210368569 A CN 202210368569A CN 115281345 A CN115281345 A CN 115281345A
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optionally
diabetes
probiotic composition
lactobacillus
probio
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包维臣
张建军
其木格苏都
刘晓军
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Jinhua Yinhe Biotechnology Co ltd
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Jinhua Yinhe Biotechnology Co ltd
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Abstract

The invention provides an application of a combined biguanide antidiabetic medicament in preparing foods, health products or medicaments for preventing, relieving, adjunctively treating or treating diabetes, wherein the composite probiotic composition comprises: lactobacillus casei Zhang (Lactobacillus casei Zhang); bifidobacterium lactis V9 (Bifidobacterium animalis subsp. Lactis V9); lactobacillus plantarum P-8 (Lactobacillus plantarum P-8); lactobacillus rhamnosus Probio-M9 (Lactobacillus rhamnosus Probio-M9); and Bifidobacterium lactis Probio-M8 (Bifidobacterium lactis Probio-M8); the composite probiotic composition has the effects of preventing, relieving, and assisting in treating or treating diabetes, and can be combined with metformin to synergistically prevent, relieve, assist in treating or treating diabetes, especially type II diabetes.

Description

Application of composite probiotic composition in combination with dimethylguanidine to treatment of type II diabetes
Technical Field
The invention relates to the technical field of probiotics, in particular to application of a composite probiotic composition in combination with dimethylguanidine to treatment of type II diabetes.
Background
Type ii diabetes is the most common type of diabetes worldwide, accounting for 90-95% of all diabetes. Type II diabetes is non-insulin dependent diabetes, generally has a relatively slow onset, and is common in adults and middle-aged and elderly people. The incidence of type ii diabetes is increasing, has reached epidemic levels, and is becoming younger. The diagnostic criteria for type ii diabetes are: has diabetes symptom and random blood sugar more than or equal to 11.1mmol/L; the fasting blood glucose is more than or equal to 7.0mmol/L; the blood sugar is more than or equal to 11.1mmol/L in two hours during the oral glucose tolerance test. Type II diabetes can be classified into obese type and non-obese type. Obese patients are mainly insulin resistant, and the patients are obese mostly, insulin resistance is reduced, insulin sensitivity is increased in blood to compensate the insulin resistance, but insulin secretion is still insufficient relative to hyperglycemia of the patients. The treatment method generally adopts diet treatment and oral hypoglycemic agent. Non-obese patients are mainly deficient in insulin secretion and need to be clinically supplemented with exogenous insulin. In addition to the problem of insulin resistance, the beta cells in the pancreas produce and secrete reduced insulin. Type ii diabetes is more likely to be associated with other diseases such as atherosclerosis, coronary heart disease, hypertension, obesity and dyslipidemia. Insulin resistance is exacerbated and may directly lead to these problems. Up to now, there is no control of human genetic factors. However, the prevalence of type ii diabetes can be reduced by intervention with environmental factors.
Probiotics have allowed use in the clinical treatment of many diseases, and are generally defined as a general term for a group of active microorganisms that are capable of regulating and improving the intestinal flora, resulting in a clear benefit to the health of the human body, when ingested in sufficient amounts from the diet. In the scientific consensus of probiotics (2020 th edition), the core characteristics of probiotics are "sufficient number, viable status and healthy functions", and therefore, the selection needs to be precise and scientific. The probiotics can directly or indirectly act on intestinal epithelium to exert beneficial effects, balance intestinal flora, and regulate intestinal barrier function and permeability. The composite probiotic composition is in a powder shape, a granular shape or a block shape, and the composite probiotic composition is canned after mixing the probiotic powder and various raw and auxiliary materials, and is convenient to carry and eat.
Metformin, as a biguanide drug, is one of the first choice drugs for treating early-stage type II diabetes, and has good effects of reducing hepatic gluconeogenesis and inhibiting intestinal absorption of sugar. In addition, researchers found that insulin resistance improved after probiotic intake in obese mice on a high-fat diet; the drinking of the probiotic yoghurt can obviously reduce the blood sugar concentration and the glycosylated hemoglobin concentration. At present, no report is available about synergistic treatment of type II diabetes by combining probiotics and metformin.
Disclosure of Invention
Therefore, the technical problem to be solved by the invention is to provide the application of a composite probiotic composition in combination with a biguanide antidiabetic medicament in preparing foods, health products or medicaments for preventing, relieving, adjunctively treating or treating diabetes, wherein the composite probiotic composition can be used for synergistically preventing, relieving, adjunctively treating or treating diabetes, especially type II diabetes, in combination with metformin.
Therefore, the invention provides the following technical scheme:
use of a complex probiotic composition in combination with a biguanide antidiabetic agent in the preparation of a food, health product or medicament for the prevention, alleviation, co-treatment or treatment of diabetes, the complex probiotic composition comprising:
lactobacillus casei Zhang (Lactobacillus casei Zhang) with the preservation number of CGMCC No.5469;
bifidobacterium lactis V9 (CGMCC No. 5470);
lactobacillus plantarum P-8 (Lactobacillus plantarum P-8), with the preservation number of CGMCC No.6312;
lactobacillus rhamnosus Probio-M9 (Lactobacillus rhamnous Probio-M9) with the preservation number of CGMCC No.18639;
bifidobacterium lactis Probio-M8 (Bifidobacterium lactis Probio-M8) with the preservation number of CGMCC No.18610.
Optionally, the total viable count of the probiotic composition is not less than 3.0 × 10 10 CFU/g；
Optionally, the viable count of lactobacillus casei Zhang is not less than 50 hundred million, the viable count of bifidobacterium lactis V9 is not less than 75 hundred million, the viable count of lactobacillus plantarum P-8 is not less than 50 hundred million, the viable count of lactobacillus rhamnosus Probio-M9 is not less than 50 hundred million, and the viable count of bifidobacterium lactis Probio-M8 is not less than 75 hundred million.
Optionally, the viable count of each strain is not less than 6.0 × 10 11 CFU/g；
Optionally, the biguanide antidiabetic agent comprises metformin, sitagliptin phosphate, linagliptin, pioglitazone, phenformin or buformin.
Optionally, the raw material of each strain in the composite probiotic composition comprises any one of a culture, a fermentation product or freeze-dried powder of the strain;
optionally, the raw material of each strain is freeze-dried powder of the strain.
Optionally, the composite probiotic composition further comprises an auxiliary material;
optionally, the auxiliary material is prebiotics and/or dietary fibers;
optionally, the auxiliary material comprises at least one of galacto-oligosaccharide, fructo-oligosaccharide, inulin, polydextrose and maltitol;
optionally, in the composite probiotic composition, the mass ratio of the total bacterial powder to the auxiliary materials is 10-15:85-90.
Optionally, the preparation method of the composite probiotic composition comprises the step of mixing raw materials containing various strains;
optionally, the method further comprises the step of adding auxiliary materials after mixing the raw materials containing the strains.
The application also has the following applications:
(a) The application of the probiotics solid beverage or the functional health care product in the preparation of leaven, fermentation product or probiotic solid beverage;
(b) The application in preparing food, health care products or medicines for improving insulin secretion, reducing blood fat, reducing blood sugar, reducing glycosylated hemoglobin content, reducing uric acid content or improving pancreatic island function;
(c) The application of the extract in preparing food, health-care products or medicines for preventing, relieving, assisting in treating or treating gout.
Optionally, the diabetes is type 2 diabetes;
optionally, the alleviating diabetes comprises alleviating the risk of developing diabetes;
optionally, in order to alleviate the risk of type 2 diabetes;
optionally, the food product comprises a traditional food, a health food or an adjuvant therapeutic food composition.
Optionally, the preventing, alleviating, adjunctively treating or treating diabetes comprises increasing insulin secretion, lowering blood glucose, lowering glycosylated hemoglobin content, lowering uric acid content, lowering blood lipid, or improving pancreatic islet function.
Optionally, in the (a), the fermented product includes a bean product, a dairy product or a fruit and vegetable product.
A composition for the prevention, alleviation, co-treatment or treatment of diabetes comprising:
a complex probiotic composition as described in any one of claims 1 to 9; and
biguanide antidiabetic drugs;
optionally, 1-2 parts by weight of the composite probiotic composition and 1-2 parts by weight of biguanide antidiabetic medicine;
optionally, 2 parts by weight of the composite probiotic composition and 1.5 parts by weight of biguanide antidiabetic medicine;
optionally, the biguanide antidiabetic agent comprises metformin, sitagliptin phosphate, linagliptin, pioglitazone, phenformin or buformin.
The technical scheme of the invention has the following advantages:
1. the invention provides an application of a composite probiotic composition in combination with a biguanide antidiabetic medicament in preparing foods, health products or medicaments for preventing, relieving, adjunctively treating or treating diabetes, wherein the composite probiotic composition comprises the following components in parts by weight: lactobacillus casei Zhang (Lactobacillus casei Zhang) with the preservation number of CGMCC No.5469; bifidobacterium lactis V9 (Bifidobacterium animalis subsp. Lactis V9) with a preservation number of CGMCC No.5470; lactobacillus plantarum P-8 (Lactobacillus plantarum P-8), with the preservation number of CGMCC No.6312; lactobacillus rhamnosus Probio-M9 (Lactobacillus rhamnous Probio-M9) with the preservation number of CGMCC No.18639; and Bifidobacterium lactis Probio-M8 (Bifidobacterium lactis Probio-M8) with the preservation number of CGMCC No.18610; the composite probiotic composition and the biguanide antidiabetic medicament have the effects of synergistically preventing, relieving and assisting in treating or treating diabetes, especially type II diabetes.
Furthermore, in the composite probiotic composition, lactobacillus casei Zhang, bifidobacterium lactis V9, lactobacillus plantarum P-8, lactobacillus rhamnosus Probio-M9 and bifidobacterium lactis Probio-M8 have good intestinal colonization capacity.
Furthermore, the composite probiotic composition can be combined with metformin to synergistically prevent, relieve, assist in treatment or treatment of gout.
2. The total viable count of the composite probiotic composition is not less than 3.0 x 10 10 CFU/g, viable count of each strain is not less than 6.0 × 10 11 CFU/g; under the condition of the viable count, the composite probiotic composition provided by the invention has the beneficial effects of regulating intestinal flora, preventing diarrhea and constipation, enhancing immunity and the like.
3. The composite probiotic composition provided by the invention is combined with a biguanide antidiabetic medicament, and has the application in preparing foods or medicaments for preventing, relieving, adjunctively treating or treating diabetes or gout.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.
FIG. 1 is a graph showing the change of glycated hemoglobin in blood of a probiotic group and a placebo group at 0 month (0M) and 3 months (3M) in the change of physicochemical indexes of blood glucose in the experimental example of the present invention; in the figure, p < 0.01, with significant differences;
FIG. 2 shows the change of uric acid content in blood of 0 month and 3 months in the experiment of changing uric acid content in the probiotic group and the placebo group; in the figure, p < 0.01, with significant differences;
FIG. 3 shows the change of uric acid content in blood of the probiotic group and the placebo group in the experiment of uric acid content change in the experimental example of the present invention for 0 month and 3 months;
FIG. 4 is a graph showing the change of high density low density lipoprotein (HDL-CH) in blood serum of the probiotic group and the placebo group at 0 month and 3 months in the experiment for the change of lipid physicochemical index in the experimental example of the present invention;
fig. 5 shows the change of fasting blood glucose, blood glucose at 0.5h, blood glucose at 1h, blood glucose at 2h and blood glucose at 3h in the blood of the probiotic group and the placebo group in the blood glucose and glucose tolerance analysis experiment in the experimental example of the present invention.
FIG. 6 is an insulin curve of oral glucose tolerance test in probiotic group versus placebo group in the insulin related index change experiment of the experimental example of the present invention.
Detailed Description
The following examples are provided to better understand the present invention, not to limit the best mode, and not to limit the content and protection scope of the present invention, and any product that is the same or similar to the present invention and is obtained by combining the present invention with other features of the prior art and the present invention falls within the protection scope of the present invention.
The examples do not show the specific experimental steps or conditions, and can be performed according to the conventional experimental steps described in the literature in the field. The reagents or instruments used are not indicated by manufacturers, and are all conventional reagent products which can be obtained commercially.
Lactobacillus casei Zhang is 1 strain of probiotics with various probiotic functions separated from natural fermented mare milk in inner Mongolia grassland in 2002, is the probiotic bacteria for completing whole genome sequencing of the 1 st strain in China, has been preserved in 2011 at 11/18 days, is preserved in China general microbiological culture Collection center of China Committee for culture Collection of microorganisms, and has the preservation address of No. 3 Xilu-Shi-1, beijing, the rising area of Beijing, and the preservation numbers are: CGMCC No.5469. The experimental research shows that: and L, casein Zhang intervention can accelerate fatty acid oxidation so as to play a role in reducing blood fat. The clinical evidence-based research shows that L.casei Zhang increases the level of anti-inflammatory factors in blood and enhances the immune response to influenza viruses, and the flora analysis result shows that the intestinal flora of the old can be younger.
Bifidobacterium lactis V9 (Bifidobacterium animalis subsp. Lactis V9) is 1 strain of probiotic bacteria separated from intestinal tracts of healthy Mongolian children in 2005, and is preserved in China general microbiological culture Collection center at 11-18 days 2011, with the preservation address of No. 3 Xilu No.1 North Chen of the Yangzhou region in Beijing city, and the preservation numbers are: CGMCC No.5470. Genomics researches find that the strain has extremely low probability of recombination and mutation and stable heredity. The experimental study shows that: the lactis V9 has obvious antagonistic action on intestinal pathogenic bacteria, can improve the capability of resisting pathogenic bacteria infection of the intestinal tract, obviously improve the recovery rate of diarrhea, can effectively treat the diarrhea and can make the intestinal flora structure of a human body healthy.
Lactobacillus plantarum P-8 (Lactobacillus plantarum P-8) is 1 Lactobacillus plantarum with excellent probiotic properties isolated in 2005 from the natural fermented yoghurt sample of the hermink family in the Bayangtze Bayankeen. Has been preserved in China general microbiological culture Collection center at 28.06.2012, the preservation address of No. 3 Xilu No.1, north Cheng of the south Kogyo area, beijing city, with the preservation numbers: CGMCC No.6312. The experimental study shows that: l. plantarum P-8 has excellent gastric acid, intestinal juice and bile salt tolerance and good stability. Can improve lipid metabolism, reduce blood lipid, improve immunity, relieve anxiety, and improve cognitive ability.
Lactobacillus rhamnosus Probio-M9 (Lactobacillus rhamnous Probio-M9) was isolated from breast milk of healthy women in 2017. Has been preserved in China general microbiological culture Collection center in 8.10.2019, the preservation address is No. 3 Xilu No.1 of the Chaoyang district, beijing, and the preservation numbers are: CGMCC No.18639. Has effects in regulating intestinal flora homeostasis, and resisting tumor.
Bifidobacterium lactis Probio-M8 (Bifidobacterium lactis Probio-M8) was isolated from breast milk of healthy women in 2017. Has been preserved in China general microbiological culture Collection center at the general microbiological culture Collection center of China general microbiological culture Collection center at 2019, no. 3 of Xilu No.1 of Beijing, chaoyang, with the preservation numbers: CGMCC No.18610. Has the functions of regulating intestinal flora homeostasis, relieving allergy, improving sleep, etc.
The preparation method of each probiotic powder in the following examples comprises the following steps:
1) Activation of strains: respectively inoculating strains (Lactobacillus casei Zhang, bifidobacterium lactis V9, lactobacillus plantarum P-8, lactobacillus rhamnosus Probio-M9 and Bifidobacterium lactis Probio-M8) which are frozen and preserved at the temperature of-40 ℃ into corresponding liquid culture media sterilized at the temperature of 121 ℃ for 15min, and carrying out anaerobic culture at the temperature of 37 ℃ for 18-24h, thus carrying out subculture for 1-2 times to obtain activated strains; the liquid culture medium corresponding to lactobacillus (Lactobacillus casei Zhang, lactobacillus plantarum P-8, lactobacillus rhamnosus Probio-M9) is MRS liquid culture medium, and the liquid culture medium corresponding to Bifidobacterium (Bifidobacterium lactis V9 and Bifidobacterium lactis Probio-M8) is TPY liquid culture medium.
2) Preparation of an optimized culture medium:
preparing the components of the optimized culture medium in proportion, uniformly mixing, adjusting the pH value to 6.5,121 ℃ and sterilizing for 15min;
the optimized culture medium of bifidobacterium (bifidobacterium lactis V9 and bifidobacterium lactis Probio-M8) comprises the following components: 12.0Kg of lactose, 7.0Kg of beef extract, 7.0Kg of yeast powder, 12.0Kg of casein peptone, 7.0Kg of soybean peptone, KH 2 PO 4 4.0Kg，K 2 HPO 4 1.0Kg，MgSO 4 0.05Kg, tween-800.15Kg, L-cysteine hydrochloride 0.7Kg, calcium carbonate 1.2Kg, and distilled water 1000L.
The optimized culture medium of the lactobacillus (Lactobacillus casei Zhang, lactobacillus plantarum P-8 and Lactobacillus rhamnosus Probio-M9) comprises the following components: 23.5Kg of sucrose, 12.0Kg of lactose, 15.0Kg of soyabean peptone, 5.0Kg of yeast powder, 12Kg of yeast peptone, na 2 HPO 3 21.0Kg, 2.0Kg of citric acid, mgSO 2 4 ·7H 2 O0.6Kg，MnSO 4 ·5H 2 0.3Kg of O, 1.0Kg of Tween-80, 0.3Kg of L-cysteine hydrochloride and 1000L of distilled water.
3) Preparing a seed solution:
inoculating each strain activated in the step 1) into the optimized culture medium prepared in the step 2), and stopping anaerobic culture at 37 ℃ until the pH value is 4.5-4.8;
4) Inoculation and fermentation:
inoculating the seed liquid obtained in the step 3) into the optimized culture medium prepared in the step 2) according to 1 per mill, and fermenting for 18 hours under controlled fermentation conditions;
the fermentation conditions are controlled as follows: the first stage is as follows: culturing at 30 deg.C before fermentation, and naturally fermenting until pH is 5.0; and a second stage: then adjusting the fermentation temperature to 37 ℃ for constant-temperature culture, controlling the pH value to keep 6.0, and keeping anaerobic fermentation. The total fermentation time for the first and second stages was 18h.
The pH is controlled by feeding a neutralizing agent, wherein the neutralizing agent is NaOH.
Wherein the anaerobic condition is achieved by passing nitrogen every two hours.
5) Terminating the fermentation
When the bacteria produce acid, the fermentation is stopped to obtain high-density fermentation liquor of each bacterial strain, and the viable count of the fermentation liquor reaches more than 2 multiplied by 1010 cfu/ml.
Wherein, whether the acid production is stopped or not can be judged according to the condition that the pH value is not reduced any more and the feeding of the neutralizing agent is stopped.
6) Freeze drying
a. And (3) thallus concentration: carrying out centrifugal concentration on the high-density fermentation liquor by 12000g to obtain thalli;
b. adding a protective agent: adding a protective agent solution with the volume multiple of 3-8 into the thallus concentrated solution; the protectant solution consisted of: 10-15Kg of skim milk, 8-12Kg of lactose, 1-2Kg of vitamin C, 1-2Kg of sodium glutamate and 1000L of distilled water.
c. And (3) drying: freeze drying the bacterial suspension after adding the protective agent to obtain freeze dried bacterial powder, wherein the viable count of the bacterial powder of each probiotic reaches 6.0 multiplied by 10 11 cfu/g or more.
Example 1
A composite probiotic composition comprises the following components in percentage by weight:
8.4mg of lactobacillus casei Zhang powder;
12.5mg of bifidobacterium lactis V9 powder;
8.4mg of lactobacillus plantarum P-8 bacterial powder;
8.4mg of lactobacillus rhamnosus Probio-M9 bacterial powder;
12.5mg of Bifidobacterium lactis Probio-M8 powder;
the auxiliary material is galacto-oligosaccharide, 451.8mg.
The preparation method of the composite probiotic composition comprises the steps of weighing freeze-dried powder of each strain according to a formula, uniformly mixing, adding auxiliary materials, and uniformly mixing.
Example 2
A composite probiotic composition comprises the following components in percentage by weight:
1g of lactobacillus casei Zhang powder;
1g of bifidobacterium lactis V9 powder;
1g of lactobacillus plantarum P-8 powder;
1g of lactobacillus rhamnosus Probio-M9 bacterial powder;
1g of bifidobacterium lactis Probio-M8 bacterial powder;
28.3g of auxiliary material polydextrose.
The preparation method of the composite probiotic composition comprises the steps of weighing freeze-dried powder of each strain according to a formula, uniformly mixing, adding auxiliary materials, and uniformly mixing.
Example 3
A composite probiotic composition comprises the following components in percentage by weight:
1g of lactobacillus casei Zhang powder;
1g of bifidobacterium lactis V9 powder;
1g of lactobacillus plantarum P-8 powder;
1g of lactobacillus rhamnosus Probio-M9 bacterial powder;
1g of bifidobacterium lactis Probio-M8 bacterial powder;
35g of auxiliary material galacto-oligosaccharide.
The preparation method of the composite probiotic composition comprises the steps of weighing freeze-dried powder of each strain according to a formula, uniformly mixing, adding auxiliary materials, and uniformly mixing.
Example 4A composition for the prevention, alleviation, co-treatment or treatment of diabetes
A composite probiotic composition comprises the following components in percentage by weight: 2g of the complex probiotic composition of example 1, 1.5g of metformin.
EXAMPLE 5A composition for the prevention, alleviation, co-treatment or treatment of diabetes
A composite probiotic composition comprises the following components in percentage by weight: 1g of the composite probiotic composition of example 2 and 2g of buformin.
EXAMPLE 6A composition for the prevention, alleviation, co-treatment or treatment of diabetes
A composite probiotic composition comprises the following components in percentage by weight: 2g of the composite probiotic composition of example 3 and 1g of pioglitazone.
Examples of the experiments
1 method of experiment
1.1 sample
The composite probiotic composition comprises the following components: the complex probiotic composition prepared in example 1.
Metformin: stopping the check.
Placebo: the fungal powder of example 1 was replaced with maltodextrin, and the resulting composition was prepared without changing other conditions.
The test sample is a blood sample of a volunteer.
1.2 test grouping
The composite probiotic composition was used in combination with metformin clinical trials in a randomized, double-blind, placebo-controlled trial. The trial co-recruited 48 type ii diabetic patients into a randomized cohort of probiotic (27) and placebo (21).
The test population: the subject should be 18-70 years old, male and female unlimited, meet any one of the following or satisfy both: triglyceride is more than or equal to 1.8mmol/L, and total cholesterol is more than or equal to 5.7mmol/L. Has not been used and treatment with lipid lowering drugs has not been planned for a short period of time.
And (3) inclusion standard: subjects were eligible for inclusion in the study only if they met all of the following criteria.
1. Male or female, and the age is 18-70 years old;
BMI (Body Mass Indx) is between 24kg/m2 and 30kg/m 2;
3. the waistline of the male is more than or equal to 90cm, and the waistline of the female is more than or equal to 85cm;
4. antibiotics are not used in 1 month before the group is entered;
5. no history of chronic gastrointestinal disorders;
6. consent to participate in the study, and written informed consent was signed;
7. patients who newly found or have the existing type II diabetes mellitus can be treated without other complications and using hypoglycemic drugs (the diagnosis standard of the type II diabetes mellitus needs to be based on fasting blood sugar or postprandial blood sugar, or according to random blood sugar and glycosylated hemoglobin, the examination needs to be monitored more than twice in the same day, if the fasting blood sugar exceeds 7.0mmol/L, the postprandial blood sugar exceeds 11.1mmol/L, the random blood sugar exceeds 11.1mmol/L, the glycosylated hemoglobin exceeds 6.5 percent, and the type II diabetes mellitus can be diagnosed);
exclusion criteria: the subject is not eligible for inclusion if either:
1. women who are scheduled to be pregnant during pregnancy, lactation or within 6 months;
2. patients with hepatic insufficiency: glutamic-pyruvic transaminase and glutamic-oxalacetic transaminase are more than or equal to 2 times of the normal value;
3. renal insufficiency patients: the glomerular filtration rate is less than or equal to 90ml/min/1.72m2;
4. hypertension, and the blood pressure is still higher than 160/100mmHg by using more than 2 antihypertensive drugs;
5. patients with cardiac insufficiency;
6. those with anemia or other blood disorders;
7. those with lactic acid bacteria and products thereof having a history of allergy or high-sensitivity constitution;
8. other drug investigators were accepted within 3 months prior to screening;
probiotic group (group a): the doses administered were a complex probiotic composition (2 g/day) and metformin (glufosinate, 1.5 g/day);
placebo group (group B): the doses administered were placebo (2 g/day) and metformin (glyburide, 1.5 g/day).
The administration mode is oral.
The administration time was 3 months.
1.3 Regulation of various criteria by the probiotic composition of the invention
1.3.1 blood sugar physicochemical index changes
The main indicators for diagnosing diabetes mellitus: fasting plasma glucose and glycated hemoglobin. The detection method of the index comprises the following steps: blood was collected from each group of patients after month 0 (no drug administration on day 0) and 3 months of treatment (day 90), and fasting blood glucose and glycated hemoglobin were measured using a glucometer. The higher the blood glucose concentration, the higher the relative percentage of glycated hemoglobin.
Fasting plasma glucose results as shown in fig. 1, fasting plasma glucose was significantly reduced in the probiotic group patients after 3 months of treatment, with a significant difference compared to month 0 (P = 0.0077), whereas fasting plasma glucose was not significantly different in the placebo group patients after 3 months of treatment, compared to month 0 (P = 0.45).
Glycated hemoglobin results are shown in fig. 2, with a significant decrease in glycated hemoglobin in the probiotic group patients after 3 months of treatment, with a significant difference compared to month 0 (P < 0.001), while glycated hemoglobin in the placebo group patients after 3 months of treatment had no significant difference compared to month 0 (P = 0.87).
1.3.2 uric acid content Change
Studies have shown that elevated uric acid concentrations can increase the risk of developing diabetic nephropathy. The detection method of the uric acid index comprises the following steps: before the examination, vigorous exercise was prohibited, good diet and work and rest were maintained, and at the time of examination: that is, a part of urine is discharged and discarded to wash away bacteria left in the urethral orifice and the anterior urethra, and then the midstream urine is left for examination. Urine was collected from each group of patients after 0 months (no drug on day 0) and 3 months of treatment (day 90) and measured using an acid-base analyzer.
The uric acid content detection result is shown in fig. 3, the uric acid in the probiotic group is reduced after treatment, and the uric acid in the placebo group is increased.
1.3.3 changes in the physical and chemical indices of lipids
Detection indexes are as follows: high and low density lipoproteins (HDL-CH) in serum. The detection method of the index comprises the following steps: collecting blood of each group of patients after 0 month (no medicine on day 0) and 3 months of treatment (day 90), adding low density lipoprotein cholesterol inhibitor, hiding low density and very low density parts, directly measuring cholesterol content of high density part, measuring absorbance value at 510nm wavelength, and calculating its content. The low-density lipoprotein can react with phosphotungstic acid-magnesium and polyethylene glycol complexing agent to generate precipitate, the dispersing agent can be used for making the precipitate particles fine and uniform, the absorbance value is measured at the wavelength of 630nm, and the content of the low-density lipoprotein is calculated.
The results are shown in fig. 4, and after 3 months of treatment, the high-density and low-density lipoproteins (HDL-CH) in the serum of the probiotic group tended to increase, while the placebo group showed an increasing trend.
1.3.4 blood glucose assay results
Fasting blood glucose of volunteers in the probiotic group and placebo group at the beginning and end of the test, blood glucose 0.5h after taking glucose (1 h after taking glucose, 2h after taking glucose, and 3h after taking glucose) and total amount of glucose (1.75 g of anhydrous glucose in oral solution, calculated by children per kilogram of body weight, the total amount is not more than 75 g) were measured respectively. The detection method of the index comprises the following steps: fasting blood glucose refers to blood collected before breakfast after fasting (at least 8-10 hours without any food, except drinking water) at night, and the fasting blood glucose, the blood glucose 0.5h after taking glucose, the blood glucose 1h after taking glucose, the blood glucose 2h after taking glucose and the blood glucose 3h after taking glucose of each group of patients at 0 month (no medicine on day 0) and 3 months (day 90) of treatment are detected.
The results are shown in fig. 5, where the fasting blood glucose of the probiotic patients tended to decrease slightly. Both groups reached a peak in blood glucose levels at 1h after glucose administration and then declined.
1.3.5 insulin-related index changes
Detection indexes are as follows: total insulin secretion, insulin resistance index, insulin beta cell function index. The detection method of the index comprises the following steps: it is known as a gold standard for the diagnosis of diabetes to orally administer an aqueous solution containing 75g of anhydrous glucose to each group of patients, then to collect blood at 0.5, 1.0, 1.5, and 2.0 hours, and to measure the change in blood glucose in order to observe the ability of the patients to tolerate glucose. When blood sugar is abnormally increased but the standard for diagnosis of diabetes is not reached, the test can be used to determine whether diabetes is present.
Method for measuring total amount of insulin secretion (insulin level measuring method): the enzyme linked immunosorbent assay kit is adopted for determination, and the method is shown in the specification (Saimeifei).
The insulin resistance index is calculated as fasting blood glucose level (FPG, mmol/L). Times.fasting insulin level (FINS, mIU/L)/22.5. Fasting blood glucose level was tested as in the 1.3.4 blood glucose assay, fasting insulin level: the enzyme linked immunosorbent assay kit is adopted for determination, and the method is shown in the specification (Saimeifei).
Calculating formula of pancreatic islet beta cell function index: 20X fasting insulin level (FINS, mIU/L)/(fasting blood glucose level (FPG, mmol/L) -3.5).
The insulin resistance index of a healthy person should be less than 2.69, and if this value is exceeded, it indicates the possibility of insulin resistance. Insulin resistance is due to the body's inability to utilize insulin effectively, resulting in a compensatory increase in insulin in the body.
The total insulin secretion test results are shown in fig. 6, and the area under the OGTT (oral glucose tolerance test) insulin curve (AUCins): probiotic group AUCins =141.84; placebo group AUCins =108.18. The area under the OGTT insulin curve was significantly increased for the probiotic group, and the opposite was true for the placebo group. Therefore, the total amount of insulin secretion was higher in the probiotic group than in the placebo group.
The results of the insulin resistance index and the insulin beta cell function index are shown in table 1, and the insulin beta cell function index: the insulin beta cell function index of the probiotic group is higher than that of the placebo group, and the insulin beta cell function index of the probiotic group is obviously increased after 3 months of treatment. Insulin resistance index: the insulin resistance index was higher in the probiotic group than in the placebo group.
TABLE 1 results of insulin resistance index, insulin beta cell function index
Figure BDA0003582728860000181
Comprehensively, the composite probiotic composition disclosed by the invention can improve insulin secretion, improve the pancreatic islet function, obviously lower the blood glucose, reduce hemoglobin and fasting blood glucose and reduce the risk of diabetic nephropathy by combining metformin.
It should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. This need not be, nor should it be exhaustive of all embodiments. And obvious variations or modifications therefrom are within the scope of the invention.

Claims (10)

1. Use of a complex probiotic composition in combination with a biguanide antidiabetic agent in the preparation of a food, health product or medicament for the prevention, alleviation, co-treatment or treatment of diabetes, the complex probiotic composition comprising:
lactobacillus casei Zhang (Lactobacillus casei Zhang) with the preservation number of CGMCC No.5469;
bifidobacterium lactis V9 (CGMCC No. 5470);
lactobacillus plantarum P-8 (Lactobacillus plantarum P-8), with the preservation number of CGMCC No.6312;
lactobacillus rhamnosus Probio-M9 (Lactobacillus rhamnous Probio-M9) with the preservation number of CGMCC No.18639;
bifidobacterium lactis Probio-M8 (Bifidobacterium lactis Probio-M8) with the preservation number of CGMCC No.18610.
2. Use according to claim 1, characterized in that the probiotic composition has a total viable count not lower than 3.0 x 10 10 CFU/g；
Optionally, the number of live lactobacillus casei Zhang is not less than 50 hundred million, the number of live lactobacillus lactis V9 is not less than 75 hundred million, the number of live lactobacillus plantarum P-8 is not less than 50 hundred million, the number of live lactobacillus rhamnosus Probio-M9 is not less than 50 hundred million, and the number of live lactobacillus lactis Probio-M8 is not less than 75 hundred million.
Optionally, the viable count of each strain is not less than 6.0 × 10 11 CFU/g；
Optionally, the biguanide antidiabetic agent comprises metformin, sitagliptin phosphate, linagliptin, pioglitazone, phenformin or buformin.
3. The use according to claim 1 or 2, wherein the raw material of each strain in the composite probiotic composition comprises any one of a culture, a fermentation product or a freeze-dried powder of the strain;
optionally, the raw material of each strain is freeze-dried powder of the strain.
4. Use according to claim 1 or 2, characterized in that the complex probiotic composition further comprises adjuvants;
optionally, the auxiliary material is prebiotics and/or dietary fibers;
optionally, the auxiliary material comprises at least one of galacto-oligosaccharide, fructo-oligosaccharide, inulin, polydextrose and maltitol;
optionally, in the composite probiotic composition, the mass ratio of the total bacterial powder to the auxiliary materials is 10-15:85-90.
5. Use according to any one of claims 1 to 4, characterized in that the complex probiotic composition is prepared by a process comprising the steps of mixing raw materials containing the strains;
optionally, the method further comprises the step of adding auxiliary materials after mixing the raw materials containing the strains.
6. The use according to any one of claims 1 to 5, further having the use of:
(a) The application of the probiotics solid beverage or the functional health care product in the preparation of leaven, fermentation product or probiotic solid beverage;
(b) The application in preparing food, health care products or medicines for improving insulin secretion, reducing blood fat, reducing blood sugar, reducing glycosylated hemoglobin content, reducing uric acid content or improving pancreatic island function;
(c) The application of the extract in preparing food, health-care products or medicines for preventing, relieving, assisting in treating or treating gout.
7. The use according to any one of claims 1 to 6, wherein the diabetes is type 2 diabetes;
optionally, the alleviating diabetes comprises alleviating the risk of developing diabetes;
optionally, in order to alleviate the risk of type 2 diabetes;
optionally, the food product comprises a traditional food, a health food or an adjuvant therapeutic food composition.
8. The use according to any one of claims 1 to 7, wherein the prevention, alleviation, co-treatment or treatment of diabetes comprises increasing insulin secretion, decreasing blood glucose, decreasing glycated hemoglobin content, decreasing uric acid content, decreasing blood lipids or improving pancreatic islet function.
9. The use of claim 6, wherein in (a), the fermented product comprises a soy product, a dairy product, or a fruit and vegetable product.
10. A composition for the prevention, alleviation, co-treatment or treatment of diabetes comprising:
a complex probiotic composition as described in any one of claims 1 to 9; and
biguanide antidiabetic drugs;
optionally, 1-2 parts by weight of the composite probiotic composition and 1-2 parts by weight of biguanide antidiabetic medicine;
optionally, 2 parts by weight of the composite probiotic composition and 1.5 parts by weight of biguanide antidiabetic medicine;
optionally, the biguanide antidiabetic agent comprises metformin, sitagliptin phosphate, linagliptin, pioglitazone, phenformin or buformin.
CN202210368569.8A 2022-04-06 2022-04-06 Application of composite probiotic composition in combination with dimethylguanidine to treatment of type II diabetes Pending CN115281345A (en)

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