CN109364269A - A kind of composition, evaluation method and its preparation predicted and treat diabetes B - Google Patents
A kind of composition, evaluation method and its preparation predicted and treat diabetes B Download PDFInfo
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- CN109364269A CN109364269A CN201811424064.9A CN201811424064A CN109364269A CN 109364269 A CN109364269 A CN 109364269A CN 201811424064 A CN201811424064 A CN 201811424064A CN 109364269 A CN109364269 A CN 109364269A
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Abstract
The present invention provides a kind of prediction and composition, evaluation method and its preparation for the treatment of diabetes B, the composition includes hyocholic acid, hyodesoxycholic acid, sweet ammonia hyocholic acid, sweet ammonia hyodesoxycholic acid, ox sulphur hyocholic acid, ox sulphur hyodesoxycholic acid and the pig gall acid derivative by hyocholic acid or hyodesoxycholic acid and the amino acids formed steroidal amides other than glycine, taurine.The composition production drug target first is that gut epithelium endocrine cell, it, can exciting bile acid membrane receptor TGR5, while antagonism bile acid nuclear receptor FXR by medicine irritation, achieve the effect that Endocrine Cells In The Gut is stimulated to secrete GLP1 jointly, blood glucose is reduced with this；Meanwhile the content of human body the composition is detected, it can predict the following diabetes risk, screening diabetes or early detection, strive for treatment time for patient；Moreover, after treatment therapeutic effect can also be evaluated by detecting the composition content.
Description
Technical field
The invention belongs to medicine, field of biotechnology, in particular to the composition of a kind of prediction and treatment diabetes B,
Evaluation method and its preparation.
Background technique
Diabetes (diabetes mellitus, DM) are a kind of using hyperglycemia as the chronic metabolic disease of main feature,
And with multiple complications, such as heart, blood vessel, eye, kidney and nerve, a variety of symptoms can be generated, as frequent micturition, it is thirsty, hungry,
Diabetes ketoacidosis and hyperosmolar coma.With aging of population and the raising of quality of life, the disease incidence of diabetes also with
Surprising speed is gradually increasing.Global diabetes total number of persons 1.5 hundred million in 2000, and development in 2017 is 4.22 hundred million, annual death rate
1,600,000 people are reached.The year two thousand forty is expected, global diabetic's quantity is up to 6.42 hundred million.China has 92,400,000 within 2007
There are 1.09 hundred million diabetics, illness rate 10.6% in diabetic, illness rate 9.7%, China in 2015, and growth rate is shied
People.Meanwhile increasingly increasing in the Children and teenager of diabetes in the world.Because of Diabetes Death number and medical expense
Expenditure increasingly increases, and diabetes conditions burden is on the rise.In particular, diabetes are fast in China and other developing countries
Speed increases, and the social and economic development to these countries brings heavy burden.Diabetes how are prevented and treated to compel in eyebrow
Eyelash.
Bile acid is the general name of a kind of cholanic acid, it is the main component in bile, by cholesterol in liver microsomal body
Synthesis is discharged into enteron aisle by biliary system, mediates the absorption of the substances such as lipid, liposoluble vitamin.Research in recent years
It was found that bile acid is not only the important substance in food digestion absorption, more adjustable endocrine metabolism has with metabolic disease
Substantial connection.Early stage has had result of study to show, the bile acid of type 2 diabetic patient is abnormal, after insulin therapy
Patient's bile acid can also be improved extremely.The discovery such as Rebecca, in type 2 diabetic patient, bile acid composition is become
Change, increases the hydrophobicity of bile acid, especially 12 α hydroxylating bile acids are (including cholic acid, deoxycholic acid and their combination shape
Formula is catalyzed by key enzyme CYP8B1) it changes, research finds 12 α hydroxylating bile acids with the ratio of other types bile acid
Raising is related with insulin sensitivity reduction, and confirms this viewpoint in animal model and human body by clamp experiment.Separately have
The study found that significant disorder occurs for the bile acid levels of diabetic, after metabolism operative treatment, not only blood glucose level is obtained
Improvement is arrived, bile acid levels are also restored, and postoperative bile acid pond significantly rises.
In recent years, more and more studies have shown that bile acids can be used as signaling molecule, by the bile acids such as FXR, TGR5 by
Body regulation metabolism, including blood glucose.FXR is bile acid nuclear receptor, and there are FXR in pancreatic beta cell, and the combination of bile acid and FXR can
Stimulate insulin releasing；There is also FXR in small intestine cells, in conjunction with bile acid after FGF19 can be activated to be secreted into blood, and
FGF19 has the effect of para-insulin sample；In addition FGF19 can inhibit cAMP response element binding protein (cyclic AMP response
Element binding protein, CREB) phosphorylation to reducing liver gluconeogenesis.Bile acid can also pass through FXR-
SHP approach inhibits the expression of gluconeogenesis related gene.In addition, having been reported that display, antagonism enteron aisle FXR can induce enteral instead
Secretory cell secretes glucagon-like peptide 1 (glucagon-like peptide 1, GLP-1).TGR5 be bile sorrel by
Body can express in the multiple organs of human body, relevant to metabolic disease to have enteron aisle, pancreas, skeletal muscle tissue etc..TGR5 activation
Induce enteroendocrine cell GLP1 secretion.In addition bile acid also can directly stimulate the TGR5 receptor in islet cells to promote insulin
Release.In skeletal muscle tissue, the activation of TGR5 can induce the table that 2 types take off iodine enzyme gene (deiodinase type 2, D2)
It reaches, increases energy consumption.
The neurological susceptibility of different plant species diabetes is different.Pig diet is done more physical exercises less, easily fatting habitus, is typical easily initiation glycosuria
The life style of disease.But even if pig is not also susceptible to suffer from diabetes under high-sugar-fat-diet induction.Because of this metabolic characteristics,
Pig is even taken as animal model to be used to study hypoglycemia disease.We analyze the blood glucose for comparing pig and people, mouse, find pig
Average blood sugar be 4.4 ± 0.1mmol/L, 5.5 ± 0.0mmol/L of average blood sugar of people, the average blood sugar 5.3 of mouse ±
0.2mmol/L (Fig. 1), pig exactly lower species of blood glucose level.
Also there were significant differences between different species for bile acid spectrum.A nearest report has studied hyocholic acid
(hyocholic acid(HCA,also known as 3α,6α,7α-trihydroxy-5β-cholanic acid,and
Gamma-muricholate)) and its sweet ammonia and cow-bezoar mating type derivative, discovery have accounted for bile acid about 42% in pig blood,
And there was only about 1% in people's blood and rat serum.Compare pig, people, the bile acid distribution in mice serum, shows total pig gall in pig blood
Juice acid series (including HCA and HDCA and their summations in conjunction with glycine and taurine) content is up to 75.96%, and
Artificial 4.99%, mouse is 3.11% (Fig. 2).The concentration of swine bile acids series again with the negatively correlated property of blood glucose.
In various swine bile acids series, hyocholic acid and hyodesoxycholic acid are separated from pig's bile by Windaus for the first time.This
Route of synthesis and physiological function of two kinds of bile acids in different plant species are different.It is how to be synthesized still in human body
It not will be apparent that.The in vitro study of early stage shows that hyodesoxycholic acid passes through 6alpha by precursor of lithocholic acid in hepatomicrosome
Hydroxy compound at.Hereafter the CYP3A4 liver enzyme found also demonstrates the route of synthesis.Other research discovery hyocholic acids can be with goose
Deoxycholic aicd as precursor by CYP3A4 adjust 6alpha hydroxy compound at.In addition there are the study found that hyocholic acid and pig
Deoxycholic aicd can be precursor by CYP3A1 enzymatic conversion using chenodeoxycholic acid, in conjunction with enterobacteriaceae allomerase and generate.?
In rat body, hyodesoxycholic acid is produced by the enterobacteriaceae conversion of the cowardly acid of beta, or pass through by precursor of lithocholic acid
Liver enzyme is converted to 3 α, and 6 β-dihydroxy cholanoic acid are further converted to 3 α-hydroxy-6- by enterobacteriaceae
Keto cholanoic acid, is eventually converted into hyodesoxycholic acid.
Can the special bile acid being rich in pig body play hypoglycemic effect? pig gall conduct has been mentioned in Compendium of Material Medica
Important medicinal material treatment is quenched one's thirst obstructed simply, is continued to use in Chinese medicine so far.Pulvis Fellis Suis (suis fellis pulvis) is used as pig gall
The dry product of juice, is incorporated into Chinese Pharmacopoeia.But what ingredient can be hypoglycemic in pig gall, is hypoglycemic by what mechanism
, it is not very clear so far.
Summary of the invention
Place in view of above-mentioned deficiencies of the prior art, the purpose of the present invention is to provide 2 type glycosurias of a kind of prediction and treatment
Composition, evaluation method and its preparation of disease, it is intended to which the novel drugs and offer one of a kind of prediction and treatment diabetes B are provided
EARLY STAGE EVALUATION index after kind treating diabetes.
In order to achieve the above object, this invention takes following technical schemes:
A kind of composition predicted and treat diabetes B is pig's bile acid compounds, including hyocholic acid, pig deoxidation
Cholic acid, sweet ammonia hyocholic acid, sweet ammonia hyodesoxycholic acid, ox sulphur hyocholic acid, ox sulphur hyodesoxycholic acid.
Preferably, the swine bile acids can be by hyocholic acid or hyodesoxycholic acid and other than glycine, taurine
Amino acids formed steroidal amides pig gall acid derivative.
Preferably, the pig's bile acid compounds are that pig's bile or Pulvis Fellis Suis refine.
The evaluation method of a kind of prediction of composition and treatment diabetes B, which is characterized in that measure the composition in people
Or other intracorporal contents of mammal, and with the content balance under health status, can be predicted future diabetes risk.
Preferably, content of the composition in people or other mammal bodies in serum or blood plasma is measured.
Preferably, content of the composition in people or other mammal excrement is measured.
Preferably, content of the composition in people or other mammal urines is measured.
Preferably, content of the composition in people or other mammal salivas is measured.
It is a kind of prediction and treatment diabetes B composition preparation, which is characterized in that for capsule, tablet, liquid and
One of granule oral preparation.
Preferably, the oral preparation is enteric coated preparations or enteric-coated sustained-release preparation.
Compared with prior art, beneficial effects of the present invention:
A kind of composition for treating diabetes B provided by the invention, including hyocholic acid, hyodesoxycholic acid, sweet ammonia pig gall
Sour, sweet ammonia hyodesoxycholic acid, ox sulphur hyocholic acid, ox sulphur hyodesoxycholic acid.The composition production drug target first is that
Gut epithelium endocrine cell, by medicine irritation, can exciting bile acid membrane receptor TGR5, while antagonism bile acid nuclear receptor
FXR achievees the effect that Endocrine Cells In The Gut is stimulated to secrete GLP1 jointly, reduces blood glucose with this；Meanwhile detecting the human body combination
The content of object can predict the following diabetes risk or diabetes auxiliary screening or early detection, when striving for treatment for patient
Between；Moreover, after treatment therapeutic effect can also be evaluated by detecting the composition content.
Detailed description of the invention
Fig. 1 is the average blood sugar content schematic diagram of normal person of the present invention, mouse, pig.
Fig. 2 be normal person of the present invention, mouse, pig serum swine bile acids series account for the accounting schematic diagram of total bile acid.
Fig. 3 is after GW4064 of the present invention intervenes 24 hours, and the concentration of serum swine bile acids series is remarkably decreased (a), blood glucose
Rise (b) schematic diagram.
Fig. 4 is melbine of the present invention, hyocholic acid (HCA) (50mg/kg/day, 100mg/kg/day), hyodesoxycholic acid
(HDCA) (50mg/kg/day, 100mg/kg/day) intervenes after a week, mouse blood sugar level schematic diagram.
Fig. 5 is after HCA of the present invention intervenes mouse 1 week, and blood glucose level is remarkably decreased (a), insulin level rises (b) signal
Figure.
Fig. 6 is that HCA of the present invention intervenes db/db mouse 15 minutes (a) and after 2 days (b), blood glucose level is remarkably decreased signal
Figure.
Fig. 7 is the serum total bile acids of large sample collection (a) of the present invention and matched sample collection (b) in normal lath (HL
Group), the healthy person (HO group) of overweight not diabetes, indifference schematic diagram between overweight diabetes patient (OD group) group.
Fig. 8 is all kinds of bile acids of the present invention in normal lath (HL group), the healthy person (HO group), super of overweight not diabetes
The variation tendency schematic diagram of weight diabetes patient (OD group).
Fig. 9 is the present invention normal lath's (HL group), the healthy person (HO group) of overweight not diabetes, overweight diabetes patient
The swine bile acids series total level (a) of (OD group), and the horizontal signal of individual HCA (b), HDCA (c), GHCA (d), GHDCA (e)
Figure.
Figure 10 is the schematic diagram of swine bile acids series of the present invention and the negatively correlated property of diabetes index of correlation.
Figure 11 is normal person of the present invention (C group), prediabetes (Pre group), the serum swine bile acids of diabetes patient are serial
Horizontal contrast schematic diagram.
Figure 12 is normal person of the present invention (C group), prediabetes (Pre group), diabetes patient's excrement swine bile acids Series of Water
Flat contrast schematic diagram.
Figure 13 is serum of the present invention and excrement swine bile acids series and the negatively correlated property schematic diagram of blood glucose target.
Figure 14 be the present invention after 10 years normal (MH group) and occur after 10 years metabolic disorder (MU group) 10 before baseline blood
The horizontal contrast schematic diagram of clear swine bile acids series.
Figure 15 is baseline serum swine bile acids series total level of the present invention and various swine bile acids to prediction metabolism state
ROC analyzes contrast schematic diagram.
Figure 16 is that diabetic's stomach bypass surgery of the present invention is preoperative and postoperative 1,3,6,12 month serum tolal bile acid
With swine bile acids series summation contrast schematic diagram.
Figure 17 is that diabetic's stomach bypass surgery of the present invention is preoperative and postoperative 1,3,6,12 month serum swine bile acids
The variation of series and the variation contrast schematic diagram of diabetes index of correlation.
Figure 18 is preoperative and postoperative 12 months serum swine bile acids series total level of the invention and various swine bile acids pair
ROC analyzes contrast schematic diagram.
Figure 19 is after GW4064 of the present invention intervenes pig 24 hours, and serum GLP1 level reduces schematic diagram.
Figure 20 is the immunofluorescence results pair of terminal ileum GLP1, TGR5 and FXR after HCA of the present invention intervenes mouse seven days
Compare schematic diagram.
Specific embodiment
To make the purpose of the present invention, technical solution and effect clearer, clear and definite, right as follows in conjunction with drawings and embodiments
The present invention is further described.It should be appreciated that described herein, specific examples are only used to explain the present invention, is not used to
Limit the present invention.
The composition of a kind of prediction provided by the invention and treatment diabetes B, is pig's bile acid compounds, including pig
Cholic acid, hyodesoxycholic acid, sweet ammonia hyocholic acid, sweet ammonia hyodesoxycholic acid, ox sulphur hyocholic acid, ox sulphur hyodesoxycholic acid.
Specifically, this composition can be hyocholic acid, hyodesoxycholic acid, sweet ammonia hyocholic acid, sweet ammonia hyodesoxycholic acid, ox sulphur
At least one of hyocholic acid, ox sulphur hyodesoxycholic acid.
The pig's bile acid compounds can also be refined from pig's bile or Pulvis Fellis Suis and be obtained.
As shown in Figure 1, it can be seen that the average blood glucose levels of normal condition servant, mouse and pig, the blood glucose of pig are minimum.Such as
Fig. 2, which can be seen that, compares pig, people, the bile acid distribution in mice serum, shows (including the HCA of total swine bile acids series in pig blood
And HDCA and their summations in conjunction with glycine and taurine) content is up to 75.96%, and artificial 4.99%, mouse is
3.11%, the concentration and the negatively correlated property of blood glucose of swine bile acids series.
In some embodiments, the swine bile acids can be by hyocholic acid or hyodesoxycholic acid and in addition to glycine, ox
The pig gall acid derivative of amino acids formed steroidal amides other than sulfonic acid.
The evaluation method of a kind of prediction of composition and treatment diabetes B, measures the composition in people or other lactations
The intracorporal content of class animal, and with the content balance under health status, can be predicted future diabetes risk.
In some embodiments, the composition containing in serum or blood plasma in people or other mammal bodies is measured
Amount.
In some embodiments, content of the composition in people or other mammal excrement is measured.
In some embodiments, content of the composition in people or other mammal urines is measured.
In some embodiments, content of the composition in people or other mammal salivas is measured.
It should be noted that there is no multipair urine and saliva these body fluid to do excessive explanation in experimental example of the present invention, this
Invention is more biased towards makes explanations explanation in serum, blood plasma and excrement.
The preparation of a kind of prediction and the composition for treating diabetes B is that capsule, tablet, liquid and granule are oral
One of preparation.
In some embodiments, the oral preparation is enteric coated preparations or enteric-coated sustained-release preparation.
Prediabetes and the hyocholic acid in the serum of diabetic, hyodesoxycholic acid, sweet ammonia hyocholic acid, the deoxidation of sweet ammonia
Cholic acid and total swine bile acids series content are substantially reduced；Meanwhile prediabetes and hyocholic acid in the excrement of diabetic,
Hyodesoxycholic acid and total swine bile acids series content are substantially reduced.
To fat complication with diabetes patient carry out metabolic operation (and become loss of weight and perform the operation, including stomach band plasty, stomach
Sleeve resection, stomach bypass surgery etc.), the preoperative serum hyocholic acid of patient, hyodesoxycholic acid, sweet ammonia hyocholic acid, sweet ammonia deoxygenate gallbladder
Acid and total swine bile acids series content are substantially reduced, and are significantly risen within one month after surgery.
The action target spot of composition of medicine first is that gut epithelium endocrine cell, can exciting bile by medicine irritation
Sorrel receptor TGR5, while antagonism bile acid nuclear receptor FXR reach the effect that stimulation Endocrine Cells In The Gut secretes GLP1 jointly
Fruit reduces blood glucose with this.
It is specifically described below by way of experiment, experimental method is as follows:
Experiment one, swine bile acids series compound have the function of significant decrease blood glucose, which is better than other bile acids
Bile acid biosynthesis inhibitor GW4064 has been gavaged to pig.The results show that after GW4064 intervenes 24 hours, such as a in Fig. 3
Can be seen that the concentration of swine bile acids series in Swine serum significantly reduces 60%, including hyocholic acid HCA, hyodesoxycholic acid HDCA,
Sweet ammonia hyocholic acid GHCA, sweet ammonia hyodesoxycholic acid GHDCA, ox sulphur hyocholic acid THCA and ox sulphur hyodesoxycholic acid THDCA.Such as Fig. 3
Middle b can be seen that while the blood glucose of pig also significantly increases 25%.It is negative that the experimental result illustrates that swine bile acids series level has with blood glucose
The reduction of correlativity, hyocholic acid level will lead to the raising of blood glucose, while also prompt hyocholic acid has treatment hyperglycemia
Effect, can be used as the therapeutic agent of diabetes.Wherein decline hundred of each bile acid after intervention in swine bile acids series
Divide than being HCA-76.6%, GHCA-41.6%, THCA-12.0%, HDCA-86.8%, GHDCA-65.4%, THDCA-
41.5%.
Further, by swine bile acids series HCA (50mg/kg/day, 100mg/kg/day) and HDCA (50mg/kg/day,
100mg/kg/day) give C57BL/6 Mouse oral, and using melbine (200mg/kg/day as positive control).Such as Fig. 4 institute
Show, intervene after a week the level and positive control the results show that the blood glucose of all intervention groups all significantly reduces, reduced quite or
Person is lower.As shown in figure 5, Mouse oral 50mg/kg/day HCA result shows that sugar tolerance all makes moderate progress after 1 week simultaneously,
The AUC of OGTT reduces 20%, and fasting insulin increases 74%.
As shown in fig. 6, particularly, we fill HCA to the diabetes model db/db mouse that leptin receptor knocks out
Stomach, after intervening 15 minutes, the blood glucose of mouse just reduces by 24% (Fig. 6 a) for discovery.Two days later, blood glucose reduces by 26% (Fig. 6 b).This
A little results all show that hyocholic acid has the function of significantly reducing blood glucose.
Swine bile acids Series of Water is flat in experiment two, diabetes patient's serum is decreased obviously
1107 crowd's samples (including 610 males and 497 women) serum swine bile acids series is carried out
Analysis and research.First we analyze include 585 normal laths's (HL group), 419 overweight not diabetes health
The difference that the total bile acid of person's (HO group) and 103 overweight diabetes patients's (OD group) is horizontal and swine bile acids series is horizontal.
Age has further been extracted in three groups of crowds, BMI, the matched part sample of gender carry out going deep into again the analysis of a step and compare.
As is seen in figs 7-10, the results show that no matter large sample collection (Fig. 7 a) or matched sample concentrate (Fig. 7 b), three
The level of the serum tolal bile acid of group crowd is similar, and indifference between gender.In all bile acids measured, only pig's bile
The levels of substance of sour series is presented from normally having the tendency that being gradually reduced (Fig. 8) to diabetes patient to overweight.Swine bile acids series
Total level (Fig. 9 a), and individual HCA (Fig. 9 b), HDCA (Fig. 9 c), GHCA (Fig. 9 d), GHDCA (Fig. 9 e) concentration in normal person
And identical variation tendency is all presented overweight and have minimum in diabetes patient in highest between gender.By swine bile acids series
Total level, and the level of individual HCA, HDCA, GHCA, GHDCA, with diabetes index of correlation fasting blood-glucose, postprandial 120 minutes blood
Sugar, fasting insulin, postprandial 120 minutes insulin, HOMA-IR do correlation analysis, and discovery swine bile acids Series of Water is gentle big
Index mostly relevant to diabetes is in significant negative correlation (Figure 10).
It can be seen that clearing from overweight to diabetes, swine bile acids series total level and individual swine bile acids Series of Water
Now successively downward trend, the i.e. summation of HCA, HDCA, GHCA, GHDCA in diabetes patient and these hyocholic acids and normal
People compares and significantly reduces.Prompt swine bile acids series can be used as the new diagnosis index of diabetes.
Experiment three, prediabetes and diabetes patient's serum and excrement swine bile acids Series of Water are averagely decreased obviously
As depicted in figs. 11-12, to 32 normal persons (C group), 34 prediabetes (Pre group), 40 diabetes patient (DM
Group), amount to 106 (including 44 males and 62 women) in serum and excrement in hyocholic acid total level and HCA,
HDCA, GHCA, GHDCA are analyzed and researched.It is compared with normal people as the result is shown, the serum of prediabetes and diabetes patient
Swine bile acids series in (Figure 11) and excrement (Figure 12) is all substantially reduced, and does not have gender differences.What is become apparent is pig gall
Reduction of the juice acid series in excrement is more significant.Unlike the case where serum, since GHCA and GHDCA are dense in excrement
Spend lower, the swine bile acids series in excrement is mainly HCA and HDCA.
As shown in figure 13, further, in excrement swine bile acids series all and and before the meal, postprandial blood sugar be in significant negative
It closes, and related coefficient is more significant than serum.
In summary as a result, illustrating that hyocholic acid total level and various hyocholic acids in serum and excrement can be used as glycosuria
The early diagnosis standard of disease.
Experiment four, the decline of serum swine bile acids series can predict the generation of the following metabolic disorder
As shown in figs. 14-15, the serum hyocholic acid level to 132 (including 36 males, 96 women) and generation generation
The case where thanking property disease, has made retrospective study.This 132 before 10 years the metabolic index such as clinical blood glucose, blood lipid be all normal
's.After 10 years, wherein the metabolism states such as blood glucose or blood lipid exception occur in 86 people, 46 people's metabolic index still keep normal.We
The matching of gender, age, BMI is further done to information of this crowd of people before 10 years, before and after final choice 46 10 years all just
Often (MH group) and 46 were normal before 10 years, occurred people's (MU group) of metabolic disorder after 10 years, serum pig gall before carrying out 10 years
The horizontal analysis of juice acid series.The results show that the swine bile acids series level occurred in this group of human serum of metabolic disorder wants bright
Aobvious (Figure 14) lower than without generation metabolic disease.Logistic regression result shows, swine bile acids series and following generation
Thank to the relationship of state, swine bile acids series total level, HCA, GHCA, HDCA, GHDCA OR value (95%CI) be respectively 0.89
(0.86,0.93), 0.91 (0.87,0.94), 0.90 (0.84,0.96), 0.92 (0.85,0.99), 0.52 (0.40,0.69) and
0.90(0.86,0.94).ROC the results show that the gentle various swine bile acids of swine bile acids Series of Water have all reached AUC > 0.63,
The AUC highest of middle swine bile acids series total level, reaches 0.83, illustrates swine bile acids series total level and various swine bile acids
Series can predict following metabolism state (Figure 15).
The flat rebound significantly of serum swine bile acids Series of Water after experiment five, treating diabetes
As shown in figs. 16-18, the diabetic for having carried out stomach bypass surgery to 38 is preoperative, 1,3,6,12 month postoperative
Serum in swine bile acids series analyzed and researched.The results show that postoperative total cholic acid is gradually increasing, 12 months after surgery aobvious
It writes and is higher than preoperative, and serum swine bile acids series total level one month after surgery just significantly rises, hereafter again lasting to increase (figure
16).Elevated-levels are consistent with the improvement of BMI, fasting blood-glucose, postprandial blood sugar, HbA1c and insulin resistance (Figure 17).ROC analysis
It has been shown that, postoperative 12 months clear swine bile acids series total levels, the AUC of HCA, HDCA, GHCA, GHDCA be 0.80 respectively,
0.70,0.66,0.76,0.72 (Figure 18).The result shows serum swine bile acids series total level and various swine bile acids
Series can predict stomach bypass surgery for the improvement situation of diabetes.
Experiment six, swine bile acids series play hypoglycemic effect by increasing GLP1
By 6 kinds of swine bile acids series materials and other 19 kinds of bile acids to two kinds of enteroendocrine cell NCI-H716and
STC-1 is intervened.The results show that after 48 hours of incubation, the bile acid of 10 and 25 μM of concentration can stimulate the table of GLP1
It reaches, especially 6 bile acid stimulation GLP1 of swine bile acids series secrete more significant.It finds simultaneously, bile acid membrane receptor TGR5
The marker phosphorylation CREB of excitement can be by swine bile acids series excitement, and then the excitement secretion of the GLP1 in downstream.Simultaneously
It was found that nuclear receptor FXR is suppressed (FXR enter to examine and make cuts few), the effect simultaneously can also excitement GLP1 secretion.Therefore, bile acid by
The excitement of body TGR5 and the antagonism of FXR, while playing stimulation GLP1 and secreting and hypoglycemic effect.
It as shown in figure 19, whether is mechanisms play effect in animal body to verify, we have gavaged bile acid to pig
Synthetic inhibitor GW4064, whether the raising of the reduction and blood glucose that determine its swine bile acids series, which secretes to play by GLP1, is made
With.The results show that while blood glucose rise, we have also observed that the significant decrease (Figure 19) of Swine serum GLP1 level.
As shown in figure 20, further, we by the method for immunofluorescence have detected HCA (50mg/kg/day) intervene it is small
After mouse 7 days, the case where terminal ileum GLP1, TGR5 and FXR.The results show that the expression of terminal ileum GLP1 is aobvious after HCA intervenes
It writes and increases (Figure 20 a), the marker phosphorylation CREB of TGR5 excitement is by significant excitement (Figure 20 b), while FXR is suppressed that (FXR enters
Examine and make cuts few) (Figure 20 c).Change result verification cell experiment as a result, the excitement of Farnesoid X receptor TGR5 and the antagonism of FXR, together
When play stimulation GLP1 and secrete and hypoglycemic effect.
In conclusion a kind of composition for treating diabetes B, mensuration mode and its preparation provided by the invention, the group
Close the drug target of object production first is that gut epithelium endocrine cell, can exciting bile sorrel by medicine irritation
Receptor TGR5, while antagonism bile acid nuclear receptor FXR achieve the effect that stimulation Endocrine Cells In The Gut secretes GLP1 jointly, with
This reduces blood glucose；Meanwhile the content of human body the composition is detected, it can predict the following diabetes risk or diabetes auxiliary sieve
It looks into or early detection, strives for treatment time for patient；Moreover, can also be controlled after treatment by detecting the composition content to evaluate
Therapeutic effect.
It, can according to the technique and scheme of the present invention and its hair it is understood that for those of ordinary skills
Bright design is subject to equivalent substitution or change, and all these changes or replacement all should belong to the guarantor of appended claims of the invention
Protect range.
Claims (10)
1. the composition of a kind of prediction and treatment diabetes B, which is characterized in that be pig's bile acid compounds, including pig gall
Acid, hyodesoxycholic acid, sweet ammonia hyocholic acid, sweet ammonia hyodesoxycholic acid, ox sulphur hyocholic acid, ox sulphur hyodesoxycholic acid.
2. the composition of prediction as described in claim 1 and treatment diabetes B, which is characterized in that the swine bile acids are
Spread out by the hyocholic acid of hyocholic acid or hyodesoxycholic acid and the amino acids formed steroidal amides other than glycine, taurine
Biology.
3. the composition of prediction as described in claim 1 and treatment diabetes B, which is characterized in that the pig's bile acids
Compound is that pig's bile or Pulvis Fellis Suis refine.
4. a kind of predicted and treated the evaluation method of diabetes B, spy using the described in any item compositions of claim 1-3
Sign is, measures the composition in people or the intracorporal content of other mammals, and with the content under health status
Future diabetes risk, screening diabetes, evaluation therapeutic effect can be predicted in comparison.
5. evaluation method as claimed in claim 4, which is characterized in that measure the composition in people or other mammals
Content in internal serum or blood plasma.
6. evaluation method as claimed in claim 4, which is characterized in that measure the composition in people or other mammals
Content in excrement.
7. evaluation method as claimed in claim 4, which is characterized in that measure the composition in people or other mammals
Content in urine.
8. evaluation method as claimed in claim 4, which is characterized in that measure the composition in people or other mammals
Content in saliva.
9. a kind of preparation using the described in any item compositions predicted and treat diabetes B of claim 1-2, feature
It is, is one of capsule, tablet, liquid and granule oral preparation.
10. the preparation of composition as claimed in claim 9, which is characterized in that the oral preparation is enteric coated preparations or enteric
Sustained release preparation.
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| CN110220987A (en) * | 2019-06-11 | 2019-09-10 | 上海市内分泌代谢病研究所 | Bile acid combines marker in preparation for predicting or diagnosing the detection reagent of diabetes or the purposes of detectable substance |
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| WO2021036998A1 (en) * | 2019-08-23 | 2021-03-04 | 深圳云合医药科技合伙企业(有限合伙) | Bile acid derivative, composition and application thereof |
| CN115813936A (en) * | 2022-11-22 | 2023-03-21 | 中国农业科学院北京畜牧兽医研究所 | Application of Hyodeoxycholic Acid in Reducing Animal Fat Deposition |
| CN116570601A (en) * | 2023-05-06 | 2023-08-11 | 山东第一医科大学(山东省医学科学院) | Pharmaceutical composition for treating non-alcoholic fatty liver |
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|---|---|---|---|---|
| CN110220987A (en) * | 2019-06-11 | 2019-09-10 | 上海市内分泌代谢病研究所 | Bile acid combines marker in preparation for predicting or diagnosing the detection reagent of diabetes or the purposes of detectable substance |
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| CN115813936A (en) * | 2022-11-22 | 2023-03-21 | 中国农业科学院北京畜牧兽医研究所 | Application of Hyodeoxycholic Acid in Reducing Animal Fat Deposition |
| CN116570601A (en) * | 2023-05-06 | 2023-08-11 | 山东第一医科大学(山东省医学科学院) | Pharmaceutical composition for treating non-alcoholic fatty liver |
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