CN1762485A - Aglycin group and its application in preparation of medicine or food for treating diabetes - Google Patents

Abstract

The invention relates to the use of Yi'an peptide family in preparing medicament or food for treating diabetes, which is the mixture of any one or more of four kinds of Yi'an peptides, each Yi'an peptide is 37 peptide, wherein the aminothiopropionic acid and its disulfide bond are highly conservative, the three pairs of disulfide bonds in the molecule form a cysteine bond. The invention can realize low preparation cost than insulin.

Description

Yian peptide group and making treatment diabetes medicament or Application in Food

Technical field

The invention belongs to the crude drug of treatment, prevent diabetes.

Background technology

Diabetes (diabetes) are a kind of sugar, protein and lipodystrophy disease, and are all very high at global sickness rate, become the third-largest " healthy killer " after cardiovascular and tumor.China's prevalence reaches 3%, though lower than American-European countries 8%, total number of persons has surpassed 3,000 ten thousand, occupies first of the world.Along with increasing and human aging of expanding economy, blue-collar minimizing, overweight people, the sickness rate of diabetes is with sustainable growth.

1980, (the World Health Organization of World Health Organization (WHO), WHO) diabetes are divided into: insulin-dependent diabetes (insuin-dependent diabetes melitus, IDDM claims the I type again), noninsulindependent diabetes (noninsuin-dependent diabetesmelitus, NIDDM, claim the II type again) and other type diabetes, as gestational diabetes, but generally can die away after the pregnancy period.Type i diabetes is a kind of self property immunological diseases, and the normal onset of patient, was caused by the endogenous insulin hyposecretion so be called juvenile morbidity type again childhood, needed the exogenous insulin treatment.The a lot of diseases of II type patient claimed the morbidity type of growing up sometimes after 40 years old.Patient's hyperglycemia is mainly due to the insulin signaling pathway obstacle, the ability drop of insulin stimulating cellular uptake glucose.Present global diabetics is about 1.3 hundred million, and predict global patient in 2010 and will reach 2.2 hundred million, wherein more than 90% type ii diabetes, its potential maximum growth crowd accounts for more than 60% of overall growth in the Asia.Moreover, the Susceptible population of type ii diabetes also is extended to person between twenty and fifty even child by the old people gradually.Because diabetes cause of disease complexity, pathogenesis also imperfectly understands, and has brought great difficulty to treatment.

At present, mainly be the injection exogenous insulin to the treatment of type i diabetes, but have following drawback: need injecting drug use; Wayward to individual dose, often cause hypoglycemia; Life-time service produces insulin antibody and causes side effect such as drug failure.The treatment insulin injection of type ii diabetes is usually inoperative, main oral chemical classes hypoglycemic medicine such as the sulphur of relying on is urinated class, biguanides, alpha-glucosidase inhibitor, thiazolidinediones etc., their all multiple side effect in various degree of tool are as skin allergy, gastrointestinal upset reaction, hepatic and renal function damage etc.

Summary of the invention

The present invention proposes yian peptide group and is making treatment diabetes medicament or Application in Food, and its objective is provides that a kind of side effect is low, curative effect is high, standard compliant treatment diabetes crude drug.

Yian peptide group of the present invention is used for the treatment of diabetes, comprises any one or more than one mixture among following 4 kinds of pancreases peace peptide, and its aminoacid sequence is expressed as:

Aglycin a ASCNGVCSPFEMPPCGSSACRCIPVGLVVGYCRHPSG 37 3743.424

Aglycin b ISCNGVCSPFDIPPCGTPLCRCIPAGLFVGKCRHPYG 37 3880.672

Aglycin c VSCNGVCSPFDIPPCGTPLCRCIPYGLFVGNCRHPYG 37 3944.672

Aglycin d VSCNGVCSPFEMPPCGSSACRCIPYGLVVGNCRHPSG 37 3786.449

Wherein, A-alanine, C-cysteine, D-aspartic acid, E-glutamic acid, F-phenylalanine, G-glycine, H-histidine, I-isoleucine, K-lysine, L-leucine, M-methionine, N-agedoite, P-proline, R-arginine, S-serine, T-threonine, V-valine, Y-tyrosine;

The primary structure of yian peptide group: all pancreas peace peptides are 37 peptides, wherein cysteine and disulfide bond high conservative thereof, and three pairs of disulfide bond of intramolecularly form cystine knot, protect its opposing protease hydrolysis;

The yian peptide group outward appearance is white or flaxen powder, very easily is dissolved in water isopolarity solvent, to thermally-stabilised, and the resistant protease hydrolysis.

Described yian peptide group is being made treatment diabetes medicament or Application in Food, it is characterized in that a kind of or any one above mixture in the described yian peptide group, as the medicine or the food of raw material manufacturing treatment diabetes.

The preparation process of yian peptide group is as follows: 500 kilograms of leguminous seeds (Semen sojae atricolor, Semen Pisi sativi etc.) soak and germinate, and smash the back to pieces and stir with 0.2M acetic acid solution 1000L, and 5-10C ° was extracted 10 hours. cross the leaching supernatant.With 5 kilograms of alginic acid absorption, with 0.1M hydrochloric acid eluting.Filtrate is saltoutd with 320g/L sodium chloride, filters and collects the thing of saltouing.The thing of will saltouing is dissolved in the 0.2M acetic acid solution, and glucosan SephadexG-25 gel filtration obtains crude product with the filtrate drying, and the reversed-phase liquid chromatography (HPLC) by the preparation type obtains 5 kilograms of yian peptide group products at last.Yian peptide group is 37 peptides (sequence is seen Fig. 1), structure height is conservative, has extremely approaching physicochemical properties, but utilizes its hydrophobic difference, can further be separated into Aglycin a to Aglycin d at reversed-phase liquid chromatography (HPLC), collecting continuously then is the yian peptide group product.

Aglycin a is carried out physiology and pharmacological evaluation to health, a type, type-II diabetes Mus, and demonstration can reduce a type, type-II diabetes Mus hyperglycemia effectively, eliminates diabetic symptom, has tangible effect.The mice of [2.5 micrograms/gram body weight/day] does not observe any teratogenesis after 1 year to using, carcinogenic pathogenic phenomena and other side effect.Use 4 kinds of pancreas peaces of yian peptide group peptide mixer to carry out same dosetest and also obtained consistent result; Because 4 kinds of pancreas peace peptides have proximate primary structure and identical physicochemical property in the yian peptide group, Aglycin b to Aglycin d should have the performance same with The above results.

Physiological test result such as following table:

Table 1: a type Mus (NOD Mus) medicining condition (coming from Beijing Chinese Academy of Medical Sciences experimental animal center) dosage: 2.5 micrograms/gram body weight (blood sugar concentration unit: mmol/L)

The Mus number	1	2	3	4	5	6	7	8	9	10
											The beginning blood sugar concentration	14.5	17.9	9.8	12.3	11.8	15.7	13.6	12.5	8.7	14.6
Blood sugar concentration after three weeks	6.5	7.3	6.7	8.1	6.2	7.2	7.6	6.8	7.7	8.2

Table 2: two type Mus (KK Mus) medicining condition (coming from Beijing Chinese Academy of Medical Sciences experimental animal center) dosage: 2.5 micrograms/gram body weight (blood sugar concentration unit: mmol/L)

The Mus number	1	2	3	4	5	6	7	8	9	10
											The beginning blood sugar concentration	18.6	21.5	17.5	16.8	9.9	18.7	19.6	23.5	21.1	15.7
Blood sugar concentration after three weeks	7.8	6.9	6.7	7.2	6.3	7.9	8.2	6.7	9.1	7.9

Table 3: the healthy Kunming of wild type white mice medicining condition dosage: 2.5 micrograms/gram body weight (blood sugar concentration unit: mmol/L)

The Mus number	1	2	3	4	5	6	7	8	9	10
											The beginning blood sugar concentration	7.1	7.2	6.5	6.8	6.5	6.7	7.4	7.1	7.8	7.7
Blood sugar concentration after three weeks	7.2	6.5	7.1	6.4	6.5	6.8	6.9	7.2	7.5	7.2

The present invention is a raw material with the abundant edible animal and plant resource of originating, and pancreas peace peptide (English name Aglycin, because of its aminoterminal is Alanine, c-terminus is Glycine, so name) is extracted and prepared to extensive the expression.Pancreas peace Toplink reduces wild type kunming mice, type i diabetes NOD Mus and type ii diabetes KK Mus postprandial hyperglycemia.Find that by Cell Biology Experiment pancreas peace Toplink makes the growth of homogeneous Beta cell mass vigorous, life-saving.By external biological chemical experiment proof pancreas peace Toplink antitrypsin and pepsic hydrolysis, this is because cystine knot (cystineknot) domain of pancreas peace peptide molecule and two basic amino acids are present in the cause of kernel.By reaching the observation in 1 year behind the animal edible, animal does not all have adverse effect, does not see any drug side effect.Present stage yian peptide group be the novel material medicine of standard compliant treatment diabetes.

Pancreas peace peptide compares as treating diabetes crude drug and insulin, has following advantage:

1 preparation cost is lower than producing commensurability insulin;

2 pancreases peace peptide not only can play the effect of symptomatic treatment, also has the effect of etiological treatment;

3 medications are more convenient than insulin, can develop into peroral dosage form;

4 rely on the concentration of glucoses and blood sugar lowering is not brought into play function of polysaccharide when blood glucose is lower than physiological level;

5 derive from edible animals and plants, also may be the endogenic biologically active peptides of human body, so there is not the toxic and side effects of other chemical classes hypoglycemic medicines (sulfonylurea, biguanides);

The specific embodiment

According to diabetics can not edible glucose pathological characters, with mixture a kind of in the yian peptide group or more than any one, with calcium lactate, citric acid science compatibility, form the functional food and the beverage of prevention and treatment diabetes, can be made into two kinds of dosage forms of solid and liquid.

Table 4: to type ii diabetes mice administering effect

Group	Type ii diabetes mice (KK/upi-A y) blood sugar concentration (mmol/L)
				Time 0min 20min 40min 60min 80min 100min	Normal saline 14.80 14.40 12.77 10.30 10.01 11.30	Confection 18.5 14.2 10.6 8.6 7.5 6.4	Insulin 17.6 15.3 12.1 9.4 6.3 5.2

Table 5: to type i diabetes mice administering effect

Group	Type i diabetes mice (STZ) blood sugar concentration (mmol/L)
				Time 0min 20min 40min 60min 80min 100mm	Normal saline 22.15 21.51 20.51 19.63 18.86 18.67	Confection 27.30 21.77 15.3 12.1 9.4 7.5	Insulin 14.25 9.30 6.65 5.45 5.03 4.83

Table 4, table 5 are to the statistical result of type i diabetes mice, type ii diabetes mice administering effect (two kinds Mus each 40) with the confection (abbreviation confection) of pancreas peace peptide adding citric acid, lactic acid, compare with normal saline and normal insulin respectively, numeral blood sugar concentration wherein, the mode of administration adopts subcutaneous injection.The consumption of pancreas peace peptide, citric acid, lactic acid is respectively 5ug/g body weight, 2.5ug/g body weight, 3ug/g body weight in the confection, and normal saline is a 100ul/ Mus, and insulin is 2 a units/Mus.Numeral explanation confection all has tangible blood sugar reducing function to type i diabetes, type ii diabetes mice in the last table.

Below for preventing and treat the functional food composition compatibility of diabetes:

Component content (percentage by weight)

Yian peptide group 3-10%

Hydrolysis soybean protein 20-55%

Lactic acid 3-11%

Citric acid 3-8%

Plant cellulose 20-60%

Embodiment 1 is by weight percentage: yian peptide group 3%, lactic acid 6%, citric acid 7%, dry hydrolysis soybean protein 27%, adjuvant are plant cellulose 57% mixed pressuring plate.

Embodiment 2 is by weight percentage: pancreas peace peptide 5%, and adding normal saline, to become concentration be that 5% aqueous solution is for drinking; And all the other percentage by weight lactic acid 6.5%, citric acid 7.5%, dry hydrolysis soybean protein 45%, adjuvant is plant cellulose 36% mixed pressuring plate.

Embodiment 3 is by weight percentage: yian peptide group 10%, lactic acid 7.6%, citric acid 5.7%, dry hydrolysis soybean protein 34%, contain the mixing electuary of plant cellulose 42.7%.

Claims (2)

1. yian peptide group is used for the treatment of diabetes, comprises any one or more than one mixture among following 4 kinds of pancreases peace peptide, and its aminoacid sequence is expressed as:

Aglycin a ASCNGVCSPFEMPPCGSSACRCIPVGLVVGYCRHPSG 37 3743.424

Aglycin b ISCNGVCSPFDIPPCGTPLCRCIPAGLFVGKCRHPYG 37 3880.672

Aglycin c VSCNGVCSPFDIPPCGTPLCRCIPYGLFVGNCRHPYG 37 3944.672

Aglycin d VSCNGVCSPFEMPPCGSSACRCIPYGLVVGNCRHPSG 37 3786.449

Wherein, A-alanine, C-cysteine, D-aspartic acid, E-glutamic acid, F-phenylalanine, G-glycine, H-histidine, I-isoleucine, K-lysine, L-leucine, M-methionine, N-agedoite, P-proline, R-arginine, S-serine, T-threonine, V-valine, Y-tyrosine;

In the primary structure of yian peptide group, all pancreas peace peptides are 37 peptides, wherein cysteine and disulfide bond high conservative thereof, and three pairs of disulfide bond of intramolecularly form cystine knot;

The yian peptide group outward appearance is white or flaxen powder, very easily is dissolved in water isopolarity solvent, to thermally-stabilised, and the resistant protease hydrolysis.

2. the described yian peptide group of claim 1 is being made treatment diabetes medicament or Application in Food, it is characterized in that a kind of or any one above mixture in the described yian peptide group, as the medicine or the food of raw material manufacturing treatment diabetes.