JP2003503038A - Preventive supplements based on milk - Google Patents

Abstract

  (57) [Summary]  Milk is commonly and widely consumed in many societies with a high risk and incidence of diabetes and vascular disease (coronary heart disease, cerebrovascular disease, peripheral vascular disease) or certain cancers. Death is often the result of exposure to high blood sugar levels in diabetes and the loss of blood vessel walls resulting from high plasma levels affecting many of the population, and is a major risk factor for vascular disease. Diabetes is equally widespread. (1) Extensive and frequent intake of milk; (2) Possibility to control plasma by treating folate (other vitamin) deficiency; (3) Opportunities including control of neural tube disease; (4) Diabetes Against the background of a hypothetical causal link between casein and type A and type B caseins, the present invention relates to (1) the use of cobalamin, pyridoxine, folate, and (2) substantially only the fraction of type A2 casein. To provide a population with processed milk or dairy products that include fortification using betaine with In addition, it contributes to reducing the incidence of diabetes through utilization of the immunological properties of β-casomorphin 9 (digested fraction of A2β casein). A realistic and convenient fortified diet would include the processed milk and foods as well as dairy products and processed cereals.

Description

Detailed Description of the Invention

FIELD OF THE INVENTION The present invention relates to the development and use of modified forms of dairy products for use in foodstuffs, which variations reduce the incidence of cardiovascular and cerebrovascular diseases and diabetes in the population. Intended to. The modification is the fauna of the product,
And / or can be imposed between manufacturing phases.

Definitions Vascular disease (VaD) as used herein refers to coronary (or ischemic) heart disease (CHD), cerebrovascular disease (CVA) and peripheral vascular disease (PVD). Atherosclerosis is one of the related syndromes.

[0003]   Diabetes includes juvenile / IDDM / type I and adult-onset / type II diabetes.

Other disorders include: premature aging, memory loss in the elderly, Alzheimer's disease, teratogenic effects, neural tube defects (NIDs) such as atresia leading to spina bifida etc.
, Asthma, and cancers such as colon (colorectal) cancer, cervical cancer and / or endometrial cell dysfunction, multiple myeloma (see Figure 2) and hematopoietic abnormalities.

[0005]   tHcy is an abbreviation for plasma homocystine (homocysteine) concentration.

Dairy product as used herein refers to a food product made from milk or a fraction of milk, such as various food products including casein, chocolate, and ice cream, yogurt, and cheese, condensed milk, dried milk powder. Such as more obvious examples, or other dairy products, as well as "non-dairy creamers" chocolate, cheese, etc. Also included are various forms of liquid milk such as homogenized milk, low fat milk, high calcium milk, flavored milk, and other milks.

[0007]   "Substantially" as used herein also includes separation in relative degree.

Chemical type, CAS number, and synonyms (Group I is our name for this set.) Betaine (trimethylglycine, CAS number 107-43-7 ^* ) Cobalamin ( Vitamin B12, CAS 68-19-9) -Folic acid (vitamin M, CAS 59-30-3) (folate, folate or ester) -pyridoxine (vitamin B6, CAS 58-56-0 ^* ( ^* indicates hydrochloride) CAS number; it is provided as an example and does not mean that the HCl salt is specifically required).

BACKGROUND OF THE INVENTION Milk is commonly and widely consumed in many societies where both diabetes and VaD are at high risk and incidence. More and more evidence is being presented in the form of repeatedly confirmed strong correlations for pre-existing forms of milk from bovines leading to both groups of diseases.

Is it the protein or fat in the dairy product that causes it? There is strong evidence that human plasma homocystine (homocysteine) (tHcy) levels generally correlate higher with heart disease and VaD and are a more accurate risk indicator than high cholesterol levels (Pietrzik 1998). Graham et al. (19
77) provided a large study evaluating tHcy as an independent risk factor for VaD, and the study has been extended to other diseases (hypertension, smoking, etc.). In diabetic patients who are clinically diabetic, or in fact not yet recognized, vascular wall integrity is severely compromised. Although Graham et al. Do not mention diabetes-related events, Hoogevenn (2000) found that tHcy is a stronger (1.9-fold) risk factor for mortality in type 2 diabetic patients than in non-diabetic subjects. Report what you think.

The incidence of diabetes in New Zealand is 9.8 / 100 for type I
2,000 (Elliott 1999), whereas Type II diabetes affects as many as 20% of adults in some societies. In the western world, heart problems cause about 45% of deaths. The 2000 World Health Organization report was 199
The total number of deaths due to diabetes in 9 years was 777,000 (1.4%), cardiovascular disease was 1.7 million (30.3%), and cerebrovascular disease was 5.5 million (
9.9%). In the United States, 600,000 people develop a stroke each year,
Of these, 160,000 have died. The incidence of neural tube defects (New Zealand: 1991) is 1 case per 1750 newborns, plus an unclear abortion / abortion.

Supplemental Vitamin and Plasma Homocystin (Homocysteine) (tHcy) Levels At least clinical levels of folate deficiency are endemic, poorly recognized problems leading to many diseases, including VaD. This is due in part to: (a) current suboptimal dietary intake levels are common; (b) the actual requirement was originally underestimated (see, for example, Rimm (1998)), and (C) Due to some common mutations associated with folic acid metabolism in the general population. A rare genetic disorder, homocystinuria with hyperhomocystinemia, is associated with the childhood onset of cardiovascular obstructive disease. A milder variant form of the disease (non-thermostable methylenetetrahydrofolate reductase) occurs in 10-15% of some populations, while at the same time normal V
It poses a higher risk than aD. Folate deficiency also causes some defects in early embryonic development, such as spina bifida and other neural tube defects. Milk with added folic acid is therefore marketed as a prophylactic agent. There are currently national programs for adding folic acid to bread and flour, mainly for "nerve tube" reasons. Folic acid can be provided in several forms. Monoglutamate (more easily absorbed by the body)
Is preferred over natural polyglutamate with an absorption of 50%.

Deficiency of folic acid, pyridoxine and cobalamin leads to higher tHcy. Gra
Ham et al. (1997) and many other authors have reported that folic acid, pyridoxine and cobalamin (to reduce tHcy, an important independent and frequent risk factor for clinical atherosclerosis and venous thrombosis, And in some cases also betaine) is proposing to the health authorities the utility of a truly adequate dietary supply. For example, Bro
nstrup et al., 1998, Ward et al., 1997, Graham et al., 1997.
reference. This adjunct also helps people who are genetically predisposed to hyperhomocystinemia (Malinow 1999). Graham reported a reduction in the risk factor of cases (of VaD) observed in individuals who took supplements containing folic acid, cobalamin, or pyridoxine in the study compared to non-user = 1
． It was calculated to be 38 (05% C.I. 0.2-0.72), but points out that those individuals may be otherwise more cautious about their health.
Furthermore, betaine can reduce tHcy in individuals with at least deficiency of cystathione β-synthetase activity (Dudman 1996.
).

There is no absolute value for tHcy “turn on” for vascular disease. Although the biology of vascular wall disease is not yet fully understood, it is thought to involve superoxide and, in diabetes, sugar-protein condensation. Individual tHc
y also changes over time. It is known that renal and thyroid function and some drugs modulate tHcy (see Pietrzik 1998).

The most common group of individuals with folate deficiency are the elderly, who often have an associated cobalamin deficiency. It is important to correct two deficiencies simultaneously, apart from the additional tHcy-lowering effects that result from cobalamin treatment, because correcting folate deficiency without simultaneously correcting cobalamin deficiency can cause adverse neurological effects. . A common genetic variant of cobalamin metabolism has been described, which may result in high dietary intake requirements for cobalamin and promote relative cobalamin deficiency.

A patent specification describing a milk-based supplement containing all three of folic acid, pyridoxine and cobalamin is US Pat. No. 5,985,339, Kamarel, for adult use, especially for cardiovascular disease, among a wide range of diseases. US Pat. No. 5,985,339, for "complete nutritional composition" for the purpose of making no mention of tHcy, K
Amarel, DE 2917239, Saiki apparently teaches a low-calorie complete food product for adults, and US 6030650, Kamarei provides a nutritional dairy product for use in, for example, ice cream and yogurt, soy milk. Have independently claimed the same. Regarding children, EP951842, Bindels et al. Is an example of a common pediatric prescription that meets amino acid demands similar to human milk, and EP129418, Barr, provides food for low birth weight children. There is. US5631231, Serf
ontein provides a composition specifically related to the biochemistry of pyridoxine,
Contains no cobalamin and folic acid. In that set, Surfontei
n specifically refers to hyperhomocysteinemia for children. Compositions based on homogenized milk powder for premature babies during the first few days of life and the disadvantages of using milk for methionine metabolism.

Diabetes Diabetes affects carbohydrate metabolism and blood glucose levels, resulting in significant morbidity and mortality, leading to significant financial costs for individual patients and health care systems.
It is a general endocrine disorder. There are several forms of this disease. Type I diabetes (
Insulin-dependent diabetes mellitus or IDDM) is the expression of antibodies against pancreatic islet cells,
It is a type of autoimmune disease that later blocks the production of endogenous insulin and requires exogenous insulin therapy for the rest of the patient's life. Generally the onset is during early childhood. Treatment with insulin or a diet and hypoglycemic agents provides relief from the condition, but often fails to prevent diseases of vascular complications such as the concern of early coronary heart disease. Type II or adult-onset diabetes is believed to be due to diet.

Although it is known that diabetes causes VaD, it is unclear how diabetes acts on the vascular wall. There may be a general background for tHcy. Diabetes is also one of the largest causes of coronary heart disease. The patient may present with the symptoms of heart disease without overt manifestation of diabetes, and is then (first time) diagnosed with diabetes. For example, vascular occlusive disease of the legs, eyes or brain, gangrene of the feet,
It is a common consequence of acquired blindness and possibly stroke. It should be noted that the WHO report does not list diabetes as the underlying cause of coronary heart disease.

The milk protein casein is known to exert detrimental effects on some individuals in a variety of ways, including peptide-based effects. The apparent causal relationship of casein type to the incidence of diabetes is of particular interest. Among some of the proposed prevention strategies,
Identification and elimination of environmental triggers of disease (Porpharn 1978, Elliot
t 1999, Padburg 1999 et al.), and / or changes in coexisting metabolic conditions have received the most attention.

The causal relationship between casein variants in milk and diabetes itself is still under debate. Several β-casein fragments (peptides) have a structure in which proline residues are replaced by amino acids, which make them resistant to digestion by intestinal endoproteases, and are intact after passing through the intestinal wall. It may remain and may be found in circulation. Casomorphin has that alternation structure. Bovine β-casein variants A1 and B show several β-casomorphins 7 (PRO-GLY-PRO-) at residues 63 (for A1 type) to 68 (inclusive) after intestinal proteolysis.
ILE-PRO-GLY). β-casomorphin 7 has opioid-like properties, including effects on the gut itself such as motility, absorption and secretion. It is a direct inhibitor of acetylcholinesterase. The A2-type β-casein is due to an additional proline residue at the 67 position of the casein, resulting in β-casomorphin-7.
Yields a 9 rather than. See structure (sequence) in FIG. Teschemacher (U
S4681871) teaches the isolation and use of various orally active casomorphins, preferably short peptides having an opiate-like or analgesic effect, such as β-casomorphin 3 for use in the analgesic method. , A2 type β-casein or casomorphin and no functional relationship between diabetes. Elitsur
Et al. Discuss the interrelationship between lymphocytes and casomorphin in the intestinal wall.

[0021] Over the last fifteen years or so, there have been studied within each country and its societies, as well as between countries and societies, the numerical links between the intake of milk or its products and the development of diseases such as type I diabetes. It was Important Analysis by the Inventor-Elliot (199
9) Reference-refers to the incidence of type I diabetes and A1 and B type β-casein (ie A
A strong correlation between the weighted averages of consumption (except type 2) was identified. This comparison is comparable to the anomalous Icelandic statistics (high milk consumption; low incidence). Icelandic cows almost exclusively secrete A2.

WO 96/14577 discloses that milk protein genes are co-dominantly expressed, so that the phenotype of an individual typically results in a mixed casein comprising a β-casein mixture such as A1A2, A2A3, A2B and the like. : There are many alleles. Gene frequencies differ among varieties and Holstein / Friesian tends to be low among A2 variant alleles. The above application selects, for use in dairy production, only cows having the A2A2 genotype and producing only the β-casein A2 variant (no A1, A1A2 or B), or alternatively β-. It teaches that consuming a dairy product that does not contain casein A1 will reduce the incidence of diabetes. It has been speculated in the prior art that the diabetogenic effect of milk containing β-casein A1 (or the like) is the result of β-casomorphin 7, which is inevitably released during proteolysis in the intestine. Was done. Monetini et al. Describe the finding of significantly higher antibody levels to β-casein in type I diabetic patients.

References Abby et al., JA Am Board Fam Pract 11 (5): 39.
1-398 (September 1998) [FDA levels for grain enrichment are not sufficient (FDA level of grain enrichment is n.
ot enough)] Akerblom et al., 1999 Proceedings 4th Immu.
noology of Diabetes Society Conference
e, Rome. p. 123 Bennett G et al., Nutr Rev May 1999 57 (5pt2.
) 551-4 Review. Bronstrup et al., Am J Clin Nutr; 68 (5): 110.
4-1110 November 1998 [folic acid plus cobalamin (folic aci
d plus cobalamine)] Dudman et al., J Nutr (US) 1996 126 (4 Suppl).
1295S-1300S [use of betaine] Elitsur Y & Lud G Clin exp Immuno
85: 493-497 (1991) Elliott RB et al. "Type I (insulin-dependent) diabetes and milk: consumption of casein variants (Type I (insulin-dependent) diab.
ets mellitus and cow milk: casein va
riant consultation "(Diabetologia (199
9) 42: 292-296) Graham IL et al., JAMA 277: 1775-1781 (June 1997) "Plasma homocysteine as a risk factor for vascular diseases. The European Collaborative Research Project (Plasma Homocysteine as a Risk).
Factor for Vascular Disease. The Eur
open Concerned Action project) ". Hackam et al., Am J Hypertens 2000 Jan; 13 (1
Pt1) 105-110 [Improvements in carotid plaques after anti-homocystin (homocysteine) hyperemia treatment.
laques following anti-hyper homocyst
(E) ineamia treatment)]. Hoogeveen et al., Circulation 2000 4; 101 (1
3): 1506-11 [tHcy and diabetes (Linking tHc
y and diabetes)] Lobo A et al., Am J Cardiol 83 (6): 821-519.
March 1999 [B6, cobalamin and folic acid therapy trial (Testing B6, co
balamine and folic acid therapy)]. Malinow MR Can J Cardiol April 1999; 15
Suppl B: 31B-34B [Hcy (t-lowered by vitamin B group)
tHcy red by by B vitamins)] Monetini L et al., "Antibodies to bovine beta-c in diabetes and other autoimmune diseases.
ase in in diabetes and other auto-imm
une diseases ”(unpublished) Oakley G“ Fortification enhances the rate of decline in stroke mortality in the United States (
Folic acid fortification intentions
he rate of decline of stroke mortal
ty in the United States)] Lancet Editor's unpublished letter Padburg S et al., "A1 and A for β-casein in type I diabetes"
2 Importance of the antibody (The signature of A1 and A
2 antibodies against beta-casein in
Type I diabetes mellitus) "Dutsch Med
Wochenschr Dec 1999; 124 (5): 1518- (Me.
dline abstract seen Pietrzik K "Homocysteine and folic acid (Homocysteine)
and folic acid) "BASF Transfer (April 1998)
Mon) www. basf-ag. basf. de ... tran0498. htm (2
Available from June 2000) Popham RE et al. "Variation in Mortality from Mortality Due to Ischemic Heart Disease Associated with Alcohol and Milk Consumption"
Ischemic Heart Disease in relation t
o Alcohol and Milk Constraction) "Medi
cal Hypotheses 12: 321-329 (1978) Rimm EB et al., JAMA February 1998 4; 279 (5); 359.
-364 Scott FW Am J Clin Nutr 51; 489-491 (
1990) Ward et al. QJM 90 (8) 519-524 August 1997 [3 rates of folic ac given to 30 subjects.
id admistered to 30 subjects]] Wasmuth HE et al. "[beta] -casein A1 consumption and the incidence of type I diabetes in Germany.
incident of type I diabetes in Germ
any) ”Woo et al., J Am Coll Cardiol December 1999 34 (
7); 2002-2006 [Reduction of atheroma in the brachial artery (Decrea
sed atheroma in brachyartery)] Virtane et al., Diabetes 2000 Jun; 49 (6): 912.
-7 [Sibling case of children with diabetes-case-control study (Case-control
study of siblings of children with
diabetes)].

[0024]

[Object of the Invention]

It is an object of the present invention to provide fortified supplements capable of reducing vascular disease and / or diabetes, or at least to provide the public with a useful choice.

DETAILED DESCRIPTION OF THE INVENTION In a first broad aspect, the invention provides that the supplement comprises betaine, cobalamin, folic acid,
Pyridoxine, and fortified supplements which have been fortified by the addition of an effective amount of at least one compound selected from the group comprising pharmaceutically acceptable analogues of each substance (known herein as Group I). Can reduce the plasma level (tHcy) of homocystine (homocysteine) when consumed, resulting in vascular disease (VaD), particularly cardiovascular and cerebrovascular disease, and the development of NID in a mammalian population. Provide a fortified supplement containing milk or dairy products that can reduce the rate.

In a closely related aspect, the present invention provides a supplement wherein the supplement is fortified by the addition of an effective amount of each of at least two compounds selected from Group I.

More preferably, the present invention provides fortified supplements comprising milk or dairy products, wherein the selection from Group I comprises folic acid (or a pharmaceutically acceptable analogue thereof) and at least one other member. To do.

The preferred concentration of any two or more of the above compounds is assumed to be the same amount as if each were used separately.

[0029]   Preferably folic acid is used with at least cobalamin.

[0030] In a related aspect, the invention provides for a reduction in tHcy and indirect V in a population.
Provided is the use of an effective amount of at least one compound selected from Group I with milk and dairy products in the manufacture of a dietary supplement intended to produce a reduction in aD.

A preferred range for an amount of folic acid supplement suitable for adults is from about 300 to about 500 μ per day.
g intake, more preferably 400 μg, and assuming a daily intake of milk of 400 ml, this corresponds to a pharmaceutically equivalent amount of 1 μg folic acid or analogue per ml of milk. Preferably the formulation suppresses the incidence of neural tube defects in a population,
Provide an acceptable method.

A preferred range for the amount of cobalamin is about 4 to about 7 μg per day, more preferably 5 μg, and assuming a daily intake of milk of 400 ml this is 0.012 μg of cobalamin or its equivalent. Equivalent to the equivalent. Higher amounts can optionally be provided in cases of malabsorption.

A preferred range for the amount of pyridoxine is about 1.5 to about 4 mg per day, more preferably 2 mg, and assuming a daily intake of milk of 400 ml, this is 1 m of milk.
This corresponds to 5 μg of pyridoxine or its equivalent per liter.

At least one further compound capable of lowering tHcy is betaine, and a preferred effective daily intake of betaine is 1 g or less per day, more preferably about 1 day per day. 100 g, preferably inoculated with other specific compounds.

In a second broad aspect, the present invention provides that the milk or dairy product further comprises a controlled bovine β-casein content consisting essentially of the A2 variant, for which the dietary supplement is earlier in this chapter. As a result of lowering tHcy by additives such as those described in
And reducing the incidence and / or effects of vascular disease (VaD) in a population as a result of reducing the incidence of type 1 and type 2 diabetes through modification of casein compositions, earlier in this chapter. A supplement containing fortified milk or dairy products as described in 1.

In a related aspect, the invention relates to the production of a dietary supplement intended to produce a reduced effect of diabetes in a population and, consequently, a reduced effect of VaD in the population. Provided is the use of milk or dairy products from bovine characterized by the substantial absence of at least) A1 or B type β-casein.

In another related aspect, the present invention provides the manufacture of a fortified supplement intended to help reduce the effects of diabetes in a population and, consequently, VaD in a population. Milk of bovine origin, characterized in that the A1-type or B-type β-casein is substantially excluded, and an effective amount of at least one compound selected from Group I is added. Provide product use.

[0038]   Preferably the supplement comprises A2-type β-casein.

In a third broad aspect, the invention provides that the milk or dairy product is additionally of bovine origin and comprises a regulated β-casein content consisting essentially of the A2 variant, at least during the course of digestion. At the time of digestion, at least a part of β-casein A2 is converted into a relatively stable active compound capable of promoting immunity to diabetes by the action occurring in or near the intestinal wall. Food supplements containing fortified milk or dairy products as described earlier in this chapter.

In a related aspect, the invention provides relatively stable active compounds capable of promoting immunity to diabetes, such compounds comprising peptides that are relatively stable in the intestine where digestive enzymes are present. Preferably, such a peptide comprises from 7 to 12 amino acid residues, with proline making up the majority of the residues.

In a further related aspect, the invention provides that the relatively stable active compound is a peptide having 7 or more amino acid residues, more particularly the relatively stable active compound is a peptide as shown in FIG. A peptide, known as β-casomorphin-9, having a sequence, wherein said compound has the ability to confer at least partial protection from diabetes, such as a food supplement as previously described in this chapter. To do.

[0042]   Other caseins include caseins derived from other species of mammal.

Alternatively, the active compound based on the structure of bovine β-casomorphin 9 can be produced from casein by recombinant methods or by proteolysis, or as a peptide or as a pharmaceutically acceptable salt thereof or as a pharmaceutical. It can also be synthesized as its upper acceptable ester and can be supplied in stabilized form as part of a dietary supplement.

[0044] Preferably, the relatively stable active compound capable of promoting immunity to diabetes comprises at least one agent having an adjuvant-like effect in the diet, which is capable of enhancing the expression of immunity. Assisted by Optionally,
The stabilized form allows a slow release of the active compound such that it is released in the intestine over a period of time.

In a fourth broad aspect, the present invention provides fortified supplements capable of eliminating two risk factors associated with diabetes and VaD;
A combination of an effective amount of at least one compound selected from the group with a milk or milk product substantially free of A1 and Bβ-casein.

In a related aspect, the invention provides a fortified supplement comprising at least one compound as previously described in this chapter and A2 casein; such a product improves cardiovascular conditions, The risk of initiating a diabetic condition can be reduced.

In a fifth broad aspect, the present invention provides a milk having a specific composition of casein as previously described in this chapter, optionally pasteurizing or sterilizing the milk, from group I Enrichment as set forth in any of the above claims, comprising the step of adding at least one compound selected in an amount sufficient to reach an effective final concentration of each compound as previously described in this chapter. A method for preparing a dairy product is provided.

Optionally, so that the milk is substantially free of A1-type or B-type β-casein,
Process milk.

In a sixth broad aspect, the present invention provides a method for minimizing the incidence and / or effect of diabetic disease comprising the step of using in a diet an effective amount of a fortified dairy product as described earlier in this chapter. Provides a way to keep it to the limit.

[0050] In a seventh broad aspect, the invention provides for the incidence and / or VaD of a population in a population comprising the step of using an effective amount of a fortified dairy product as previously described in this chapter in a diet.
Alternatively, a method for minimizing the effect is provided. In a related aspect, the invention also provides methods for minimizing the incidence and / or effects of NTDs in a population.

Preferably, in the diet, the non-fortified dairy product is replaced with a fortified dairy product.

Optionally, the fortified dairy product has a modified casein composition as described above in this chapter.

In an eighth broad aspect, the present invention provides a fortified dairy product comprising an effective amount of at least one compound selected from Group I.

In a first related aspect, the present invention provides an A2-type β-casein such that A1-type β-casein is substantially absent, and preferably B-type β-casein is also substantially absent. Provide a fortified dairy product made from milk. Alternatively, casein can be defined as "substantially free of casein in the fortified dairy product that can produce β-casomorphin-7 upon digestion in the intestine."

In a ninth broad aspect, the present invention comprises A2β-casein, wherein A1 and Bβ-
Producing a dietary supplement in the form of a dairy product that is substantially free of casein and fortified by the addition of an effective amount of at least one compound selected from Group I and providing it to the population. at least one population of a) type I diabetes, (b) type II diabetes, (c) cardiovascular disease, (d) cerebrovascular disease, (e) peripheral vascular disease, or (f) vascular wall degeneration To provide a method for reducing the incidence in. Preferably, further diseases as listed herein under the name "other diseases" are also covered.

In a tenth broad aspect, the invention provides that a member of the population has an opportunity to consume the identified dairy product and that the individual has a therapeutically effective amount of β-casomorphine 9.
High risk individuals identified dairy products obtained from dairy cows of breeds or strains that produce only β-casein A2 and substantially no A1 and β-casein B as protected by contact with By providing to the group, a method for minimizing type I diabetes is provided.

In a related aspect, the present invention provides a method for minimizing type I diabetes by oral administration of a dairy formulation containing added β-casomorphin 9 or a precursor thereof.

In an eleventh broad aspect, the present invention provides a dairy industry, or at least of a dairy cattle of a breed or line that produces β-casein A2 and substantially no β-casein A1 and β-casein B. Its use in some commercial aspects is provided.

In a twelfth broad aspect, the present invention provides a dairy cow of a breed or strain that produces β-casein A2 and substantially no β-casein A1 or A1A2 and β-casein B from a mixed population. To produce a dairy product that is confirmed to contain substantially only type A2 casein, such that suitable animal selection or Including animal isolation methods.

In a thirteenth broad aspect, the present invention provides for the removal of at least β-casein A1, if not β-casein B at the same time, from the product during the manufacturing process in order to remove at least β-casein A1. Provide a dairy product that has been subjected to refining.

In a fourteenth broad aspect, the present invention provides β- as a result of the selection of contributing cows.
Casein B also provides milk, milk-based products, or dairy products that have at least a reduced concentration of β-casein A1, if not simultaneously. In a related aspect, the invention provides a milk, milk-based product, or dairy product having a reduced concentration of at least β-casein A1, if not simultaneously β-casein B, as a result of subsequent manufacturing processes. I will provide a.

In a fifteenth broad aspect, the present invention enables people who for some reason cannot consume dairy products to nevertheless receive regular tHcy reduction assistance with artificial, eg soy milk. , I as mentioned earlier in this chapter
Provided is a milk-free substitute product fortified by effective daily replacement of at least one compound selected from the group.

In a sixteenth broad aspect, the present invention provides a food supplement for the treatment of mammals other than humans, such as cats or dogs that may develop diabetes.

Preferred Embodiments The description of the invention provided herein is provided purely by way of illustration and should not be construed as limiting the scope or limit of the invention in any way.

Principles Milk is commonly and widely consumed in many societies with high risk and incidence of both diabetes and VaD. Pre-existing forms of milk can contribute to both diseases; there is published and unpublished epidemiological evidence. Dietary intake of milk containing type A1 β-casein or type B β-casein is closely correlated with type I diabetes, whereas no correlation is seen with milk containing only type A2 β-casein (Elliott, 1999). . Perhaps this dietary threat could be translated into an opportunity to replace or supplement health-depleting milk ingredients with health-promoting ingredients. Then the high risk population would simply replace one type of milk with another.

Aspects of the specification raise the theory that (1) β-casomorphin 7 is clearly prone to diabetes, and (2) β-casomorphin 9 can be used in immunization. And (3) providing that the population is provided with milk containing only β-casein A2 variant, optionally with a compound that reduces tHcy, suggests that it will significantly reduce diabetes and vascular disease. .

The present specification refers to a disease process (here, vascular disease or V
The focus is on a). Diabetes and (tHcy) for the management of vascular wall disease
Combined therapies that include both strategies will show additional effects, and perhaps even synergistic effects. It is recalled that Graham et al. (1997) recognize a synergistic effect between (tHcy) and, for example, smoking. Trials of the invention have not yet been performed, and significant population-based results will only come from the actual use of the invention. Woo et al. (1999) describe improvements measured on repeated scans of the brachial artery during and after folic acid treatment, and Hackam et al. (2).
000) describes the measured improvement in carotid sinus / carotid plaque in adults with reduced tHcy after several weeks of folic acid supplementation.

Prophylactic milk and milk compositions according to the present invention provide milk directly through the use of a tHcy lowering agent and (a) high A2 and low A1 and B variants of β-casein, and / Or (b) β-casomorphin 9 (having 9 amino acids, A2β
It is intended to indirectly reduce the VaD incidence by reducing the incidence of diabetes through the use of the immune properties of the active and relatively stable peptide digest fraction of casein). A reduction in tHcy levels that is strongly correlated with improved vascular wall integrity is indicated by an effective amount of a casein variant as described above and at least one compound selected from the group consisting of betaine, cobalamin, folic acid and vitamin B6 (pyridoxine). Is achieved through a fortified food formulation containing milk containing. The actual fortified diets that will be widely consumed by high-risk populations include processed and selected milk, and also selected milk in combination with processed grain. Fortified dairy products such as ice cream, yogurt, dried milk powder and the like can also be added.

Experiment 1 This study involved "Biobreeding" (BB) rats. See FIG. 1, which shows the results graphically with the incidence of diabetes (1.0 = 100%) as the vertical axis. The control diet was the soy formulation "Prosobee (TM)" used as a rat diet in the laboratory. The spontaneous incidence of diabetes in the control population was approximately 38%. Rats fed "Prosobee" (TM) plus 10% mixed casein (ie A1 and A2) had an incidence of approximately 27%. "
Rats fed Prosobee '(TM) plus 10% type A1 casein had an incidence of about 45%. Rats fed "Prosobee" (TM) plus 10% A2 type casein showed an incidence of about 20%. Consistent with the teaching of WO96 / 14577, the incidence of diabetes in the A1 group was higher than in the control group.

If the A2 casein (or its degradation product) is simply a “neutral” substance, β-
Since there is no adverse effect of casomorphin 7, the incidence of diabetes in the A2 group should be similar to the control group. In fact, the incidence of diabetes was significantly reduced in the A2 group, the lowest of all groups. The inventor therefore proposes that β-casomorphin 9 has a beneficial effect on the incidence of type I diabetes. Perhaps it acts as an immune regulator. The actual mechanism of action of casein fragments from the milk of certain animal species on antibodies to pancreatic β-islet cells in at least humans and susceptible rodent experimental animals is unknown, but It has been found that small peptides such as casomorphin can act as intracellular messengers.

Experiment 2 The effect of two peptides derived from β-casein was investigated by comparing the results in normal (SWR / J) and NOD (diabetes susceptible) mice. The two peptides were: β-casomorphin-7, which is an enzymatic digestion product of A1 β-casein but not A2 variant, or A2 β-casein digestion product, but digestion of A1 variant. Non-product β-casomorphin-9. 30-day-old female mice were bred on a milk protein-free diet after weaning. There were 10 animals in each group. Adjuvant (Freund's complete) on day 30
Animals were injected with 10 mg ovalbumin and 1 mg of one or more peptides. The peptide injections were repeated daily for another 10 days. Animals were bled on days 7 and 11 and analyzed for IgG and IgM antibodies to ovalbumin.

Results: NOD mice were characterized by low IgM and IgG responses on day 7 compared to control animals. This persisted up to day 11 for IgM but not for IgG. The average immunoglobulin response to ovalbumin is 7
Normal mice fed either β-casomorphin-7 or 9 were larger on day than controls treated with saline, but not on day 11 (Table 1).
.

[0073]

[Table 1]

Both peptides promoted an early immune response, presumably β-casomorphin-9 had a greater effect than β-casomorphin-7.

On the other hand, this early peptide enhancement of the antibody response was not seen in day 7 NOD mice, only for day 11 BCM IgG responses (Table 2).

[0076]

[Table 2]

These experiments confirm that in a diabetic model (NOD mice), there is an early antibody response deficiency to the parenterally administered antigen that is not corrected by any of the co-administered milk peptides. However, I in SWR / J animals
The early stimulatory effect of β-casomorphin-9 on gG levels is retained better than in NOD mice. Milk producing β-casomorphin-9 (NO
D / SWR / J ratio = 0.36), milk producing β-casomorphin-7 (NOD /
SWR / J ratio = 0.05) can improve the early antibody response deficiency. β
-The slight "dominance" of casomorphin-9 is thought to reflect the causal mechanism of diabetes. Needless to say, these experiments are based on infused antigen rather than intestinal contact antigen.

Experiment 3 Figure 2 summarizes the results of this experiment: incidence of some selected diseases and amount of milk consumed per capita in the population, more specifically per capita consumption. This is a retrospective survey of information for investigating the relationship with the amount of A1β-casein. This figure uses the dairy literature of each country and uses the proportion of A1β-casein for each dairy cow that contributes to milk in a given country and the proportion of the nationwide group of each breed. Calculated. Milk protein consumption was obtained from the FAO website. Data on the incidence of diabetes were restricted to the Caucasian population to reduce confounding due to race-related genetic variation in type I diabetes. Data on the prevalence of asthma are available at the International Study Group on Childhood Asthma and Allergies.
f Asthma and Allergies in Childhood)
Based on the "12-month prevalence of wheezing" published by. Data on the incidence of multiple myeloma were obtained from almost 1990 cancer registry data.

This experiment is an ecological test with all attendant limitations. We have found that A1 casein (around 1980) in per capita dietary supply is
) Significantly correlates with incidence of childhood diabetes over the same time period, (2) mortality of ischemic heart disease in adults in 1990, and (3) incidence of multiple myeloma in men and women in 1990 And that the rates of these diseases are correlated with each other. (Probably the biological basis of myeloma is related to β-casomorphin-7-mediated lymphocyte suppression from A1 milk.) Even though some statistically significant correlations were observed, this was a causal link. Not, but the possibility is raised.
However, regarding type I (IDDM) diabetes and ischemic heart disease (CHD) (whole milk)
The changes in the numerical value and significance of the correlation between and (A1β casein) must be explained.
We also found that the correlation weakened when Bβ casein was added along with A1 for consumption. This study and two animal studies support the claimed invention for the health-improving properties of milk or dairy products free of or low in A1 beta-casein without the extra health-improving properties of Group I supplements. .

BEST MODE FOR CARRYING OUT THE INVENTION The present invention proposes various combinations of milk consisting mainly of type A2 casein or the like. Example A is a conventional milk-based fortified supplement containing an effective amount of folic acid added with B6 and cobalamin known to have effects on tHcy. Example B has a "controlled casein composition". The combination of (A) and (B) (Example C), at a pathophysiological level to the vascular wall, etc. in patients with known or suspected diabetes, or homocystine (homocysteine) blood,
It is expected to show additional effects, if not actual synergistic effects. Healing may occur.

Example A alone is useful in minimizing the effects of diseases other than diabetes, a group commonly known herein as “VaD”. In such cases,
The controlled casein example of the present invention (B) has at least no adverse effects and may actually reduce the development of diabetes in high-risk people. It should be noted that the incidence of "suspected diabetes" in patients with vascular disease is surprisingly high.

Illustrative Example (A) This example demonstrates the use of betaine, cobalamin, folic acid, in order to reduce tHcy.
And fortifying commercially produced milk with an effective amount of at least one compound selected from the group of vitamin B6. The preferred prescription amount of the enhancer is tHc
It is determined in relation to the known "recommended daily dose" (RDA), together with reports from the literature for y, and the estimated daily consumption of fortified milk or dairy products by the typical consumer.
(The LD50 coefficient for the additive is high). Applicable "quantitative" references include: Ohbo's Lobo et al. (1999) reported 1 mg of folic acid (
B6 and cobalamin) was similar to 400 μg for tHcy (95 patients with mean age 61 years), (B) Ward et al. (199).
7) used 40% to reduce tHcy in young men in Northern Ireland.
Although 0 μg and 200 μg are similar, but admitting that 200 μg is more effective than 100 μg (30 volunteers over 26 weeks), (C) Bronstrup et al. (1998) found that cobalamin (6) in young German women. Or 400 μg)
We found that 400 μg folic acid in combination with was significantly more effective on tHcy levels than folic acid alone. Furthermore, the recommended daily dose of folate to avoid neural tube defects is about 400 μg / day. Effective supplemental dose of folic acid is about 400μ / day
Although it can be concluded that these studies are for normal people, they do not address environments that are otherwise completely folate-free. Therefore we have 3
It is considered that a folic acid intake of 00 to 500 μg / day is suitable as a daily dose for adults (when it contains one additional compound). Assuming a daily intake of milk of 400 ml, this corresponds to about 1 μg of folic acid or its equivalent per ml of milk.

Although less clear, there is data to establish a preferred range for the amount of cobalamin (whether it is a single addition compound or not). At this time, we prefer 4 to 7 μg / day. 5 μg corresponds to 0.012 μg cobalamin / ml (assuming no malabsorption in the recipient). Similarly for pyridoxine the preferred range is 1.5-4 mg / day. 400m milk
A daily dose of 2 mg in 1 corresponds to 5 μg of pyridoxine per ml of milk or its equivalent.

It is known that betaine can also reduce tHcy. A preferred effective daily intake is preferably up to 1 g / day, more preferably about 100 mg / day, together with other defined compounds. Analogues of all of these ingredients are known in the pharmaceutical art and corresponding effective doses can be titrated. Mixtures of two or more of the compounds described above have evidence of increased efficacy (eg, Bronstrup et al. (1998)
))) For each, the amount is estimated to be the same as if each was used separately. It should be noted that when folic acid is administered, it should take an amount similar to the average daily requirement (5 μg) of cobalamin. This amount prevents adverse effects of folate (such as effects on brain function) when the above dose is administered to individuals who may be deficient in cobalamin (such as the elderly with poor absorption).

Preferably, such vitamin enrichment is supplemented with a metering line feeder method familiar to the person skilled in the art, before the milk is subjected to consumption or further production into dairy products. Although cobalamin and B6 are degraded by light, they are not extremely heat-sensitive and survive normal pasteurization. In fact, it can survive extensive treatments such as drying. Preferably such milks / dairy products are analyzed for confirmation of vitamin supplementation prior to consumption by methods familiar to those skilled in the art. The liquid milk thus fortified can take any commercially available form of milk including, but not limited to, low fat milk, ultra high temperature treated milk or pasteurized milk. The invention also applies to "dairy products" as defined above.

One obstacle to the widespread adoption of this “auto-administration” route to reduce tHcy in a population is that some individuals drink milk (or milk) for medical reasons such as allergic reactions. To eat products made from, and some societies do not consume milk for cultural, unavailability, or religious reasons. The present invention therefore proposes to provide such people or society with several options of fortified liquids, which are often consumed daily instead of milk.
The invention therefore also comprises at least one compound selected from Group I, preferably at least folic acid and cobalamin, each having a concentration which provides a suitable daily dose for most users. ) Fortified soy milk or the like, (2) "tea / coffee additive" possibly water or possibly fortified sweetener, (3) fortified carbonated beverage, and (4) bottled fortified drinking water.

Illustrative Example (B) This aspect of the invention provides the teaching of Example A for the prevention of VaD to the β-casomorphin 7 or β-casomorphin 7 following intestinal digestion in recipient mammals, including humans. Additional information on the prevention of both type 1 and type 2 diabetes by providing milk or dairy products that are substantially free of proteins (casein) capable of producing other longer peptides containing the sequence To do. This can be achieved by: a) Selection of cows that produce only β-casein of the A2 breed that provides milk, for use in the milk supply-such milk contains β-casomorphin 7 or related peptides after intestinal digestion. Do not generate. There are cows that produce A1, A2, or B casein mixedly, reflecting the proteins expressed as a result of the presence of several codominant genes, and using selection means known in the dairy technology, (1) Selectively breeding animals that provide only A2 casein (selection of bulls is one of the methods for achieving rapid changes in the genetic composition of the cow population that provides the potential for artificial fertilization). Shortcuts), (
2) able to select animals homozygous for A2 from the mixed population and provide quality assurance procedures for the product, b) (optionally) all from milk by physical, chemical or enzymatic means. Or removal of substantially all β-casein, or A1 and B leaving only A2 casein
Removal of β-casein, c) (optionally) genetically modifying the cows of the milk source so that β-casein, which produces β-casomorphin 7 or related peptides, does not occur after digestion. Such genetic modification can completely remove the required gene sequences for specific or all β-caseins.

The selection of cows that produce the required milk involves identification by measuring various β-caseins in individual milk samples and using only cows that produce A2β-casein. β-casein variants can be identified by gel electrophoresis or other methods familiar to those of skill in the art.

[0089]   We believe that the present invention can be theoretically explained by the following findings.

Part 1: The nature of dietary environmental factors that can trigger diabetes. Previous studies have revealed an epidemiological link between liquid milk consumption and type I diabetes (Scott et al.), Further suggesting that the probable cause of this association is attributed to the A1 and Bβ-casein portions of milk. Shown (Elliott et al., 1999, Laug.
esen et al. (unpublished). It is not known that other milk proteins are linked to disease. In particular, the A2 variant β-casein appears to be harmless. Other studies have shown a link between type I diabetes and high levels of antibodies to A1β-casein, but not A2, in at least some populations (Elliott et al., 1999).

Virtanen et al. (2000) showed that when developing a genetic predisposition to diabetes, children who develop diabetes consume more milk than children who do not. Infants born with a genetic predisposition to diabetes and fed a milk-free diet during the neonatal period show earlier signs of disease affecting insulin-producing cells in the body than do infants fed milk. Unlikely to be expressed (Akerbl
om et al., 1999). Bennett et al. Have shown an association between early childhood milk consumption and type 2 diabetes. Therefore, in humans, milk consumption is considered to be an environmental trigger for both types of diabetes, and in at least type 1 diabetes this is milk A1 and Bβ.
-Related to casein content and not to A2β-casein content.

Both A1 and Bβ-casein produce β-casomorphin-7 after digestion with intestinal digestive enzymes, but not A2β-casein. β-casomorphin-7 exerts opiate-type effects upon intestinal transit in animals (including humans) and immunosuppressive effects on human intestinal lymphocytes (Elitsur 1992). Such opiate-like effects are believed to exacerbate the genetic predisposition to type 1 and type 2 diabetes.

Part 2: The (known) link between diabetes and coronary heart disease. Both type 1 and type 2 diabetes increase the risk of coronary heart disease by 5-10 fold. See FIG.
In some societies, type 2 diabetes occurs in over 10% of the adult population over the age of 40,
Diabetes is the leading cause of coronary heart disease in these societies. Type 1 diabetes contributes less to the proportion of coronary heart disease in the population. The incidence of diabetes (both types) is increasing dramatically worldwide.

Part 3: The association of coronary heart disease with consumption of liquid milk, especially milk containing the A1 and B variants of β-casein. Some epidemiological studies quoted above (see Figure 2)
, The association of liquid milk consumption with coronary heart disease mortality appears to be due to milk protein content rather than fat content. As one might expect, A1β-casein appears to be better associated with coronary heart disease mortality than any other component of milk when considering the link between diabetes and heart disease.

Part 4: Is There a Real Link Between tHcy and Diabetes? Hoog
eveen (2000) found that tHcy is associated with a 5-year mortality rate independent of other major risk factors and has a stronger (1.9-fold) risk of death in type 2 diabetic patients than in non-diabetic subjects. Seems to be a factor.

Part 5: Association of elevated cardiovascular mortality with high tHcy. The literature discussed in this heat leads to the conclusion that the most effective way in which high tHcy can be lowered is to give all three vitamins and betaine. Va that occurs
Decreased D risk is likely to work through mechanisms that reduce vascular resistance and thrombotic propensity. As a further useful (although not relevant) consequence of such additions (especially of folic acid), consumption of these vitamin supplements early in pregnancy results in the development of neural tube closure defects and related defects such as spina bifida. Decrease.

Part 6: β-Cazomorphin-7 from A1 and B-type β-casein appears to be a harmful component of some milks, whereas one specific peptide from casein,
A possible immunological mechanism by which β-casomorphin-7 appears to be beneficial through immunological properties. One property of casomorphin is that alternating proline residues "protect" adjacent peptide bonds from attack by endopeptidases. Casein may include a repeating alternating proline-X residue sequence. One persistent array-
There are only residues 60 to 68-, but another pro-tyr-pro
The -glu sequence is at residue 180. An alternative explanation is based on the finding that the peptide β-casomorphin 9 fits the amino acid residues from position 60 to position 68 (inclusive) of bovine β-casein A2 (see Figure 3). The composition of this peptide confers resistance to further digestion using endopeptidase cleavage. This peptide is released in the intestine during digestion of milk containing the variant of casein.

The peptide, β-casomorphin-9, is believed to have an immunoprotective or at least immunomodulatory effect on type 1 diabetes, resulting in β-casein A2.
Consumption of milk containing (and substantially free of β-casein A1 and β-casein B) results in a decrease in diabetic incidence below that in the control population. β
-Some experiments intended to demonstrate the immunological activity of casomorphin-9 are described below.

[0099]   Exemplary embodiment (A) + (B)   Further examples of fortified supplements include:

1. A liquid milk comprising an A2-type casein composition with an additive compound selected from Group I (see Definitions) and substantially free of A1-type and B-type caseins. Preferably at least two compounds are added to take advantage of the interrelationship and the preferred daily intake is the generally accepted human daily requirement, ie 400 μg folic acid, 5 μg cobalamin and 2 mg B62. Assuming an average daily intake of milk of 400 ml, a concentration of 100 μg folic acid, 1.25 μg cobalamin and 0.5 mg B6 per 100 ml milk with A2-type casein and without A1-type casein provides this intake. We also recognize special cases such as the elderly who may require extra cobalamin to offset the low absorption rate. For these special cases, extra cobalamin, or special fortified dairy products with endogenous factors may also be provided. The other components can be adjusted.

2. A flour supplemented with folic acid or an analogue thereof is provided. Other members of the tHcy-lowering group can be added; however, providing cobalamin in this way is considered uneconomical. Some individuals are unable to eat flour or at least tolerate gluten.

3. An alternative (from the perspective of achieving a reliable daily intake goal) is
A fortified breakfast cereal containing an additive compound according to the invention for supplying a daily intake as described above, sold with a container of properly preserved A2-casein milk as a "kit of parts". is there. This may include a fixed amount of "UHT" or long-term storage milk in aliquots, the combination being as milk corresponding to a single "ready-to-use" breakfast cereal. It can be sold or distributed.

4. Fortified ice cream, yogurt, etc. made from A2-type casein milk.

[0104]   5. Other foods made with casein that are not an obvious type of dairy product.

6. An infant formula made from milk of type A2 casein, possibly fortified to a lesser extent, also suitable for very young children.

7. A dairy product, made from vitamin A-enriched casein A2 milk, designed to be accepted by young people. (Young women who are not yet aware of pregnancy are at risk of spina bifida damage that occurs early in embryogenesis). Arterial lesions are not absent in young people.

8. Any one of a whole range of edible milk-based products, such as milk powder, milk chocolate, cheese, etc. made from milk of type A2 casein, fortified with a compound according to the invention.

Water, then flour, then milk appear to be the three most likely components of the average Western diet. Cereals are very often the "standard breakfast". We therefore select those ingredients without special efforts-such as not having to remember to take the pill, etc.- so that an appropriate daily intake can be achieved. Perhaps the various products proposed in this specification will be offered for sale as "heart friendly" or similar alternatives.

Although natural folic acid has a low thermal stability, artificial folates or combinations tolerate pasteurisation, eg with minimal loss. Cobalamin (and B6) in milk has low photostability,
Therefore, any product according to the invention should preferably be stored out of the sun.

The theoretical basis for this prophylactic treatment approach is the removal of dietary factors found in milk and involved in both diabetes and coronary heart disease, and group B vitamins and // that can reduce tHcy. Or a combination of fortification of milk or dairy products free of harmful dietary factors in combination with betaine. Methods of producing such individual properties of milk or dairy products are known to those skilled in the art, but the combination of such properties with the intention of preventing obstructive vascular disease is unique to the present invention.

[0111]   Many ways can be explored to take advantage of this discovery. For example:

1. Use in the dairy industry of dairy cows of breeds or strains that produce β-casein A2 and substantially not β-casein A1 and β-casein B. (For example: Bos
(Indicus subspecies, and the use of dairy cows, goats, and even humans, the latter present in Iceland, the latter can avoid contact with certain milks or their products, especially in the early postnatal period).

2. From a mixed population of dairy cattle of breeds or strains that produce β-casein A2 and do not substantially produce β-casein A1, A1A2 or B using some or all of the selection methods known to those skilled in the art. Choice. For example, dairy cows can be population tested for production variants other than secreted casein variants and rejected A2 variants. Bulls considered as AI sire are tested directly using genetic engineering methods, or daughter cows from early-tested offspring (preferably born to A2-type mothers) are tested as described above.

3. Β by at least an individual known to be susceptible to type I diabetes
-Use of dairy products only from dairy cows of breeds or strains which produce casein A2 and substantially not β-casein A1 or B.

4. Oral administration of formulations containing β-casomorphin-9 with dairy or otherwise food products. β-casomorphin-9 can be made by recombinant means from casein or synthesized.

5. Administration of β-casomorphin-9, presumably in a sustained release formulation, to enhance or prolong the immune response.

6. Administration of a "helper substance" which may include: (a) a substance that promotes the enzymatic cleavage of β-casomorphin-9 from the protein, (b) β-casomorphin-9 in at least the lamina propria of the intestine (C) A substance that enhances the response of cells having immunocompetence in the body to the presence of (c) β-casomorphin-9, which aids in transportation.

7. Any of the above, but strategies using improved peptides or the like that have an enhanced capacity over that possessed by β-casomorphin-9 in conferring resistance to type I diabetes. (Β-casomorphin-9 is a naturally occurring peptide with desirable activity, but further studies will likely lead to more active substances with less adverse effects).

[0119]

[Commercial benefits or advantages]

In view of the incidence of heart and other vascular diseases and the difficulty of reliable diagnosis of diabetes, as well as the marginalities of many people with regard to the required intake of folic acid, the present invention provides Without major cost or manufacturing difficulties,
It is clear that many of the institutional (treatment) and labor costs associated with the widespread diseases diabetes and VaD can be saved.

For convenience, the present invention is marketed just like normal milk, and preferably as a full-fledged food supplement to ensure a daily dose, possibly as a substitute milk called "heart milk". You can The additive is sufficiently heat stable to withstand use in tea or coffee. In addition, some specific benefits of the invention include the following:

(1) At least reduction in the incidence of type I diabetes in a population. This avoids a great deal of human suffering, saving about $ 1 million in the life of each affected individual in New Zealand (population 3.8 million).

(2) Little information is available about type II diabetes, but a reduction in tHcy should benefit patients.

(3) Reduction of VaD as manifested by mortality from heart disease, morbidity and mortality from stroke, amputation as a result of peripheral vascular disease, kidney transplantation, and so on.

(4) The product provides all women of childbearing age, if tolerated, as a kind of milk with a sufficient daily dose of folic acid to avoid neural tube defects. Should be used to eliminate the problem from the population.

(5) The recognized role of casein varieties will allow establishing an improved national herd of cows by rational selection.

[0126]   (6) It is possible to improve people's health without actually administering medication.

Finally, it should be clear that the scope of the invention described and / or illustrated herein is not limited to the preferred embodiments described herein for purposes of illustration. Those skilled in the art will appreciate that various modifications, additions and substitutions can be made without departing from the scope and spirit of the invention as set forth in the claims below.

[Brief description of drawings]

[Figure 1]   It is a graph of the result of a BB rat / Prosobee test.

[Fig. 2]   International correlation between A1β casein and the rates of four diseases.

[Figure 3]   It is the sequence of bovine β-casein A2 showing the position of casomorphin.

[Procedure for Amendment] Submission for translation of Article 34 Amendment of Patent Cooperation Treaty

[Submission date] February 1, 2001 (2001.2.1)

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be amended] Claims

[Correction method] Change

[Contents of correction]

[Claims]

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Claims (15)

[Claims] 1. The supplement is betaine, cobalamin, folic acid, pyridoxine,
And at least one compound selected from the group comprising pharmaceutically acceptable analogues of each substance (known herein as Group I), which is fortified with such an enriched supplement, When consumed, it is possible to reduce the plasma level (tHcy) of homocystine (homocysteine), thus reducing the incidence of vascular disease (VaD), especially cardiovascular and cerebrovascular diseases in the mammalian population. Supplements containing milk or dairy products, characterized by being capable of 2. A supplement according to claim 1, characterized in that the supplement is fortified by the addition of an effective amount of each of at least two compounds selected from Group I. 3. The concentration of folic acid is about 300-per day depending on the consumption of supplements.
2. The food supplement according to claim 1, characterized in that the concentration is such that an effective amount (for adults) of about 500 μg can be taken. 4. The concentration of cobalamin is about 4 per day depending on the consumption of supplements.
A concentration that allows the intake of an effective amount of about 7 μg.
Supplements described in. 5. The concentration of pyridoxine according to claim 1, characterized in that the consumption of supplements allows the intake of an effective amount (for adults) of about 1.5 to 4 mg per day. Supplements. 6. The concentration of betaine is about 10 per day depending on the consumption of supplements.
The food supplement according to claim 1, characterized in that the concentration is such that an effective amount (for adults) of 0 mg to about 1 g can be taken. 7. Providing a population with the supplement of claim 3.
A method for reducing the incidence of neural tube defects in a population. 8. At least one fraction derived from milk and a part I in the manufacture of a supplement which, when consumed, can reduce tHcy and thereby reduce VaD in the population. Use of an effective amount of at least one compound selected from the group. 9. The dietary supplement milk is further of bovine origin and comprises a β-casein content consisting essentially of the A2 variant, which results in the dietary supplement lowering tHcy and the occurrence of diabetes. The supplement according to claim 1, characterized in that the incidence and / or action of VaD in the population can be reduced as a result of the lowering of the rate. 10. The supplemental milk is further of bovine origin and comprises at least A1.
And the B variant comprises a regulated β-casein content in which the variant is substantially eliminated, so that the dietary supplement is as a result of reducing tHcy and as an indirect result of reducing the incidence of diabetes. The supplement according to claim 1, characterized in that the incidence of VaD in the population can be reduced. 11. The supplemental milk, as a residue of digestion of A2β casein,
10. The immune characteristic according to claim 9, characterized in that it is capable of exerting its immune properties in the course of digestive action in contact with a relatively stable peptide known as β-casomorphin 9, which is capable of promoting an immune response in the body. Supplements. 12. A relatively stable active peptide known as β-casomorphin-9, when supplemented by ingestion by an individual, because the supplement is released in the intestine so that it can promote immunity to diabetes. The supplement according to claim 1, characterized in that the analogue is contained in the supplement. 13. A comparatively stable active compound capable of promoting immunity to diabetes is contained in a sustained release formulation such that it is released in the intestine over a period of time. Supplements described in. 14. An active compound capable of promoting immunity to diabetes is characterized by being supplemented by including in the supplement at least one agent capable of enhancing the expression of immunity. Item 12 is a supplement. 15. A dairy product form supplement comprising A2β-casein but substantially A1 and Bβ-casein, enhanced by the addition of an effective amount of at least one compound selected from Group I. (A) type I diabetes mellitus, (b) type II diabetes mellitus, (c) cardiovascular disease, (d) cerebrovascular disease, (e) peripheral vascular disease, including the steps of producing a food and providing it to a population ( A method for reducing the incidence in at least one population of f) neural tube defects, or (g) vascular wall degeneration.