CN1368853A - Prophylactic dietary supplement based on milk - Google Patents

Abstract

Milk is commonly and extensively consumed in many societies where the risk and incidence of diabetes, vascular disease (CHD, CVA, PVD) and some cancers are also high. Death is a frequent sequel of systemic vascular wall damage, resulting from exposure to high sugar levels in diabetes and also from high plasma homocyst(e)ine (tHcy) levels that affect much of the population and comprise a major risk factor for vascular disease. Diabetes is similarly widespread. Given (1) widespread and regular consumption of milk, (2) the possibility to control tHcy by treating the underlying folate (and other vitamin) insufficiency, (3) the opportunity to simply include control of neural tube defects and (4) the presumed causal link between diabetes and type A1 with type B casein consumption, the invention offers remediation by supplying a population with a modified milk or milk product including (1) fortification using cobalamin, pyridoxine, folic acid, and betaine, with (2) a substantially type A2 casein fraction only. In addition, exploitation of the immunological properties of beta-casomorphin 9 (a peptide digest fraction of A2 beta-casein) may assist in control of diabetes. Practical and convenient fortified diets include treated, selected milks and food products including derivatives of milk, also selected milks together with treated cereals.

Description

Prophylactic dietary supplement based on milk

Invention field

The present invention relates to be used for the development and application of the dairy produce improved form of food, carry out being intended that of these variations and relate to and reduce the cardiovascular and cerebrovascular disease and the incidence of disease of diabetes in the crowd.Animal stage and/or fabrication stage that this improvement can be used for producing.

Definition

Vascular diseases used herein (VaD) refer to coronary heart disease (CHD) or ischemic heart disease, cerebrovascular disease (CVA) and property angiosis (PVD) on every side.Atherosclerotic is a kind of relevant syndrome.

Diabetes comprise adolescence/IDDM/I type and the morbidity/type ii diabetes of growing up.

Other diseases comprises: precocious, senile memory loss, Alzheimer's, teratogenesis; Nerve channel is complete (NTD) not, as closed-ended question, causes spina bifida etc.; Asthma and cancer, as intestines (colon) cancer, the cancer of the uterus and/or endometrial cell dysfunction, Huppert's disease (see figure 2) and hematopoiesis are unusual.

THcy is the abbreviation of blood plasma homocystine concentration.

Dairy produce used herein is the edible food made from milk or milk component, comprise for example various caseic foods that contain, chocolate, more obviously example is ice cream, sour milk and cheese, condensed milk, drying powdered milk or other dairy produces, even " vegetable fat powder ", chocolate, cheese etc.Also comprise various forms of liquid milks, as even matter milk, low fat milk, high calcium milk, flavored milk and other milk.

" basically " used herein also comprises the separation of relative extent.

The chemicals kind, cas number and abbreviation (group I is the title that we get to them).

Betaine (betaine aldehyde, CAS 107-43-7*)

Cobalamin (cobalamin, CAS68-19-9)

Folic acid (vitamin(e) M, CAS59-30-3) (Folates)

Pyridoxine (vitamin B6, CAS58-56-0 ^*) ( ^*It is the cas number of hydrochloride; As an example; Be not meant and need HCl salt especially.)

Background

In all very high many communities of the danger of diabetes and VaD and the incidence of disease, milk generally and is widely drunk.Milk and this two kinds of diseases of the existing form of the evidence that continues to increase confirmation repeatedly are closely related.

That protein or fat in the dairy produce has caused these diseases? there is good evidence to show, human plasma homocystine (tHcy) level is generally speaking closer with the relation of heart disease and VaD, and the index of conduct danger is than cholesterol levels rising more accurate (Pietrik 1998).Graham etc. (1997) provide once big investigation, and estimate tHcy and can be used as independently VaD hazards, but also superimposed with other factors (hypertension, smoking etc.).Have clinical diabetes or do not recognizing that also the patient's medium vessels wall health that truly has diabetes is badly damaged.Graham etc. do not make report to the relevant incident of diabetes, but Hoogeveen (2000) has reported with the non-diabetic patient and compare that tHcy is the hazards of diabetes B patient stronger (1.9 times) seemingly.

In New Zealand, the incidence of disease of diabetes is per 100,000 philtrums of I type 9.8 people (Elliott 1999), and type ii diabetes in the influence of some communities up to 20% adult.In the Western countries, cardiac problems has caused about 45% death.The World Health Organization in 2000 estimates that total death toll that diabetes caused in 1999 is 777,000 (1.4%), and heart disease is 17,000,000 (30.3%), and cranial vascular disease 5,500,000 (9.9%).In the U.S., 600,000 people's apoplexy are arranged, wherein 160,000 people's death every year.The incidence of NTD (NZ:1991) is among 1750 neonates 1, adds unknown miscarriage/termination (gestation).

Replenishing vitamins and blood plasma homocystine (tHcy) level

The folic acid defective of subclinical level is region and impercipient problem at least, and it causes numerous disease, comprises VaD.This part is owing to the actual dietetic level that (a) is lower than the best is general, (b) has underestimated actual needs (seeing for example Rimm (1998)) at the very start, exists several common sudden changes relevant with folic acid metabolism with (c) general crowd.Rare congenital disorders homocystinuria (with homocystinemia) is relevant with the cardiovascular closed disease that takes place infancy.The gentle mutation of this disease (thermal instability tetrahydrofolic acid methylene ester reductase) is 10-15% in some crowd, also has the danger bigger than general VaD.The folic acid defective also causes some defective (as spina bifida) and other NTDs in the early embryonic development.Containing the milk that adds folic acid sells as the prevention purpose with this.Main reason is for " nerve channel " problem, and country has planned to add folic acid in bread and wheat flour now.Can several forms provide folic acid.Be better than natural many glutamates, the absorptivity of single glutamate (easier absorbed by body) is 50%.

The defective of folic acid, pyridoxine and cobalamin causes higher tHcy.Graham etc. (1997) and many other authors remind healthy authority enough diet Supplement of folic acid, pyridoxine and cobalamin (also replenishing betaine aldehyde in some cases), can be used for reducing tHcy (a kind of important independence and common risk factors that clinical atherosclerotic and phlebothrombosis form).See for example Br  nstrup etc. 1998, Ward etc. 1997, and Graham etc. 1997.Should replenish even help those heredity to go up the individual (Malinow 1999) who easily suffers from homocystinemia.Find that the individuality studied has absorbed that the hazards of VaD case reduce behind the additive that contains folic acid, cobalamin or pyridoxine, Graham is calculated as 0.38 (95%C.I., 0.2-0.72), and user=1 not by comparison, but notice that these people may more note their health in other respects.In addition, cobalamin can reduce tHcy (Dudman 1996) at least in those individualities with cystathionine beta-reductase activity defective.

The tHcy absolute value that does not have " initiation " vascular diseases.Biology to the vascular wall disease is still known little about it, but may relate to superoxides, and may relate in the diabetes condensation of sugar and protein.Individual tHcy is also along with the time changes.Known kidney and thyroid function and some drugs can be regulated tHcy (seeing Pietrzik, 1998).

Modal crowd with folic acid defective is the elderly, and they usually have relevant cobalamin defective.Correct the folic acid defective, may produce bad neurology influence, therefore reduce the effect, importantly correct this two kinds of defectives simultaneously except cobalamin-therapeutic causes the tHcy that adds and correct the cobalamin defective not according to same ratio.The heredity of having described a kind of common cobalamin metabolism changes, and it causes the diet of cobalamin is needed to increase, and may increase the weight of relative cobalamin defective.

Some patent specification has been described the additive based on milk, comprise whole three kinds of folic acid, pyridoxine and cobalamins, " complete nutritional composition " that comprises US5985339 Kamerei, angiocardiopathy when being used for the various other diseases of adult's opposing (but in fact irrelevant) with tHcy, DE2917239 Salki has illustrated a kind of complete food low in calories, obviously is used to be grown up; And US6030650 Kamarei provides a kind of dietetic milk prod, is used for for example ice cream and sour milk, and the demand for independence right identical with soymilk.For the baby, the example of a kind of general infant formulas such as EP951842 Bindel has filled up amino acid and has imitated people's milk; EP129418Barr provides a kind of food for the baby of birth weight deficiency.The composition that US 5631271 Serfonein provide has comprised pyridoxine biochemistry thing especially, but is added with cobalamin and folic acid.In this group patent, only Serfotein has mentioned especially relevant with baby homocystinemia.The composition that provides a kind of preemie of being used for just to be born a couple of days based on even matter milk powder, and use relevant with the methionine metabolism shortcoming of suckling.

Diabetes

Diabetes are a kind of common endocrine system diseases, influence carbohydate metabolism and blood sugar level, cause very high M ﹠ M, and cause individual patient and the considerable economy consumption of health care system.This disease has several forms.Type i diabetes (IDD or IDDM) is a class autoimmunity disease, occurs the antibody at islet cells in the patient body, thereby has stoped the generation endogenous insulin, need treat with exogenous insulin in the remaining years patient.Usually fall ill in the childhood.Can make sx with insulin or diet and hypoglycemic drug treatment, but usually can not prevent worrying vascular complication that should disease, as prematureness coronary heart disease.The II type or the diabetes that take place of growing up may be that diet causes.

It is well-known that diabetes can cause VaD, though how the vasoactive wall is also uncertain for diabetes.This and tHcy have common base.Diabetes also are a kind of maximum reasons of coronary heart disease.May there be cardiopathic sign in patient, but does not have tangible diabetes performance, is diagnosed out (for the first time) to suffer from diabetes then.Blood vessel blockage disease (as leg, eye or brain) is common consequence, causes the foot gangrene, and posteriority is blind, possible apoplexy.The attention WHO report not can be regarded as diabetes a kind of fundamental cause of coronary heart disease.

Milk proem matter

Known casein produces harmful effect (comprising the effect based on peptide) to some individual in every way.Interested especially is to have apparent causal connection between casein type and the onset diabetes rate.In some preventative strategies that proposed, identify and remove the metabolism condition that causes this sick factor (Popham 1978, Elliott 1999Padburg 1999 and other people) in the environment and/or improve coexistence and be subjected to great attention.

The causality of casein variant and diabetes itself in the milk will be discussed now.Caseic some fragment of β (peptide) has a kind of structure, and the proline residue in this structure just provides the resistance to the digestion of intestines endoproteinase if replace with arbitrary amino acid, and these fragments can be kept perfectly, and by in circulation, being found behind the small bowel.Casein morphine peptide has this structure.Caseic modification A 1 of ox β and B after the hydrolysis, produce some the beta-casein morphine peptide 7 (PRO-GLY-PRO-ILE-PRO-GLY) that comprises residue (A1 type) 63-68 in small intestine.Beta-casein morphine peptide 7 has the character of opium, comprises for small intestine some effect of (as to motility, absorbability and secretion) itself.It is a kind of direct inhibitor of acetylcholinesterase.A2 type beta-casein produces beta-casein morphine peptide 9, rather than 7, because 67 proline residue is further replaced in this casein.See the structure (sequence) of Fig. 3.Teschemacher (US 4681871) has illustrated various oral active casein morphine peptides, preferably have opium or analgesic activity, separation and purposes as beta-casein morphine peptide 3 small peptides such as (being used for pain relieving), but do not mention A2 type beta-casein, do not mention the functional relationship of casein morphine peptide and diabetes yet.Elitsur etc. have discussed lymphocyte and the interaction of casein morphine peptide in small bowel.

Past was studied between some countries and the community thereof about suckling or the picked-up of dairy products and the relation (Padberg 1999) that disease (as type i diabetes) takes place over 15 years.Present inventor's key analysis (seeing Eliott (1999)) has identified between the weighted average that the type 1 diabetes incidence of disease and beta-casein A1 and Type B (promptly except that the A2 type) consume and has existed very strong correlation.This compares statistics (the high milk consumption with unusual Iceland; The low incidence of disease) unanimity.Iceland ox almost only secretes A2.

WO96/14577 has illustrated that the milk proem gene expresses in the codominance mode, and therefore individual phenotype causes the casein that mixes usually, comprises beta-casein mixture (as A1A2, A2A3, A2B) etc.; There are many allele.The gene frequency is different between kind, and in A2 type variant allele, the Holstein/Friesian tendency is low to be expressed.This application explanation is used for dairy produce production, should select only have the A2A2 genotype, and only produce the ox of beta-casein A2 variant, and perhaps, picked-up does not contain the dairy produce of beta-casein A1, will reduce the incidence of disease of diabetes.The supposition of doing according to prior art is to contain beta-casein A1 (or similarly the diabetes effect that causes of) milk only is owing to inevitably discharged the result of beta-casein morphine peptide 7 in the small intestine proteolysis process.Monetini etc. are described in and have found the beta-casein antibody horizontal that significantly improves among the type i diabetes patient

List of references

J Am Board Fam Practll (5): 391-398 such as Abby (in September, 1998) [the corn nourishing reinforced level deficiency of FDA]

Akerblom etc. 1999, and Proceedings 4 ^ThImmunology of Diabetes SocietyConference, Rome, p.123

Bennett G etc., Nutr Rev 1999 May 57 (5 pt 2) 551-4 summary

Br  nstrup etc., Am J Clin Nutr; 68 (5): 1104-1110 Nov 1998[folic acid adds cobalamin]

The purposes of J Nutr (US) 1,996 126 (4 Suppl) 1295S-1300S[betaine aldehydes such as Dudman]

Elitsur?Y?&?Luk?G?D?Clin?exp?Immunol?85：493-497(1991)

Elliott RB etc. " I type (insulin-dependent) diabetes and milk: the picked-up of casein variant " (Diabetologia (1999) 42:292-296)

JAMA 277:1775-1781 (in June, 1997) such as Graham IL " the blood plasma homocystine is as the hazards Europe agreement action plan of angiosis "

Hackam etc., Am J Hypertens 2000 Jan; The improvement of the anti-homocystinemia treatment of 13 (1 Pt 1) 105-110[rear neck artery plaque]

Circulation such as Hoogeveen 2,000 4; 101 (13): 1506-11[links tHcy and diabetes]

Am J Cardiol 83 (6): 821-5 such as Lobo A in March, 1999 [test b 6, cobalamin and folic acid treatment]

Malinow MR Can J Cardiol 1999 Aprl; The tHcy reduction of 15 Suppl B:31B-34B[B family vitamins]

Monetini L etc. " antibody of the anti-cattle beta-casein in diabetes and other autoimmunity diseases " (not publishing)

Oakley G " speed that U.S.'s apoplexy death rate descends has been accelerated in the folic acid defence ", inedited Lancet believes to the editor.

Padburg S etc. the importance of the A1 and the A2 antibody of beta-casein " in the type 1 diabetes at " DtschMed Wochenschr 1999 Dec 19:124 (5): 1518-(seeing the medical science summary)

Pietrzik K " homocystine and folic acid " BASF Transfer (in April, 1998) www.basf-ag.basf.de ... tran0498.htm (can get in June, 2000)

Popham RE etc., " variation of the ischemic heart disease death rate relevant with the milk picked-up " MedicalHypotheses 12:321-329 (1978) with alcohol

JAMA such as Rimm E B on February 4th, 1998; 279 (5); 359-364

Scott?FW?Am?J?Clin?Nutr?51；489-491(1990)

QJM such as Ward 90 (8) 519-524 Aug 1997[give 3 kinds of speed of 30 patient's folic acid]

Wasmuth HE etc., " incidence of disease of German beta-casein A1 consumption and type 1 diabetes "

J Am Coll Cardiol such as Woo December 34 (7) in 1999; The minimizing that 2002-2006[arteria brachialis medium sized artery is atherosis]

Diabetes such as Virtanen in June, 2000: 49 (6); Siblings' case-control study among the children of 912-7[trouble diabetes]

Target

The diet additive that the purpose of this invention is to provide a kind of reinforcement, it can reduce vascular diseases and/or diabetes, or gives the public a kind of useful selection at least.

Invention is described

In first broad aspect of the present invention, a kind of diet additive of reinforcement is provided, it contains milk or dairy produce, wherein this diet additive is at least aly to be selected from following compound and to strengthen by what add effective dose, this compound is selected from (this paper is called) I group compound, comprises acceptable analog on betaine aldehyde, cobalamin, folic acid, pyridoxine and each the material materia medica; When taking, this fortified diet additive can reduce the blood plasma level of homocystine (tHcy), thereby can reduce the incidence of disease of mammal colony medium vessels disease (VaD), particularly angiocardiopathy and cranial vascular disease and NTD.

One closely-related aspect, the invention provides diet additive, wherein this additive is strengthened at least two kinds of compounds that are selected from group I of effective dose by adding respectively.

Preferred, what the invention provides reinforcement contains the milk or the diet additive of dairy produce, and folic acid (or the acceptable analog of its materia medica) and at least a other compounds of being selected from group I are wherein arranged.

Suppose above-claimed cpd arbitrarily the preferred concentration of two or more mixtures be identical when using separately with their.

Preferred folic acid uses together with cobalamin at least.

At related aspect, the invention provides at least a compound of group I and the purposes of milk or dairy produce of being selected from of effective dose, this diet additive is the tHcy for effective reduction crowd, thereby reduces VaD indirectly.

The folic acid addition preferable range that is applicable to the adult is picked-up every day about 300-500 microgram (μ g); More preferably 400 micrograms, and supposition are absorbed 400 milliliters of milk every day, and this is corresponding to equivalent amount on the materia medica of 1 milliliter of milk 1 microgram folic acid or its analog.The acceptable method of the NTD incidence of disease among the control crowd preferably is provided with these goods.

The preferable range of cobalamin amount is about 4-7 microgram every day; More preferably 5 micrograms are supposed and are absorbed 400 milliliters of milk every day, and this is equivalent to every milliliter of milk approximately O.012 microgram cobalamin or its equivalent.

The preferable range of pyridoxine amount is about 1.5-4 milligram every day; More preferably 2 milligrams, suppose and absorb 400 milliliters of milk every day that this is equivalent to every milliliter of about 5 microgram pyridoxines of milk or its equivalent.

At least the another kind of compound that can reduce tHcy is a betaine aldehyde, and the preferred effective dose of preferably absorbing betaine aldehyde every day is that every day is up to 1 gram; More preferably about 100 milligrams of every day, preferably the compound with other appointments uses together.

Aspect second largest, the invention provides a kind of diet additive, it contains aforesaid reinforce-milk of this section or dairy produce, wherein this milk or dairy produce also contain in check cattle beta-casein composition, it is made up of the A2 variant basically, therefore this diet supplement can reduce the incidence of disease and/or the effect of crowd's medium vessels disease (VaD), and this is to have reduced tHcy owing to add this section above-mentioned substance, or has reduced by 1 type and the diabetes B incidence of disease owing to forming by the improvement casein.

In a related aspect, the invention provides milk or the milk product purposes in making diet additive, the feature of this milk or milk product is to be substantially free of A1 type or Type B beta-casein; The purpose of this diet additive is the influence of diabetes among the minimizing crowd, and this is owing to reduced the result of VaD among the crowd.

In another related fields, the invention provides milk or the milk product purposes in the diet additive of making a kind of reinforcement, the feature of this milk or milk product is to have removed A1 or Type B beta-casein basically, and at least a compound that is selected from group I of adding effective dose: the purpose of this diet additive is the influence of diabetes among the minimizing crowd, and this is owing to reduced the result of VaD among the crowd.

Preferred this diet additive comprises A2 type beta-casein.

The 3rd broad aspect, the invention provides a kind of diet additive, it contains the milk or the dairy products of the aforementioned reinforcement of this section, wherein milk or dairy produce are to derive from ox, contain the in check beta-casein of forming by the A2 variant basically, and has an immunological properties, this character shows in digestion process at least, at least some beta-casein A2 are transformed into metastable reactive compound during digestion, and it can promote to resist the immunity of diabetes by the effect of performance in small bowel or on every side.

In a related aspect, the invention provides the metastable compound that the immunity of diabetes is resisted in a kind of energy promotion; This compound contains in the presence of the digestibility enzyme metastable peptide in small intestine, and preferably this peptide has 7-12 amino acid residue, and wherein proline residue has constituted the major part of these residues.

In another related fields; the invention provides the aforesaid diet additive of a kind of this section; wherein metastable reactive compound is the peptide with 7 above amino acid residues; say that more specifically this metastable reactive compound is the peptide that is called beta-casein morphine peptide 9; it has peptide sequence shown in Figure 3, and this compound can cause to the protection of small part opposing diabetes.

Other caseins comprise derived from the mammiferous casein of other kinds.

In addition, reactive compound based on the structure of cattle beta-casein morphine peptide 9 can be used recombinant methods, or prepare from casein by proteolysis, or as peptide or as acceptable salt on its materia medica, or acceptable ester and synthesizing on the materia medica, and provide as the part of diet additive form with stabilisation.

Preferably strengthen the metastable compound of resisting diabetes immunity by add at least a preparation with the effect of adjuvant sample in this diet additive with auxiliary energy, this reagent should be able to strengthen the generation of immunity.Optional stabilized form can slowly discharge this kind reactive compound, thereby is released into small intestine in a period of time.

In the 4th broad aspect of the present invention, the invention provides and a kind ofly can remove the two the diet additive of hazard factor of diabetes and VaD; The diet additive of this reinforcement contains the composition of milk or dairy produce, their essentially no A1 or Type B caseins, at least a compound that is selected from group I that has effective dose simultaneously.

In a related aspect, the invention provides a kind of diet additive of reinforcement, it contains aforesaid compound of at least a this section and A2 casein; These goods can improve the state of cardiovascular system, and reduce the danger that causes diabetic disorders.

The 5th broad aspect, the invention provides a kind of method for preparing the dairy produce of aforesaid reinforcement, the method comprising the steps of: the milk that contains the aforementioned special casein composition of this section is provided, optional with pasteurization or additive method this milk of sterilizing, and at least a compound that is selected from group I of adding capacity, to reach effective ultimate density of aforementioned each compound of this section.

This milk of optional processing makes its essentially no A1 or Type B β casein.

The 6th broad aspect, the invention provides a kind of method that at utmost reduces crowd's onset diabetes rate and/or its influence, comprise step: the reinforce-milk goods that in diet, use the aforesaid effective dose of this section.

The 7th broad aspect, the invention provides the method for the VaD incidence of disease among a kind of at utmost reduction crowd and/or influence, comprise step: the reinforce-milk goods that in diet, use the aforesaid effective dose of this section.In a related aspect, the present invention also provides the NTD incidence of disease among the reduction crowd at utmost and/or the method for influence.

Preferably the dairy produce with this reinforcement replaces any nonreinforcement dairy produce in the diet.

Optional, these reinforce-milk goods contain the casein composition of the aforesaid change of this section.

The 8th broad aspect, the invention provides a kind of reinforce-milk goods, it contains at least a compound that is selected from group I of effective dose.

In first related fields, the invention provides reinforce-milk goods with the milk preparation of A2 beta-casein type, therefore there is not A1 type beta-casein basically, the also preferred Type B beta-casein that therefore do not exist basically.In addition, this casein may be defined as " not having the casein that can produce beta-casein morphine peptide-7 when small intestine digests in these reinforce-milk goods basically ".

The 9th broad aspect, the invention provides the method for following disease incidence among the reduction crowd: (a) diabetes I type, (b) diabetes type II, (c) angiocardiopathy, (d) cranial vascular disease, (e) peripheral vascular disease, or (f) vascular wall degeneration, the method comprising the steps of: the diet additive of making and offer a kind of dairy produce form of crowd, it contains the A2 beta-casein, but do not have A1 or Type B beta-casein substantially, and the compound of at least a group of I by adding effective dose is strengthened.Preferably also comprise this specification listed other diseases in " other diseases " is following.

The tenth broad aspect; the invention provides a kind of method that alleviates type i diabetes; this method provides the dairy produce of having identified that obtains with animal varieties or strain from milk to the population at risk; this animal only produces beta-casein A2; substantially there are not beta-casein A1 or beta-casein B; thereby the member who makes the crowd has an opportunity to absorb this dairy produce of having identified, thereby makes individual owing to the beta-casein morphine peptide 9 that has contacted the treatment effective dose is protected.

In a related aspect, the invention provides a kind of method that alleviates type i diabetes, this method has been added the diet product of beta-casein morphine peptide 9 or its precursor by oral administration.

The 11 broad aspect, the invention provides and in the milk industry, use, or at least in kind or the strain of the dairy animal of some commercial use, described animal produces beta-casein A2, and does not produce beta-casein A1 or beta-casein B substantially.

The 12 broad aspect, the invention provides a kind of selection by dairy animal kind or incross population, set up and produce beta-casein A2, and do not produce beta-casein A1 or A1A2 basically, or do not produce the kind or the strain of the dairy animal of beta-casein B, wherein this method comprises suitable animal selection known in the art or animal separation method, thereby produce the caseic dairy produce of A2 type is only arranged basically.

The 13 broad aspect, the invention provides purified dairy produce in manufacture process, thereby from goods, remove beta-casein A1 at least, (or also having removed beta-casein B), even whole casein.

The 14 broad aspect, the invention provides a kind of milk, based on the product or the dairy produce of milk, owing to selected the donor ox, the concentration of their contained beta-casein A1 (or also having beta-casein B) reduces at least.In related fields, the invention provides a kind of milk, based on the product or the dairy produce of milk, because subsequently manufacturing processing to the beta-casein A1 that they contain, also has the concentration of beta-casein B to reduce.

The 15 broad aspect, the invention provides a kind of substitute that does not have milk, but it is strengthened with a kind of effective milk substitute of the compound as aforesaid group of I of this section at least, thereby makes those people that can not absorb dairy produce owing to some reasons can often accept to reduce the additive of tHcy and their artifact (as soymilk).

The 16 broad aspect, the invention provides a kind of diet additive that is used for the treatment of the mammal (as cat or dog, they can produce diabetes) except the people.

Preferred embodiment

Description of the invention provided herein is to be used for for example purely, is not to limit the scope of the invention by any way or degree.

Figure

Fig. 1: BioBreeding rat/Prosobee result of experiment figure

Fig. 2: the international correlation of A1 beta-casein and four kinds of disease incidences.

Fig. 3: the sequence of cattle beta-casein A2, indicated the position of casein morphine peptide.

Principle

At the danger of many diabetes and VaD and incidence picked-up milk often and widely in the very high community all. The milk of existing form may work to these two kinds of diseases; The Epidemiological Evidence of having delivered He do not deliver shows that it is closely related to drink the milk and the type i diabetes that contain A1 type β casein or Type B beta-casein; Drink the milk then not (Elliott, 1999) that only contains A2 type beta-casein. Also permit this diet threatened to be transformed into a kind of chance, with sanatory composition replacement or replenish the milk composition of insalubrity. Like this, the population at risk can simply replace another kind of with a kind of milk.

The each side of this specification comprises: (1) proposes a kind of theory, be that beta-casein morphine peptide 7 significantly is easy to cause diabetes, (2) a kind of theory is proposed, be that beta-casein morphine peptide 9 can be used for the immunity inoculation process, (3) propose to provide the milk that only contains beta-casein A2 variant, and the optional compound that can reduce tHcy that adds will significantly reduce diabetes and vascular diseases to the crowd.

This specification focuses on that common site of action is the lysis (being called vascular diseases or VaD herein) of vascular wall.Therapeutic alliance comprises diabetes and tHcy, and the strategy of control vascular wall disease will show effect extra, that may or even work in coordination with.Note Graham (etc.) 1997 observe between tHcy and the smoking synergy arranged.The present invention did not carry out clinical trial as yet, and this remarkable result based on certain crowd is the actual result of the present invention of use probably.Woo etc. (1999) have described about scanning the measured improvement of arteria brachialis repeatedly during the folic acid treatment and after the treatment.Hackam etc. (2000) have described through after several all Supplement of folic acid, the improvement relevant with carotid sinus/carotid plaques that records among the adult that tHcy reduces.

Preventative milk of the present invention and milk composition purpose are to reduce the VaD incidence of disease, directly by using the preparation that can reduce tHcy, and (a) is rich in beta-casein A2 variant by providing indirectly, and the low milk that contains A1 and B variant, and/or the immunology performance of (b) utilizing β-tyrosine morphine peptide 9 (a kind of activity of beta-casein A2 and metastable peptide digestion fragment have 9 amino acid) reduces the incidence of disease of diabetes.Realized and the reduction that promotes the healthy closely-related tHcy level of vascular wall by the fortified diet preparation, said preparation contains above-mentioned casein variant milk, contains at least a compound that is selected from betaine aldehyde, cobalamin, folic acid and vitamin B6 (pyridoxine) of effective dose.To be comprised the milk of handling, selected by the diet of in fact strengthening that the population at risk extensively absorbs, also comprise milk of selecting and the cereal of handling.Also comprise the dairy produce strengthened such as ice cream, sour milk, drying powdered milk etc.

Experiment 1

This research relates to " biological breeding " (BB) rat in experiment.See Fig. 1, figure shows that the longitudinal axis is onset diabetes rate (1.0=100%) result.Control diet be " Prosobee " (TM), it is a kind of bean product, is used as the food of rat in the laboratory.Spontaneous onset diabetes rate is about 38% in contrast mouse group.Hello " Prosobee " (TM) add that 10% mixes the rat incidence of disease about 27% of casein (being A1 and A2).Hello " Prosobee " (TM) add the caseic rat incidence of disease about 20% of 10%A1 type.According to the explanation of WO96/14577, A1 group onset diabetes rate is than control group height.

If A2 casein (or its milling product) is merely " neutrality " material, the diabetes incidence of A2 group is approximately identical with control group so, because there is not the ill-effect of beta-casein morphine peptide 7.In fact the onset diabetes rate of A2 group significantly descends, and is minimum in each group.Therefore, the inventor proposes, and the incidence of disease of 9 pairs of type i diabetes of beta-casein morphine peptide has beneficial effect.Guess that it has played the effect of immunomodulator.The casein fragment of the milk of a kind of animal is to being human at least and the neurological susceptibility antibody of testing rodent pancreatic beta-islet cells has effect, the mechanism of this effect does not know that casein has participated in eucaryotic cell structure and little peptide (as casein morphine peptide) may play the effect of courier in the born of the same parents but observe.

Experiment 2

The result of relatively normal (SWR/J) mouse and NOD (diabetes susceptible) mouse has studied the effect derived from two kinds of peptides of beta-casein.These two kinds of peptides are: beta-casein morphine peptide-7, and it is the A1 beta-casein, rather than the enzymic digestion product of A2 variant; Or beta-casein morphine peptide-9, it is the A2 beta-casein, rather than the digestion product of A1 variant.From wean, female 30 age in days mouse are just fed with the diet of no milk proem.Every group of 10 animals.The 30th day, with 10 milligrams of ovalbumin and 1 milligram of one or another kind of peptide injection animals with adjuvant (Freund's complete adjuvant) preparation.In ensuing 10 days, duplicate injection every day peptide.Took a blood sample from animal on 7th and 11, analyze the IgG and the IgM antibody of antiovalbumin.

The result: when the feature of NOD mouse is 7 and control-animal relatively IgM and IgG reply lower.This lasts till 11 with regard to IgM, but IgG is not like this.Normal mouse when the average immunoglobulin (Ig) of ovalbumin is replied 7, no matter give beta-casein morphine peptide-7 or 9 all than saline treatment control mice height, and 11 days the time not like this.(table 1)

Table 1: normal mouse: the average δ OD of saline control

7 days	Beta-casein morphine peptide-7	Beta-casein morphine peptide-9
			?IgG	?0.118	?0.106
?IgM	?0.130	?0.201
			11 days
?IgG	?0.050	?0.050

?IgM

?0.020

?0.030

Two kinds of peptides all quicken early immune and reply, and beta-casein morphine peptide-9 may be stronger than beta-casein morphine peptide-7 effect.

On the other hand, do not see in the NOD mouse of this early stage peptide invigoration effect in the time of 7 days of antibody response, only see that the IgG of BCM replys (table 2) on 11st.

Table 2:NOD mouse: the average δ OD of saline control

7 days	Beta-casein morphine peptide-7	Beta-casein morphine peptide-9
			?IgG	?0.006	?0.038
?IgM	?0.007	-0.002
			11 days
?IgG	?0.102	-0.092
			?IgM	?-0.018	-0.007

These experiments are determined: diabetes model (NOD mouse) is replied defectiveness to the early antibody of parenteral administration antigen, and this defective can not be corrected by any milk peptide.Yet, in the SWR/J animal, beta-casein morphine peptide-9 for the early stage spread effect of IgG level than better keeping in the NOD mouse.The milk that can produce beta-casein morphine peptide-9 may improve this early antibody and reply defective (NOD/SWR/J is than=0.36), is better than producing the milk (NOD/SWR/J is than=0.05) of beta-casein morphine peptide-7.This slight " progress " of beta-casein morphine peptide-9 may reflect the mechanism of causing a disease of diabetes.Certainly these experiments are based on injection, rather than the antigen of small intestine contact.

Experiment 3

Fig. 2 has summed up this result of experiment: Retrospective review information, seek that everyone drinks the relation between the milk amount among the incidence of disease of some selected diseases and the crowd, and more specifically, absorb the relation of A1 beta-casein amount with everyone.Adopt each kind milk in certain country to calculate this data with the domestic herds proportional meter of each kind of composition in the A1 beta-casein ratio of ox and the various countries' milk products scientific literature.Obtained the consumption of milk proem from the FAO network address.The incidence of disease data of diabetes are limited to white man crowd, to reduce in the type i diabetes because obscuring of producing of the hereditary difference of ethnic group.The data of asthma prevalence rate are based on " stridulate 12 months popular " (delivering as childhood asthma and allergy international research meeting).Cancer registration data from about the nineteen ninety has obtained the incidence of disease data of Huppert's disease.This experiment is a kind of ecological study, the restriction that will have all to follow.We find at whole country (about 1980) the A1 casein in the provand and following significant correlation per capita: the incidence of disease of (1) same time children diabetes, (2) the nineteen ninety adult ischemic heart disease death rate, (3) nineteen ninety the masculinity and femininity Huppert's disease the incidence of disease, and the incidence of disease of these diseases also be relative to each other (it is relevant that the Basic of Biology of possible myeloma and A1 milk beta-casein morphine peptide 7 suppresses lymphocytes).Although found significant association on some statistics, this does not prove reason, though increased possibility.And, the necessary correlation between all milk and the A1 beta-casein of change value and conspicuousness explain to(for) 1 type (IDDM) diabetes and ischemic heart disease ((CHD)).We are also noted that this correlation dies down if when being added in the food with A1 β casein B.This research adds that twice zoopery supported the claim that the present invention can give health performance to milk or dairy produce, and these milk or dairy produce contain very low or do not contain A1 type beta-casein, in addition do not organize the I additive give healthy performance especially.

Implement the best approach of the present invention

The present invention proposes the various milk combinations of forming by dominant A2 type casein etc.Embodiment A is a kind of diet additive of reinforcement, and it comprises the folic acid of the interpolation of effective dose, and B6 and cobalamin, known they tHcy is worked; Additive adds according to common milk.Embodiment B is " an in check casein composition ".Can not be actual collaborative on the Pathological Physiology exposure level if estimate to vascular wall and patient known or that do not suspect diabetes or homocystinemia, (A) and combination (Embodiment C) (B) will show extra effect.Can cure these diseases.

Embodiment A only is used at utmost reducing the other diseases except diabetes usually, and this paper is called the influence of " VaD ".In these cases, the in check casein embodiment of the present invention (B) does not have ill-effect at least, and may in fact reduce the generation of diabetes in the dangerous individual.Note the surprising height of the incidence of disease of " the not diabetes of Huai Yiing " in suffering from the patient of angiosis.

Illustrative embodiment (A)

This embodiment has described with at least a compound that is selected from betaine aldehyde, cobalamin, folic acid and vitamin B6 of effective dose and has strengthened the milk of commercially producing, and reduces tHcy.According to known " recommending amount every day " (RDA) with about the document of tHcy, and the reinforce-milk that may drink every day of typical consumer or the dairy produce amount preferable amount (LD of the material of adding that determined these fortification substances ₅₀The coefficient height)." quantity determine " document of being correlated with comprises: (A) Lobo etc. (1999), Ohio finds that 1 milligram of folic acid every day (with B6 and cobalamin coupling) is better unlike 400 micrograms to reducing tHcy, (95 mean aves are 61 years old patient), (B) in order to reduce the youthful tHcy in Northern Ireland, Ward etc. (1997) find that 400 micrograms are better unlike 200 micrograms, but more effective (30 volunteers of 200 to 100 micrograms, through 26 weeks), (C) Br  nstrup etc. (1998) in the German women of youth, find 400 microgram folic acid and cobalamin (6 or 400 microgram) for the tHcy level obviously than more effective with folic acid separately.In addition, for fear of NTD, recommendation consumption every day of folic acid is about 400 micrograms every day.Effective additive capacity that people can sum up folic acid approximately is micrograms every days 400, but that these experiment usefulness is the ordinary people, and does not relate to the environment that other do not have folic acid fully.So we recommend to absorb every day 300-500 microgram folic acid is to be fit to adult dosage every day (if containing a kind of compound of adding).Suppose and drink 400 milliliters of milk every day that this is equivalent to every milliliter of about 1 microgram folic acid of milk or its equivalent.

Not too remove for the getable evidence of the preferable range of determining the cobalamin amount (no matter whether being to add a kind of compound).We recommend 4-7 microgram every day now.5 micrograms are corresponding to every milliliter 0.012 microgram cobalamin (the supposition recipient does not absorb defective).Similarly, the preferable range of pyridoxine is 1.5-4 milligram every day.2 milligrams in every day 400 milliliters of milk corresponding to 5 microgram pyridoxines or its equivalent in every milliliter of the ears of an ox or cow.

Also known betaine aldehyde can reduce tHcy.Preferred effectively daily intake is up to gram every day 1; More preferably about 100 milligrams of every day, preferably taken together with the compound of other appointments.The analog of all these components is that drug world is known, and can stipulate corresponding effective dose.The mixture of two or more of preferred above-claimed cpd, because evidence show to render a service increases (for example seeing (1998) such as Br  nstrup), and for each, the amount of supposition is identical with the amount that they use respectively.If note using folic acid, should absorb cobalamin with average daily requirement (5 microgram) analog quantity.When giving the individuality (as the elderly, having the absorption defective) of cobalamin possibility deficiency with above-mentioned dosage, this amount will prevent the ill-effect (as for cerebral function) of folic acid.

Preferably the measurement circuitry feed process of being familiar with by those skilled in the art before preparation can be taken or further be made dairy produce adds these vitamin enrichment agent.Though cobalamin and B6 can be by light degradation, they are not remarkable to the sensitiveness of heat, under will preserving in the pasteurization of routine.In fact, they will preserved in the processing (as drying) widely.Preferably these milk/dairy produces of the methods analyst of being familiar with those skilled in the art before taking confirm vitamin additives.The liquid milk of this reinforcement can be the commercial form of any milk, but is not limited to the milk of defatted milk, super heat treated milk or pasteurization sterilization.The inventive method also can be applicable to aforesaid " dairy produce ".

In the crowd, extensively adopt this " oneself is used " method with an obstacle that reduces tHcy be some owing to reasons such as allergic reaction can not have milk (or edible dairy produce), some communities owing to culture, can not get or the religion reason does not have milk.Therefore the present invention offers the selection of several reinforcement liquid of these people or community, and these liquid usually replace suckling drinking.Therefore the present invention also comprises the soymilk of (1) reinforcement etc., and (2) " tea/coffee additive " may be the sweetener of water or a kind of reinforcement, and the soda of (3) a kind of reinforcement and (4) bottled reinforcement drinking water respectively contain at least a compound that is selected from group I; Be folic acid and cobalamin at least preferably, have give most of users enough every day dosage concentration.

Illustrative embodiment (B)

This aspect of the present invention adopts the explanation that has replenished embodiment A about the information of prevention 1 type and diabetes B on prevention VaD, substantially the milk or the dairy produce that do not have these protein (casein) are provided, after these protein digest, can produce β-tyrosine morphine peptide-7 or other longer peptides that contains β-tyrosine morphine peptide-7 sequence in acceptor mammal (comprising the people) intestines.This can finish by following steps:

A) selecting only to produce the caseic ox of A2 variant β provides this milk-these milk not produce beta-casein morphine peptide-7 or relevant peptide after intestinal digestion.Existing ox produces A1, A2 or the B casein of mixed form, reflected that expressed protein is the result that several codominant genes exist, and the method for knowing in the industry field of can selecting to suckle is used for (1) selectivity and raises and the caseic animal of A2 only is provided (selection of bull is by artificial insemination, the rapid shortcut that changes cows genomic constitution of realization) (2) are picked out to isozygoty from the hybridization cows and are expressed the animal of A2, and the quality assurance to product is provided.

B) (choose wantonly) with physics, chemistry or enzyme method and remove beta-caseins all or all basically in the milk, or only remove A1 and Type B beta-casein, stay the A2 casein.

C) (choose) ox in change milk source in the heredity wantonly, thereby after digestion, do not produce beta-casein morphine peptide-7 or relevant peptide.These hereditary changes can be removed gene orders specific or whole beta-caseins fully.

The ox that select to produce required milk relates to by measuring various beta-caseins in the individual milk sample identifies and only uses the ox of generation A2 beta-casein to ox.The method that available gel electrophoresis or other those skilled in the art are familiar with is identified the beta-casein variant.

We believe that the present invention can make theoretical explanation with following discovery.

First: the character that may trigger the diet environmental factor of diabetes

Previous research has shown the association that has between the amount of drinkable liquid milk and the type 1 diabetes (Scott etc.) on the epidemiology, this related possible cause can further be shared the A1 and the Type B beta-casein composition (Elliott etc. of milk, 1999, Laugesen etc. (not delivering)).Do not know whether other milk proems are relevant with diabetes.Particularly, the A2 variant of beta-casein is seemingly harmless.Other studies show that relevant between type 1 diabetes and the high-caliber anti-A1 antibody in some crowds at least, but with A2 beta-casein irrelevant (Elliott etc., 1999).

Virtanen etc. (2000) show, and when considering the genetic predisposition of diabetes, the children that diabetes take place drink than the children that diabetes do not take place and more many milk.Have to the genetic predisposition of diabetes but the edible baby who does not contain the diet of milk of cradle, than can not the exert an influence early stage disease symptoms (Akerblorn etc., 1999) of insulin cellulation in the body of the baby of edible milk.Bennett etc. show the association between early stage milk drink and the diabetes B.Therefore, in the mankind, it seems that the drinking milk be the environmental triggers factor that causes two kinds of diabetes, and at least in type 1 diabetes this as if with milk in A1 relevant with B beta-casein composition-but irrelevant with the A2 beta-casein.

A1 and B beta-casein produce beta-casein morphine peptide-7 by digestive ferment digestion back in the intestines, and the A2 beta-casein does not produce.Beta-casein morphine peptide-7 has the effect of opium sample for the intestines transit time in animal (comprising the people), and people's IL is also had immunosuppressive action (Elitsur 1992).The effect of this opium sample can worsen the genetic predisposition to 1 type and diabetes B.

Second portion: (known) relation of coronary heart disease and diabetes.1 type and diabetes B make the danger of coronary heart disease increase 5-10 doubly.See Fig. 2.In some communities, have among the adult more than 40 years old to have diabetes B more than 10%, in these communities, diabetes are main causes of coronary heart disease.Type 1 diabetes is less to crowd's coronary heart disease incidence effect.Diabetes (two types) incidence of disease sharply increases in the whole world.

Third part: coronary heart disease and drinkable liquid are suckled, and particularly contain the relation of the milk of beta-casein A1 and B variant.Several epidemiological studies of above-mentioned (see figure 2) show, drink between liquid milk and the coronary heart disease death rate relevantly, and this is seemingly because the protein component rather than the fat constituent of milk.As expected, in view of diabetes with cardiopathic related, drink the A1 beta-casein and it seems with the relation of coronary heart disease death rate closer than any other composition in the milk.

The 4th part: between tHcy and diabetes, exist actual contact? Hoogeveen (2000) has reported the relation of tHcy and 5-annual death rate, irrelevant with other main hazard factors, and compare with the non-diabetic patient, it seems that tHcy be the stronger hazards (1.9 times) of diabetes B patient death rate.

Relation between the 5th part: tHcy raises and the cardiovascular death rate raises.The summary document of this specification is reached a conclusion people: the effective method that reduces high tHcy may provide all three kinds of vitamins and betaine aldehydes.Causing the dangerous reduction of VaD may be to work by the mechanism that reduces vascular resistence and haemolysis trend.Another useful consequence of this additive (particularly folic acid) (though irrelevant) is the generation that has reduced neural tube closure defective spina bifida and related defects, if these vitamin(e) supplements are drunk during early pregnancy.

The amynologic mechanism that the 6th part is possible.As if caseic a kind of particular peptide beta-casein morphine peptide 9 because its immunological properties is useful, and the beta-casein morphine peptide 7 of A1 and the Type B beta-casein harmful components of some milk seemingly.A kind of feature of casein morphine peptide is to change the attack that peptide bond that proline residue adjoins " protection " is not subjected to the inscribe peptase.Casein contains the proline-X residue sequence that repeats alternately by chance.The sequence of a reservation-at residue 60-68, though another pro-tyr-pro-glu sequence is at residue 180 is only arranged.The another kind of explanation is according to following discovery: beta-casein morphine peptide 9 mates (see figure 3) with the amino acid residue 60-68 of cattle beta-casein A2.The composition of this peptide has been given making the further resistance of digestion with the endopeptidase cutting.This peptide is released in the small intestine in digestion contains the milk process of this casein variant.

It is believed that beta-casein morphine peptide-9 has immanoprotection action or at least a immunoregulation effect; these effects are relevant with type i diabetes, drink milk (essentially no beta-casein A1 and the beta-casein B) result who contains beta-casein A2 and will cause the onset diabetes rate to be reduced to below contrast crowd's the incidence of disease.Some will be described now in order to show the experiment of beta-casein morphine peptide 9 immunologic competences.

Embodiment (A)+(B) is described

The example of other fortified diet additives comprises:

1. a liquid milk contains A2 type casein composition; Substantially do not have A1 type or Type B casein, also added the compound (seeing definition) of group I.Preferably add two kinds of compounds at least, utilize to interact, and the preferred amounts of picked-up every day is acceptable people's daily requirement amount, promptly about 400 microgram folic acid, 5 microgram cobalamins and 2 microgram B6.Average every day of the amount of drinking of supposing milk is 400 milliliters, per 100 milliliters of A2 type caseins but do not have the caseic milk of A1 type to replenish this picked-up with 100 microgram folic acid, 1.25 microgram cobalamins and 0.5 milligram of B6 concentration.Notice that we know special case, as absorb the elderly of the extra cobalamin compensation of few needs.For these special cases, can provide the dairy produce of special reinforcement with extra cobalamin or internal factor.Can regulate other compositions.

2. a kind of wheat flour that has added folic acid or its analog is provided.Can add other materials that can reduce tHcy; Yet it may be waste that cobalamin is provided by this way.Some can not eat wheat flour or at least glutelin be tolerated.

3. a substitute (for the target of guaranteeing reliable picked-up every day) is a kind of reinforcement breakfast cereals that contains added compound of the present invention, so that above-mentioned picked-up every day to be provided, sell together as " kit of parts " with the container of suitable preservation A2-casein milk.This may be included in a certain amount of " UHT " in the pouch or the milk of other long shelf-lifes, can unite " ready-made " breakfast amount of selling or being separated into cereal or corresponding milk.

4. with the reinforcement ice cream of A2 type casein milk preparation, sour milk etc.

5. other food, its kind and obviously be not to make by milk products, but contain casein.

6. baby milk is applicable to even very young baby, can be consolidated to than low degree, with the preparation of A2 type casein milk.

7. the dairy produce that can accept to design for the young man is used vitamin enrichment, with the milk preparation of A2 type casein (do not discover its conceived have the dangerous young woman of spina bifida damage-this usually occurs in the early stage of embryonic development).Can know arterial disease among the young man.

8. all edibles milk any for the product on basis as milk powder, milk chocolate, cheese etc., strengthened with compound of the present invention, and suckling with A2 type casein prepares.

Water, wheat flour, milk is three kinds of compositions the most predictable of general western diet seemingly.Cereal usually is breakfast of standard.So we select these components, therefore need not to make a special effort (not needing to remember the ball etc. of taking medicine) just can reach sufficient picked-up every day.The various products of most probably advising in this specification will provide sale as " being of value to heart " or other substitutes.

The heat endurance of natural folic acid is bad, but artificial folic acid or combination can tolerate pasteurization (for example, loss seldom).The photostability of cobalamin in the milk (and B6) is bad.So any product of the present invention should preferably keep in Dark Place.

This prophylactic treatment ratio juris is united to remove in milk and is found, relate to diabetes and coronary heart disease the two dietary factor and the milk and the dairy produce of reinforcement, make it not have bad dietary factor, and coupling B bunch vitamin and/or betaine aldehyde, they can reduce tHcy.The method of this milk of the various character of the known production of those skilled in the art and products thereof, but these character and the intention that prevents obliterative vascular disease are joined together then is that the present invention is distinctive.

In order to use the present invention, can explore many approach.For example

1. producing beta-casein A2, basically the milk that does not produce beta-casein A1 and beta-casein B with the kind of animal or strain (for example: Bos indicus subspecies, with Iceland existing milk cow, goat or even the people, wherein adopt the people to suckle can to avoid contacting milk or its product of some kind, particularly early stage in the life in postpartum) milk products industry in purposes.

2. use from the milk of each kind or strain with some or all of system of selection known in the art and select the hybridization population of animal to produce beta-casein A2, and do not produce the animal of beta-casein A1, A1A2 or B basically.For example, milk cow can carry out the herds test, tests the casein variant of secretion, and repels the milk cow beyond those generations A2 variant.The bull that is considered as the AI male animal will directly be tested with gene engineering method, or test daughter's (preferably from A2 type dam) of its original filial generation as mentioned above.

3. at least, the individuality that known suspection suffers from type i diabetes should be drunk and only produce beta-casein A2, does not produce the dairy produce of the milk of beta-casein A1 or B with animal varieties or strain basically.

4. no matter orally contain beta-casein morphine peptide 9 and whether suckle with the food of type.Can prepare beta-casein morphine peptide 9 from casein by recombination method, maybe can synthesize.

5. can be with the sustained release preparation administration, thus promote or strengthen the immune response of beta-casein morphine peptide 9.

6. give " auxiliary material ", it can comprise:

(a) strengthen the material that from the protein enzyme is cut beta-casein morphine peptide,

(b) help material that beta-casein morphine peptide 9 is carried at least into little intestinal lamina propria

(c) strengthen the material of the interior immunocompetent cell of body to the responsing reaction of beta-casein morphine peptide 9.

7. can make any above-mentioned strategy, but also can use improved peptide etc., they have stronger ability than beta-casein morphine peptide 9 giving aspect the type i diabetes opposing.(though beta-casein morphine peptide 9 is to have desirable active naturally occurring peptide, and it is bigger that further research may obtain activity, the material that side effect is littler).

Commercial interest or advantage

Because the incidence of disease of heart and other vascular diseases, difficulty with the reliable diagnosis diabetes, and many people are about the not enough state of folic acid picked-up demand, clearly the present invention can save cost and individual's cost of many mechanisms (treatment) relevant with disease, diabetes and the VaD of these wide-scale distribution, and does not almost have the very big difficulty of inconvenience and cost or manufacturing.

For convenience, the present invention can be used as the type that substitutes of milk and sells, and perhaps is called " heart milk ", as common milk, use, and preferred conduct substitute completely, thereby can guarantee every daily dose. Additive is enough stable to heating, and can preserve, and is used for tea or coffee. In addition, the present invention also comprises some following special benefits:

(1) can reduce at least crowd's incidence of disease of type i diabetes. This will be avoided many people to suffer hardships, and can save throughout one's life about 1,000,000 dollar for each patient in New Zealand (population 3,800,000).

(2) less to the available information of type ii diabetes, but will accumulate owing to the reduction of tHcy for patient's benefit.

(3) VaD reduce show as deaths from heart disease rate, Apoplexy Morbidity and the death rate, because of minimizings such as peripheral vascular disease amputation, kidney transplants.

(4) this product provides enough every days folic acid amount to prevent NTD, if accepted by all women of child-bearing age as a kind of milk, uses this product with this problem among the elimination crowd.

(5) effect of accepting the casein variant will by inscribe selection before reasonably, be set up improved national herds.

(6) can improve crowd's health, and not need actual medicine.

At last, should understand scope of the present invention in this manual described and/or explanation and be not limited to this paper for the described preference of illustration purpose. It will be understood to those of skill in the art that and in the situation of the scope and spirit of the present invention of listing without prejudice to claim of the present invention, many changes, interpolation and replacement may be arranged.

Claims (15)

1. a diet additive that contains milk or dairy produce is characterized in that: strengthened diet additive by at least a compound group that is selected from group I that adds effective dose; This group I compound comprises acceptable analog on betaine aldehyde, cobalamin, folic acid, pyridoxine and each the material materia medica; When taking, the diet additive of this reinforcement can reduce the blood plasma level of homocystine, thereby can reduce the incidence of disease of the incidence of disease of the vascular conditions in the mammalian fauna, particularly angiocardiopathy and cranial vascular disease.

2. diet additive as claimed in claim 1 is characterized in that, has strengthened described additive by adding respectively at least two kinds of compounds that are selected from group I of effective dose.

3. diet additive as claimed in claim 1 is characterized in that, the concentration of described folic acid is to obtain the about 300-500 microgram of effective intake every day by taking this diet additive for the adult.

4. diet additive as claimed in claim 1 is characterized in that, the concentration of described cobalamin is to obtain the about 4-7 microgram of effective intake every day by taking this diet additive for adult effective dose.

5. diet additive as claimed in claim 1 is characterized in that, the concentration of described pyridoxine is to obtain the about 1.5-4 milligram of effective intake every day by taking this diet additive for adult effective dose.

6. diet additive as claimed in claim 1 is characterized in that, the concentration of described betaine aldehyde be for adult effective dose be by take this diet additive obtain every day effective intake about 100 milligrams-1 the gram.

7. a method of controlling NTD incidence among the crowd is characterized in that, this method comprises to the crowd provides diet additive as claimed in claim 3.

8. at least a compound and at least a purposes of component in making diet additive derived from milk that is selected from group I of effective dose is characterized in that this diet additive can reduce tHcy when the bedding and clothing time spent, thus the vascular conditions among the minimizing crowd.

9. diet additive as claimed in claim 1, it is characterized in that, milk in this diet additive derives from ox, and contain the beta-casein composition of forming by the A2 variant substantially, therefore owing to reduced the tHcy and the incidence of disease that has reduced diabetes, this diet additive can reduce the incidence of disease and/or the influence of crowd's medium vessels disease.

10. diet additive as claimed in claim 1, it is characterized in that, milk in this diet additive derives from ox, and contain in check beta-casein composition, A1 and B have wherein been got rid of at least substantially, thereby owing to reduced tHcy and reduced the incidence of disease of diabetes indirectly, this diet additive can reduce the incidence of disease and/or the influence of crowd's medium vessels disease.

11. diet additive as claimed in claim 9, it is characterized in that, milk in this diet additive can be in digestion process, produce a kind of immunological properties, residue as the digestion of A2 type beta-casein, this residue is a kind of metastable peptide that is called beta-casein morphine peptide 9, can promote the immune response in the body.

12. diet additive as claimed in claim 1, it is characterized in that, in additive, contain a kind of metastable active peptide, be called beta-casein morphine peptide 9 or its analog, it can be by individual digestion the time, be released in the small intestine, thereby make diet additive can promote to resist the immunity of diabetes.

13. diet additive as claimed in claim 12 is characterized in that, contains described metastable energy promotion and resist the reactive compound of the immunity of diabetes in sustained release preparation, thereby it was released in the small intestine in a period of time.

14. diet additive as claimed in claim 12 is characterized in that, has added to strengthen at least a preparation that immunity takes place in this diet additive, helps described reactive compound to promote pin to resist the immunity of diabetes.

15. (a) diabetes I type that reduces among the crowd, (b) diabetes type II, (c) angiocardiopathy, (d) cranial vascular disease, (e) peripheral vascular disease, (f) NTD, or (g) method of at least a incidence of disease in the vascular wall degeneration, it is characterized in that, the method comprising the steps of: the diet additive of making and offer crowd's dairy produce form, this diet additive contains the A2 beta-casein, but is substantially free of A1 and B beta-casein, and has strengthened this diet additive by at least a compound that is selected from group I that adds effective dose.

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