CN102670661B - Drug for stimulating glucagon-like peptide 1 (GLP-1) secretion - Google Patents
Drug for stimulating glucagon-like peptide 1 (GLP-1) secretion Download PDFInfo
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Abstract
The invention relates to a drug for stimulating diabetes-related glucagon-like peptide 1 (GLP-1) secretion, falling into the field of diabetes prevention and treatment. The drug for stimulating GLP-1 secretion comprises effective dosage of probiotic bacteria, and effective dosage of Rhizoma Coptidis extract. The drug can effectively stimulate cell to secrete GLP-1 and improve quality of intestinal flora especially probiotic bacteria, and combines with Chinese medicinal ingredients to promote GLP-1 secretion, thereby preventing and treating diabetes.
Description
Technical field
The invention belongs to the diabetes control field, particularly for the medicine that stimulates glucagon-like peptide-1 secretion relevant with diabetes.
Background technology
Diabetes are that a kind of blood sugar level is higher than normal disease.Diabetes have three kinds of main types, i.e. type (juvenile diabetes), type and gestational diabetes.In type, the β cell of pancreas can not synthesize enough insulins.Type is the principal mode of diabetes, accounts for the 90-95% of all diabeticss.Such diabetes start from insulin resistant usually, and muscle, liver and adipose cell can not be made appropriate reaction to insulin in this case.Pancreas has finally been lost the ability that responds food intake and produce and secrete enough insulins.Gestational diabetes changes because of the phenolics hormone or causes because of insufficient insulin.Glucose in the blood can not enter cell, thus the glucose level in the elevating blood.The blood glucose glucose of high concentration is also referred to as hyperglycemia, can damage nerve and blood vessel, leads to complications as heart disease, apoplexy, renal dysfunction, blind, neurologic problems, gingival infection and amputation.Injection of insulin, hypoglycemic medicine and life style change as motion, body weight control and dietetic therapy, are the diabetes remedies of recommending.Also lack proper prophylactic methods at present, as develop as one pleases, will become the change of irreversibility, can cause the patient invalid or dead, therefore, to improving the understanding of diabetes, pay attention to early diagnosis, effectively prevent and treat the problem that intercurrent disease is current significant.
The west diabetes medicament by supplementation with insulin, improve insulin sensitivity, the insulin secretion and/or the histiocytic glucose uptake that increase pancreas correct hyperglycemia.Under normal circumstances, the enough islets of langerhans of pancreatic beta cell secretion are usually kept blood sugar concentration (72 –, 126 mg/dL) in a narrow range.Insulin stimulating causes cascade signal, has strengthened picked-up, utilization and the storage of glucose in the various tissues.In diabetics, it is because β apoptosis or insulin resistant that body loses the ability of producing insulin.Cytokine, fat toxicity and sugared toxicity are the apoptotic three kinds of main stimulating factors of β.
The hypoglycemic medicine that many types are arranged comprises insulin succagoga (sulphanylureas, fennel benzoic acid class), euglycemic agent (biguanides, metformin, thiazolidinediones), alpha-glucosidase inhibitor (miglitol, acarbose).Most of hypoglycemic medicines may have side effect, as severe hypoglycemia, lactic acidosis, speciality hepatocyte injury, nonvolatil neurological handicap, gastrointestinal upset, headache, dizziness even dead.
The secretin mainly is made up of glucagon-like-peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP).Wherein, GLP-1 plays a part even more important in the developing of type 2 diabetes mellitus.GLP-1 is a kind of intestinal source sex hormone in the human body, on the feed after, this parahormone can promote insulin secretion, performance concentration of glucose dependency blood sugar reducing function.GLP-1 is by the glucagon antigen gene expressed, in alpha Cell of islet, the main expression product of glucagon protogene is glucagon, and in the L of intestinal mucosa cell, prohormone conversion enzyme (PC1) is cut into the peptide chain-ordering of its c-terminus, i.e. GLP-1 with Proglucagon.GLP-1 has 2 kinds of biologically active forms, is respectively GLP-1 (7-37) and GLP-1 (7-36) amide, and an aminoacid sequence difference is only arranged between the two, and the circulation activity of GLP-1 about 80% is from GLP-1 (7-36) amide.Confirm that the secretin promotes the beta Cell of islet excreting insulin in concentration of glucose dependency mode, and reduce alpha Cell of islet secretion glucagon, thus blood sugar lowering.The normal person is after dining, and the secretin begins secretion, and then promotes insulin secretion, to reduce the fluctuation of post-prandial glycemia.But for the type 2 diabetes mellitus patient, its " secretin's effect " is impaired, mainly showing as the back GLP-1 concentration rising amplitude of having meal reduces to some extent than the normal person, but it is obviously impaired that it promotes that insulin secretion and hypoglycemic effect there is no, so GLP-1 and analog thereof can be used as an important target spot of type 2 diabetes mellitus treatment.
GLP-1 is mainly by following several respects performance blood sugar reducing function: (1) GLP-1 has the effect of protection β cell.GLP-1 can act on beta Cell of islet, promotes the synthetic and secretion [1] of the transcribing of insulin gene, insulin, and can stimulate propagation and the differentiation of beta Cell of islet, suppresses the beta Cell of islet apoptosis, increases beta Cell of islet quantity.In addition, GLP-1 also can act on alpha Cell of islet, the release of glucagon suppression consumingly, and act on delta Cell of islet, promote the secretion of somatostatin; (2) GLP-1 has concentration of glucose dependency blood sugar reducing function; (3) GLP-1 has slimming effect.In addition, GLP-1 also has many other biologicals and learns characteristic and function, and for example, GLP-1 may bring into play blood fat reducing, hypotensive effect, thereby cardiovascular system is produced protective effect; It also can strengthen learning and memory function, neuroprotective by acting on maincenter.Yet, GLP-1 to be applied to the clinical problem that also is faced with, that is exactly that the GLP-1 that produces of human body self is very easily degraded by the DPP IV in the body (DPP-IV), its plasma half-life less than 2 minutes, must continue intravenous drip or lasting subcutaneous injection could produce curative effect, this has limited the clinical practice of GLP-1 greatly.For solving this difficult problem, scholars have proposed two kinds of schemes, and the one, exploitation GLP-1 analog allows it both possess the effect of GLP-1, can resist degraded again; The 2nd, exploitation DPP-IV inhibitor is not degraded the GLP-1 that self secretes in the body.Clinical this class medicine of having succeeded in developing has new type of peptides analog such as Exenatide, Li Lalu peptide and DPP-4 inhibitor at present, can increase the GLP-1 serum-concentration and slow down gastric emptying.
Some Chinese medicine energy blood sugar lowering, but its test result is subjected to multiple factor affecting.At first, every kind of Chinese medicine contains thousands of composition, and it is effective wherein having only minority.The second, a kind of different piece of Chinese medicine has different formation components.And different extracting method can produce different active component.The 3rd, the Chinese medicine formula that contains plurality of Chinese may have cooperative effect.Some Chinese herbal medicine have been used to the treatment by Chinese herbs diabetes as the blood sugar lowering medical herbs, and for example, Radix Ginseng, Fructus Momordicae charantiae and Rhizoma Coptidis can be used for I and type ii diabetes.Also have many plants to be used to treating diabetes, the effect of these blood-sugar lowering tcm drugs is by the glucose uptake that increases insulin secretion, enhancing fat and muscular tissue, inhibition intestinal absorption and the inhibition hepatocyte generation glucose of glucose to be realized.
Probiotic bacteria refers to improve host's microecological balance and brings into play beneficial effect, reaches the active bacteria formulation and the metabolite thereof that improve host health level and health status.Probiotic bacteria is present in the inside, tellurian various corner, and bacteria beneficial or fungus mainly contain in the animal body: lactobacillus, bacillus bifidus, actinomycetes, yeast etc.The most powerful product of function of research mainly is the composite reactive probiotic bacteria that above each quasi-microorganism is formed in the world at present.Bacillus bifidus is one of most important probiotic bacteria wherein.Some studies show that bacillus bifidus obviously alleviates NOD mouse islets inflammation, reduce the generation of diabetes.The expression of bacillus bifidus group islets of langerhans Fas is less than matched group, also there were significant differences in the expression of FasL, shows that early stage application bacillus bifidus can reduce NOD mouse islets inflammation and the generation that delays diabetes. and its mechanism is apoptosis-related with islets of langerhans p of Fas/FasL system mediation.Equally, confirm the level of blood sugar lowering that can significance by oral nursing diabetes KK-AY mice lactobacillus casei, its mechanism may be to have suppressed the generation of some inflammatory factors in the animal body, as IFN-a, and IL-2 etc.These factors can be brought out body and be produced autoimmune diabetes, L. casei can suppress the destruction of the caused B cells of pancreas of alloxan, the B cells injury (M. Serino, the E. Luche et al. Intestinal microflora and metabolic diseases.Diabetes ﹠amp that cause with the autoimmune disease of non-diabetic mice; Metabolism 35 (2009) 262 – 272).
Summary of the invention
As previously mentioned, the prevention of the diabetes of GLP-1 that produce of intestinal cell and treatment all have important effect.The object of the present invention is to provide a kind of medicine for stimulation GLP-1 secretion, adopt Chinese medicine and the method for quality of improving probiotic bacteria in the intestinal to stimulate the generation of intestinal GLP-1, thereby reach the effect of preventing and treating diabetes.
The objective of the invention is to solve by the following technical programs:
Of the present invention a kind of for the medicine that stimulates the glucagon-like-peptide-1 secretion, comprise the probiotic bacteria of effective dose.
According to the further feature of medicine of the present invention, described probiotic bacteria is selected from: the combination of one or more of bifidobacterium longum, bifidobacterium breve, bifidobacterium adolescentis, bifidobacteria infantis and bifidobacterium bifidum.
According to the further feature of medicine of the present invention, the effective dose that described probiotic bacteria is used for animal is 2.5 hundred million antibacterials/kg body weight.
According to the further feature of medicine of the present invention, described medicine also comprises the Rhizoma Coptidis extract of effective dose.
According to the further feature of medicine of the present invention, the effective ingredient of described Rhizoma Coptidis extract is the berberine hydrochloride alkaloid.
According to the further feature of medicine of the present invention, the effective dose that described Rhizoma Coptidis extract is used for animal is 900 ug/kg body weight.
Checking by experiment, medicine provided by the present invention, but effective stimulus emiocytosis GLP-1 improve the quality that the interior flora of intestinal especially improves probiotic bacteria, and in conjunction with Chinese medicine ingredients, promote the secretion of GLP-1, thereby reach the purpose of preventing and treating diabetes.
The specific embodiment
Below the present invention is done specifying, should be noted that, following examples are used for explanation of the present invention and also unrestricted the present invention.Although with preferred embodiment the present invention is had been described in detail, those of ordinary skill in the art should be appreciated that and can make amendment, be out of shape the present invention under not departing from the scope of the present invention or be equal to replacement, all belongs to protection scope of the present invention.
One, probiotic's culture:
Bifidobacterium longum, bifidobacterium breve, bifidobacterium adolescentis, bifidobacteria infantis and bifidobacterium bifidum.Strain provides by U.S. Anderson biotechnology company (California, USA Los Angeles 1008 Ashbourne Place).
20% PTYG culture medium.PTYG contains: tryptone 5 g, yeast extract 10 g, soy peptone 5 g, glucose 10g, tween 80 1 mL, saline solution 40mL, 0.1% "diazoresorcinol" l mL, cysteine hydrochloride 0.5 g, distilled water 1000 mL, agar 15 g, pH value are 6.8～7.0,113 ℃.Available from GIBCO-BRL company (Maryland, USA Gaithersburg).
Probiotic bacteria is counted in advance, and (1,000,000/ml) antibacterial is cultivated (1640 culture medium do not contain serum and antibiotics) after 12 hours to equal number, and high speed centrifugation is collected supernatant, is kept at-20 ° of C after the packing.Adopt the protein content in the Bradford method mensuration inoculum.Sketch it, standard protein solution with 1.0mg/ml is done standard curve, give that a test tube adds 0,0.01,0.02,0.04,0.06,0.08 respectively, 0.1ml, water adds to 0.1ml then, add 5.0ml Coomassie brilliant blue G-250 reagent respectively in last each test tube, add reagent 2-5 minute after, can begin to use cuvette, measure each sample at the absorbance value A595 at 595nm place at spectrophotometer, blank is No. 1 pipe.Being abscissa with standard protein (mg), is vertical coordinate with light absorption value A595, and mapping namely gets a standard curve.Sample test is adopted and is used the same method, and at first every group of sample is 1:25 and 1:50 doubly dilutes, get 0.05ml then water add in last each test tube of 0.1ml and add 5.0ml Coomassie brilliant blue G-250 reagent respectively, working sample A595 value again.According to the linear gradient of standard curve, get final product the protein concentration in the calculation sample.Measurement result shows that the protein concentration scope of protein is 25-75mg/ml in the various bacteria culture medias.
Two, the preparation of Chinese medicine extract:
Rhizoma Coptidis is provided by U.S. Anderson biotechnology company.
Take by weighing the single medicinal material Rhizoma Coptidis of 50-100 gram, add an amount of distilled water to submergence, decoct 3 times (each 15 minutes), collecting decoction filters, and is concentrated into 1 grams per milliliter, and centrifugal (300 rev/mins) collect supernatant liquid, and packing is stored in-20 ° of C.
It is standard that the mensuration of Rhizoma Coptidis extract adopts berberine hydrochloride alkaloid wherein.Preparing standard solution at first, precision takes by weighing berberine hydrochloride (Sigma-Aldrich, Saint Petersburg, FL) reference substance 9.88,5.05 mg, use the buffer preparation of methanol and pH 7.0 respectively successively, must contrast liquid I (0.395 mgml-1) and contrast liquid II (0.101 mgml-1).Then, drawing standard is measured curve: the accurate contrast liquid II 0.4,0.6,0.8,1.0 of drawing, 1.2 ml are diluted to 2.0 ml with the buffer of pH 7.0.Add 0.007% bromothymol blue, 8.0 ml, shake up, add chloroform 10.0 ml, jolting, standing demix 2 min.Divide and get chloroform layer, filter with dry filter paper, corresponding reagent is blank, measures (Hach DR/3000 spectrophotometer) at 413 nm, is abscissa with concentration, and trap is vertical coordinate, does regression equation, calculates linear coefficient (r=0.999 6) (n=5).Sample determination: preparation liquid elder generation water is cooked 1:2,1:5,1:10 doubly dilutes, and gets different dilution extract 0.15 ml then, and as stated above, order adds all ingredients, measures, to calculate alkaloid in accordance with the law.
Between the range of linearity 1.2. of standard curve～12.94 μ g.The concentration of Rhizoma Coptidis extract is 54 ug/ml.
Three, GLP-1 secretory cell system and cultivation:
The NCI-H716 human colon adenocarcinoma cell line is available from American Type Culture Collecti (ATCC).
Cell is grown in the RPMI-1640, adds the 10%(volume respectively) hyclone and 4.5 grams per liter glucoses.Tested preceding 72 hours, with cell culture in 24 well culture plates, density 50%.Tested preceding 4 hours, and washed cell 2 times with the serum-free medium cultured cell, use same culture medium culturing cell 2 hours then.More renew culture medium, and add aforesaid Rhizoma Coptidis extract (dilution is 4-20 ug/ml) or bacillus bifidus metabolite (pressing 1:5 and 1:3 dilution) respectively, the normal saline of same volume is adopted in the check plot.Place cell and cultivated in incubator 30 minutes, the collecting cell culture fluid is collected supernatant behind the high speed centrifugation, be distributed into 2 parts.Portion is stored in the mensuration that is used for GLP-1 in-80 ° of refrigerators, and a mensuration protein content that is used for is for the secretory volume of check and correction cell GLP-1.
Four, zoopery:
Diabetes animal model (ob/ob) is available from Jackson Laborator(Maryland, USA Ba Er port).The ob/ob mice is the type 2 diabetes mellitus animal pattern, belongs to autosomal recessive inheritance, AR.Ob/ob mice onset diabetes is because the ob gene mutation causes its encoded protein leptin to lack, and causes that liver lipogenesis regulating liver-QI gluconeogenesis significantly increases, and hyperglycemia stimulates insulin secretion again, causes insulin resistant, stimulates the formation of fat.
Get totally 12 of ob/ob diabetic mices, be divided into 4 groups, raise in the aseptic Garbage cabinet, 24 ° of C of temperature, illumination and conversion in dark per 12 hours once keep the environment peace and quiet, freely ingest, drink water.
Collect whole blood from eye socket before carrying out drug treating, the preparation serum sickness is stored in-20 ° of C.
Experimental program: in the zoopery, being divided into is 4 groups: matched group (giving normal saline), Chinese medicine Rhizoma Coptidis processed group, bacillus bifidus processed group; Chinese medicine Rhizoma Coptidis and bacillus bifidus Combined Processing group.
Give probiotic bacteria (2.5 hundred million antibacterial/kg body weight), Chinese medicine (Rhizoma Coptidis 0.3ml, 54 ug/ml concentration every day respectively, through measuring and calculating, dosage is 900 ug/kg), probiotic bacteria adds Rhizoma Coptidis and raises, and collects whole blood after 1 week again from eye socket, preparation serum stores.Be used for measuring the GLP-1 level of serum.
The mensuration of GLP-1: according to " human glucagon-like-peptide 1(GLP-1) the enzyme-linked immunosorbent assay kit operation instructions " (providing Missouri, USA by Linco Research company) operation.Its experimental principle is: with the GLP-1 antibody sandwich microwell plate of purification, make solid phase carrier, the Avidin that adds specimen or standard substance, biotinylated GLP-1 antibody, HRP labelling in the micropore successively, through thorough washing back with substrate (TMB) colour developing.TMB changes into blueness under the catalysis of peroxidase, and changes into final yellow under the effect of acid.The depth of color and the GLP-1 in the sample are proportionate.Under the 450nm wavelength, measure absorbance (OD value), calculation sample concentration with microplate reader.
Before the experiment beginning, each reagent all is balanced to room temperature.
1, application of sample: establish blank well, gauge orifice, testing sample hole respectively.Blank well adds sample diluent 100ml, and surplus hole adds standard substance or testing sample 100 ml respectively, rocks mixing gently, and ELISA Plate adds loam cake or overlay film, 37 incubations 2 hours.
2, discard liquid, dry.Every hole adds detects solution A working solution 100 ml (face and use preceding preparation), and ELISA Plate adds overlay film, 37 incubations 1 hour.
3, discard liquid in the hole, dry, wash plate 3 times, soaked 1-2 minute at every turn, the every hole of about 400 ml/ dries.
4, every hole adds detection solution B working solution (face and use preceding preparation) 100 ml, adds overlay film, 37 degree incubations 1 hour.
5, discard liquid in the hole, dry, wash plate 5 times, method is with step 3.
6, every hole adds substrate solution 90 ml, and ELISA Plate adds overlay film, and 37 degree are hatched, lucifuge colour developing (response time was at 15-30 minute).
7, every hole adds stop bath 50 ml, cessation reaction, and this moment, blue upright commentaries on classics was yellow.
8, use microplate reader in the optical density (OD value) in each hole of 450nm wavelength measurement immediately.
Statistical analysis: result data is represented with meansigma methods ± standard error mark.Statistical analysis adopts the Prism software of Graphpad InStat company (www.graphpad.com).Assembly relatively adopts paired t-test, and the P value is less than being judged to be apparent difference at 0.05 o'clock.
Five, interpretation of result
1. the NCI-H716 emiocytosis GLP-1 that stimulates of Chinese medicine extract
Table 1: the NCI-H716 emiocytosis GLP-1 (pg/ml/mg protein) that Chinese medicine extract stimulates (n=3)
| Chinese medicine extract | Dosage 1(4 ug/ml) | Dosage 2 (10 ug/ml) | Dosage 3 (20 ug/ml) | The P value |
| Matched group | 63.2 +/- 4.6 | 60.9 +/- 3.5 | 67.1 +/- 4.3 | ? |
| Rhizoma Coptidis | 235.2 +/- 24.9 | 429.2 +/- 38.3 | 687.5 +/- 43.2 | ** |
**?P?<0.05
Matched group is normal saline.
Above-mentioned data analysis shows that the Chinese medicine Rhizoma Coptidis has the effect that stimulates L-secretion GLP-1 in this test dose scope, and when high dose, the secretory volume of cell GLP-1 has increased by 10 times.
2. the bacillus bifidus metabolite is induced NCI-H716 emiocytosis GLP-1
Table 2: the bacillus bifidus metabolite is induced NCI-H716 emiocytosis GLP-1 (pg/ml/mg protein) (n=3)
| Bacillus bifidus | Opsonigenous substance group 1 (the cell culture medium volume: the bacteria culture media volume=5:1) | Opsonigenous substance group 2(cell culture medium volume: the bacteria culture media volume=3:1) | The P value |
| Matched group | 5.3 +/- 1.2 | 6.7 +/- 1.5 | ? |
| Bifidobacterium breve | 34.3 +/- 4.5 | 65.5 +/- 21.6 | ** |
| Bifidobacterium longum | 54.9 +/- 10.3 | 89.4 +/- 17.4 | ** |
| Bifidobacterium adolescentis | 76.8 +/- 20.4 | 174.7 +/- 31.4 | ** |
| Bifidobacterium bifidum | 62.3 +/- 12.1 | 89.4 +/- 15.3 | ** |
| Bifidobacteria infantis | 89.1 +/- 22.4 | 132.5 +/- 34.9 | ** |
**?P?<0.05
Matched group is normal saline.
Above-mentioned data analysis shows, the metabolite of bifidobacterium longum, bifidobacterium breve, bifidobacterium adolescentis, bifidobacteria infantis and bifidobacterium bifidum, all has the effect that stimulates L-secretion GLP-1, wherein bifidobacterium adolescentis and bifidobacteria infantis, effect the strongest, when high dose, the secretory volume of cell GLP-1 has increased more than 20 times.
3. bifidobacterium adolescentis and the Rhizoma Coptidis GLP-1 level in the animal body respectively or during compound letting animals feed
Table 3: the GLP-1 level (pg/ml) when bifidobacterium adolescentis and Rhizoma Coptidis difference or compound letting animals feed in the animal body (n=3)
| Animal | Matched group | Bifidobacterium adolescentis | Rhizoma Coptidis | Bifidobacterium adolescentis and Rhizoma Coptidis |
| The ob/ob mice | 7.23+/-1.38 | 24.87+/-4.12** | 29.65+/-3,09** | 45.04+/-5.37** |
**?P?<0.05
Matched group is normal saline.
Above-mentioned data analysis shows, in living animal, giving bifidobacterium adolescentis and Rhizoma Coptidis separately all can stimulate intestinal L-secretion GLP-1, and its GLP-1 concentration has improved 3 times and 4 times respectively.But when both used jointly, the haemoconcentration of its GLP-1 had improved nearly 6 times.
Claims (1)
1. one kind is used for the pharmaceutical composition that the stimulation glucagon-like-peptide-1 is secreted, it is characterized in that: described pharmaceutical composition is that the bifidobacterium adolescentis of 2.5 hundred million antibacterials/kg body weight is the Rhizoma Coptidis extract of 900 ug/kg body weight with the effective dose that is used for animal for the effective dose that is used for animal, and the effective ingredient of described Rhizoma Coptidis extract is the berberine hydrochloride alkaloid.
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| CN110721203A (en) * | 2018-07-17 | 2020-01-24 | 深圳爱米基因科技有限责任公司 | Application of combination of bifidobacterium and berberine in treating pre-diabetes and type2 diabetes |
| CN110604749B (en) * | 2019-08-30 | 2020-08-14 | 北京农学院 | Bifidobacterium animalis A12 and its application in controlling diabetes or hyperlipidemia, especially weight gain or obesity |
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