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Nutrition & Product Information
Diabetes Mellitus & Dairy Food Consumption
Type 1 Diabetes Mellitus
Prevalence
Although an estimated 16 million people have or will have diabetes, the majority of these people will develop type 2 rather than type 1 disease. The ratio is about 9 to 1. That is, for every nine people who develop type 2 disease, 1 person will develop type 1 disease. Thus, of the approximately 16 million, 1.6 million will have type 1 diabetes mellitus. This form is the most severe form and usually occurs in childhood. Thus, it is a disease of long duration. Obesity is not a feature of this form of the disease. Secondary complications (blindness, premature heart disease, renal disease, impaired peripheral circulation, gangrene, amputations, neuropathies) are more common in this patient group than in the group with type 2 diabetes. Type 1 disease is due to pancreatic ß-cell destruction and subsequent failure to produce and release insulin. The ß-cells in this form of the disease have been destroyed either through an autoimmune reaction or through a viral attack. Loss of ß-cells through a viral attack is less common than loss through autoimmunity. Most of the people with type 1 diabetes mellitus are those with autoimmune disease.
Both children and adults can develop type 1 diabetes. It is usually of sudden onset with unexplained weight loss together with excessive urination and thirst. Fatigue, a ketone breath and glucose in the urine together with hyperglycemia are additional symptoms. Management includes insulin replacement therapy and careful balancing of both physical activity and the diet with insulin replacement therapy. The prevalence of type 1 diabetes in children has been well documented in many parts of the world (Table 4). Perusal of Table 4 shows an unequal world distribution of children with the disease. Countries such as Finland and Sweden have far more children with type 1 diabetes than countries such as Norway or Poland. The genetic mix of the peoples in these different countries is probably different even though all four countries are primarily Caucasian.
The prevalence of type 1 diabetes in adults has been difficult to ascertain. This is because an adult when interviewed, might be one who reports the use of insulin. This individual might be a person with type 2 diabetes who has proceeded to insulin therapy after many years of disease management using diet, exercise and oral hypoglycemic agents. On the other hand, the adult might have developed type 1 as an adult or as a child who is now an adult. This blurring of definitions of type 1 versus type 2 is what makes the prevalence data for adults difficult to acquire reliably. While it is easier to gather information about the number of children with type 1 diabetes, there are some figures on adults. For example, Libman et al. (34) reported a mean of 9.2 cases of adults (>20 yrs of age)/100,000. They estimated that there were 29,713 new cases of type 1 diabetes each year in the United States of which 16,542 were adults. Over the last decade the number (incidence) of new cases in children has been fairly constant in the United States but the number of new cases in adults has been rising. In part, this is probably due to better methods of identification and reporting, but, it may also be an actual increase in disease incidence. Table 4 (next page) gives information about the prevalence of type 1 diabetes in children less than 17 years of age in the United States as well as in other countries in the world. (33)
A Disease of the Immune System
Diabetes due to a viral disease
In population studies there are a number of instances where the disease is preceded by flu or some other significant viral infection. Epidemiologists have noted over the decades, that 6-9 months following major flu epidemics there are upsurges in the incidence of type 1 diabetes. (35) Documentation of the pathophysiology of this linkage between viral infections and subsequent diabetes is sparse. However, in a study of children who had died of an overwhelming viral disease, some of these children were found to have a viral invasion of their pancreatic ß-cells. (36)
Not only are the flu viruses suspect, so too are a number of other viruses. Coxsackie B viral infection can precede diabetes in susceptible individuals and so can mumps and rubella. These persistent infections can cause damage in addition to the usual lytic effect that occurs in the acute phase of the infection. Damage can take the form of producing (or inducing) small changes in the cell surface proteins that change the function of the protein or change the recognition of the protein as a normal cell constituent. These slightly modified cell proteins are then recognized as foreign by the immune system. In turn, antibodies are produced to these slightly modified self-proteins and the islet cells are destroyed. One such protein is the islet cell surface protein (ICS). Antibodies to ICS protein have been found in virally infected individuals; these antibodies could be presumed to be the instruments of ß-cell destruction.
Viruses also induce the production of cytokines such as interferon, the interleukins, and tumor necrosis factors. These substances alter the immune response by altering the production of antibodies by the B-cells and thus contribute to the development of the insulitis (inflammation of the islet cells) that often precedes islet cell destruction.
Table 4.
Prevalence (number/100,000) of Type 1 Diabetes Mellitus in Children in Various Parts of the World |
| |
| Country/region |
#/100,000* |
|
Country/region |
#/100,000* |
|
| Africa |
|
|
| Algeria/Oran |
505 |
|
Oceania |
| Libya/Benghazi |
165 |
|
Australia |
272 |
| Mauritius |
32 |
|
New Zealand |
272 |
| Tanzania/Dar es Salaam |
86 |
|
|
| |
|
Europe |
| North America |
|
Austria |
205 |
| Canada |
|
Belgium |
31 |
| |
Prince Edward Island |
92 |
|
Croatia |
72 |
| |
Montreal |
919 |
|
Denmark |
66 |
| USA |
|
Estonia |
208 |
| |
North Dakota |
204 |
|
Finland |
2062 |
| |
Wisconsin |
166 |
|
France |
261 |
| |
Pennsylvania (Allegheny Co) |
850 |
|
Greece |
137 |
| |
Rochester, NY |
38 |
|
Hungary |
256 |
| |
Colorado |
1165 |
|
Iceland |
120 |
| |
Alabama (Jefferson Co) |
175 |
|
Italy |
116 |
| |
Philadelphia, PA |
215 |
|
Latvia |
215 |
| |
San Diego, CA |
48 |
|
Lithuania |
336 |
| |
|
Luxemburg |
6 |
| Central America, West Indies |
|
Macedonia |
112 |
| Argentina/Avellaneda |
30 |
|
Malta |
66 |
| Brazil/San Paulo |
52 |
|
Netherlands |
58 |
| |
|
Norway |
158 |
| Asia |
|
Poland |
129 |
| China/Shanghai |
75 |
|
Portugal |
25 |
| Hong Kong |
22 |
|
Spain |
399 |
| Japan |
379 |
|
Sweden |
3836 |
| Korea |
71 |
|
United Kingdom |
662 |
| |
|
Yugoslavia |
259 |
| Middle East |
|
|
| Israel |
296 |
|
|
| Kuwait |
86 |
|
|
|
*The number of cases refers to those individuals 17 years of age or under.
Source: adapted from Karvonen et al. Diabetes/Metabolism Reviews 13:275-291; 1997
|
There appears to be a genetically determined susceptibility to these viral infections that may be linked to whether a virus or a group of viruses will induce type 1 diabetes. However, the identification of such susceptibility genes has not been reported in detail.
Diabetes due to an autoimmune reaction
An autoimmune reaction can destroy the islet ß cells. However, before the literature on this process is discussed, a brief explanation of how the immune system works is in order. The immune process is somewhat of a cascade system and is outlined in figure 3. There are a number of cell types involved, each having a particular role in ablating the "foreigner," be it an invading pathogen or a foreign protein or a foreign peptide. These foreigners collectively are called antigens. Two kinds of cells divide the work of the immune system between them: lymphocytes and phagocytes. Lymphocytes are specialized cells that recognize "foreignness" while the phagocytes are specialized ingesting cells. Faulty recognition of antigens by the lymphocytes could be a part of autoimmunity since the lymphocytes are supposed to recognize non-self structures. They have surface receptors that bind to whatever antigen best fits these receptors. Actually it is not so much the shape of the antigen but its distribution of charges and its regions of hydrophillicity and hydrophobicity that determines binding. Each lymphocyte has many thousand receptors and each binds the same antigen. Because each lymphocyte will bind only one type of antigen, there must be many different lymphocytes each having a specific receptor for a specific antigen that it binds. Thus, one of the traits of the lymphocyte population is its tremendous diversity. Estimates are that between 10 and 100 million different antigens can be recognized by a normal individual. An antigen must fit the lymphocyte if that lymphocyte is to become activated and stimulate the proliferation of similar lymphocytes as part of the cascade of the immune response.
The initial event in the immune response is the recognition of the antigen (see figure 3). Because lymphocytes are so long lived, once a specific antigen has been recognized and lymphocyte proliferation has occurred, the body is immune to that particular antigen. The antigen is bound by the lymphocyte or may be processed by nearby macrophages, dendritic cells or B-cells. When macrophages are activated they produce the cytokines, TNF and interleukin 1 that signal endothelial cells and lymphocytes to signal bone marrow to produce more macrophages. Macrophages can signal the bone marrow directly as well to produce more macrophages. If the antigen is not a "serious threat" macrophage phagocytosis (the macrophage surrounds the antigen and digests it) will delete the antigen and no further reaction or involvement of the immune system occurs. However, should further response be needed, then the other cells (lymphocytes, dendritic cells and B-cells) come into play. Together, these cells are called the antigen-presenting cells. The antigen presenting cells bind the antigen and present it to the T-cells (lymphocytes produced by the thymus gland). Proteins known as the major histocompatibility (MHC) proteins or class I and II MHC molecules are found on the surface of these antigen presenting cells as well as on other cell types. The pancreatic ß cell for example has MHC proteins on its surface. MHC proteins are glycoproteins. The T-cells have specific receptors (immunoglobulins) on their surfaces that recognize the MHC proteins and bind to them. This produces a T-cell-antigen-MHC complex.
The T-cells themselves are divided into two groups: CD4’s and CD8’s. This division is based on the types of accessory factors (adhesion molecules) that are needed for the binding of the T-cell to its cognate antigen-MHC complex. The formation of the T-cell-antigen-MHC complex activates the T-cell and this results in the release of one or more cytokines.
Cytokines are peptide molecules that are signaling molecules. The cytokines ensure communication between the various components of the immune system (macrophages, T-cells, B-cells, etc) as well as to cells outside of the system (e.g. endothelial cells, bone marrow cells, and fibroblasts). The cytokines are used to control local and systemic immune and inflammatory events. More than 30 of these compounds have been identified. Included are: the tumor necrosis factors (abbreviated TNF), interleukins (abbreviated IL), interferons (abbreviated ITF) and colony stimulation factors. These cytokines can have local actions (paracrine) or distant actions (autocrine) and because of this, they may be regarded as hormones. The macrophage-derived cytocines (IL-1,IL-6 and TNFa) for example exert actions on distant organs.
There are four kinds of T-cells, each of which has a different role in the immune process. The inducer T-cell recognizes the antigen and makes cytokines that activate other T-cells. These cells also make and release interferon c that attracts macrophages (the heavy duty phagocytes) to the area where the antigen has been recognized. Its close relative, helper T-cells are so termed because they "help" to mediate the cellular and humoral immune responses. Type 1 helper T-cells produce IL-2, IFN-c and TNF-ß whereas type 2 helper cells produce IL-4, IL-5, and IL-10. The activity of the helper T-cells can be suppressed by other T-cells known as suppressor T-cells. There is another T-cell and that is the killer cell. This cell is the executioner that annihilates the foreigner. The antigen-antibody reaction has immobilized the pathogen or the foreign protein and this immobilization is followed by self-destruction. The killer cell attacks the target’s membrane while signaling the target to commit suicide through activating an internal self-destruction process (apoptosis). Phagocytosis used by the macrophages is also involved. The macrophages release IL-10 and IL-12. IL-12 signals cell-mediated immunity whereas IL-10 acts as an anti-inflammatory agent. It does this by inhibiting the production of the other interleukins.
In contrast to the T-cells that adhere to the antigen (cell-mediated immunity) as described above, the B-cells produce antibodies that react with the antigen (see figure 3). The antibody structure has been well studied. The structure is in the form of a Y. At the two tips of the Y there are differences in amino acid sequence that are responsible for recognition specificity. Most of the antibody molecule is the same from one antibody to the next but the tips are different. It is estimated that there are ~10 (20) antibody molecules in each individual. Some of these will cross react to closely related antigens even in normal individuals. However, in type II immune disease, the breadth of cross reactivity is much larger. In people having mutations in the genes that dictate antibody specificity, antibodies produced by the B-cells will bind with more than just the original antigen.
The antibodies are divided into 5 classes based on their respective roles in the immune system. These classes are: IgG, IgE, IgA, IgM, and IgD. The IgG class of antibodies is the main class of antibodies that are elicited by immunization or exposure to environmental pathogens. IgE is involved in allergic reactions. IgA antibodies are thought to be those present in bodily excretions (saliva, mucus, colostrum etc). IgM and IgD antibodies function as antigen receptors on lymphocytes prior to antigen exposure. The latter two classes may have other functions as well but these are not well described. B-cells kill from a distance using their ability to produce antibodies while T-cells kill by direct contact. Some of the B-cells are the so-called memory cells. They produce soluble immunoglobulin antibodies with a high degree of recognition specificity. Once programmed to produce an antibody to a specific antigen they will produce this antibody with a high degree of fidelity. This is the basis of the immunization procedures used in infants to protect them from some of the communicable diseases. When challenged with an antigen, the memory cell is transformed into short-lived plasma cells. Plasma cells are protein factories that can produce ~2000 antibody proteins/second during their brief (5-7 days) lifespan. There are a number of diseases due to mutations in the genes that encode the many elements of the immune system. These diseases have been divided into four groups or types (Table 5). As shown in this table, autoimmune diabetes mellitus is an example of a Type II immune disease. Autoimmune disease is a generic term covering a disease state in which the body develops antibodies to its own proteins and then proceeds to destroy cells containing these proteins. For some unknown reason the body loses its ability to recognize specific antigens and instead develops antibodies to closely related antigens. Some of these may be cell surface proteins that are similar to dietary proteins. Thus, when a person’s blood is tested for the presence of antibodies to specific food proteins there is a cross reaction and it appears as though these food proteins are in the circulation. In fact, it is very unlikely that this has occurred. Nonetheless, because of the loss in specificity of antigen recognition, antibodies that react with food proteins can be found in these individuals.
|
Table 5.
Immune Disease Characteristics |
| |
| Type |
Problem |
Example |
|
| I |
Excess IgE production |
Allergic response to environmental stimulus e.g., pollens, specific food components |
| II |
Loss of antigen recognition specificity; inadequate suppressor T-cells |
Type 1 diabetes, thyroiditis, psoriasis, rheumatoid arthritis |
| III |
Leaky cell membranes allowing soluble components to act as antigens. |
Lupus, adverse response cell to some drugs, glomerulonephritis, arthritis, rash, pleurisy |
| IV |
Loss of helper cells secondary to a pathogen such as the TB bacterium or the HIV-1 virus |
Tuberculosis; AIDS |
|
In autoimmune diabetes mellitus the pancreatic ß cells are destroyed leading to an absolute insulin deficiency. The destruction is mediated by the T-cells producing antibodies of the IgG class in the immune system. There is an inflammation of the islet cells (insulitis) and these cells will contain both CD 4 and 8 T- cells, B-cells, macrophages and killer T-cells. Antibodies to a variety of antigens can be found in the circulating blood. These include antibodies to glutamic acid decarboxylase, insulin, the insulin receptor, carboxypeptidase H, c-peptide and many others. (37,38) Table 6 lists some of the antibodies found in people with autoimmune diabetes. Most of these antibodies are cell surface proteins, thus supporting the mechanism of ß cell destruction by antibodies that target this particular cell type. Destruction is random and people with autoimmune diabetes can vary in the degree to which their ß cells are destroyed by the autoimmune reaction.
|
Table 6.
Some Antibodies Found in People with Autoimmune Diabetes (37,38) |
| |
| Antigen |
Comment |
|
| Glutamic Acid decarboxylase (cell surface protein) |
Antibodies present before diabetes diagnosis |
| Insulin |
Antibodies found after diagnosis |
| Insulin receptor |
Antibodies found after diagnosis |
| Bovine serum albumin |
Antibodies found after diagnosis |
| ABBOS (albumin precursor) |
Antibodies found after diagnosis |
| C-peptide |
Antibodies found after diagnosis |
| ICA 69 (cell surface protein) |
Antibodies found prior to diagnosis |
| IAAb (an immunoglobulin) |
Antibodies found prior to diagnosis |
|
Autoimmune disease is not unique to the ß cell. It can strike a number of cell types. For example, the autoimmune disease, psoriasis, occurs when the immune system destroys the epidermal cells. Thyroid cells can be destroyed in the disease, thyroiditis that in turn develops as Hashimoto’s disease or Graves disease. The connective tissue and the cells in the material around the joints can be destroyed through autoimmunity involving both IgM and IgG in rheumatoid arthritis. Swollen and painful joints, particularly in the hands and lower extremities, characterize this arthritis. All of these diseases can be retarded with the use of immunosuppressants such as cyclosporin. Studies of children newly diagnosed with autoimmune diabetes have shown that the time course of their disease can be retarded with the use of low doses of cyclosporin. (39) Cyclosporin is one of the drugs used to prevent rejection of transplanted organs but when used in lower doses can affect the time course of autoimmune disease. There are other immunosuppressants that may be useful as well but these have not been studied extensively. The use of immunosuppressants is not without risk. Some of these drugs are known to have adverse secondary responses such as cancer.
Other Immune Diseases
Type I disease is the group of diseases known as allergies. In this situation, the body manufactures excess IgE antibodies that attach to basophils in the blood and mast cells in tissues. If an antigen is encountered, IgE stimulates the release of powerful mediators of inflammation (histamines, leukotrienes and eicosanoids). These mediators produce the symptoms of an allergic reaction to an environmental antigen such as a pollen or a specific food ingredient. If the patient makes too much IgE in response to exposure to an antigen, runny nose, watering eyes or other symptoms of allergy will appear. In some cases (~10%) the allergic response is an overwhelming one requiring medical assistance. The instance of a bee sting eliciting anaphylactic shock is an example of such a reaction. The individual having such an ability to produce excess IgE in response to certain allergens avoids exposure. While this is not truly a nutrition problem, it is another example of an environmental agent-gene interaction. It could be a food but it could also be something else in the environment.
Type III immune disease arises when antibodies to soluble cell components such as DNA or some cytoplasmic protein are formed. It is thought that this disease is due to a "leaky" plasma membrane. Such a membrane allows soluble cell constituents to "leak" out of the cell and in so doing, these constituents are recognized by the immune system as "foreign." Systemic lupus erythematosus is an example of this type of immune disease. It develops when the body manufactures antibodies to DNA. The immunopathology of this type of immune disease involves a reaction to a cell soluble antigen. That is, the antibodies are produced to materials found inside the cell and the cells are destroyed.
There is a fourth group of immune diseases that are T-cell mediated. They can be autoimmune diseases but usually the autoimmunity is a secondary effect. For example, in tuberculosis most of the destruction of the air sacs due to cavity formation (destruction of the epithelial cells lining the air sacs in the lungs) is T-cell mediated not bacterium mediated. Similarly, in acute viral hepatitis, most of the liver destruction occurs via killer T-cells attacking the virus but also incidentally killing the liver cells as well. In another example, the AIDS virus HIV-1, infects helper and induced T-cells because its envelope glycoprotein, gp 120, binds to the CD4 on their surface. Once inside the T-cell, the virus uses the enzyme reverse transcriptase to copy its RNA into the T-cell’s DNA. It then becomes latent only to be reactivated when the T-cell responds to an antigen. Ultimately this results in a loss of helper cells and the infected individual loses the response to infective agents. In other words, the patient’s cells are destroyed not by the HIV-1 virus but by the body’s failed immune system.
As can be seen, autoimmunity is not the same process as allergy (a type I immunological disease) although both involve the immune system. Both processes involve B cells and T cells. Both involve the development of antibodies however, there the similarities end. Whereas in the allergic reaction the body is responding to very specific allergens (antigens), in type II immune disease, autoimmunity, the reverse is true. The body has lost its ability to recognize specific antigens and, instead, is responding to a group of similar antigens. In autoimmune disease this loss of specificity means that the immune system has lost its ability to distinguish exogenous proteins or antigens from self-proteins or antigens. Proteins normally found in the plasma membrane are recognized as antigens rather than as normal cell constituents. Through this loss of recognition specificity, the body then develops antibodies that react not only to exogenous proteins, but also to its own cell surface proteins and, in so doing, destroys the cells of which these cell surface proteins are a part.
Can Autoimmune Disease be Identified in People with Diabetes?
Progress has been made in the identification of candidate genes that are linked to the development of diabetes due to autoimmune disease. Table 7 is a list of candidate loci that have been linked to type 1 diabetes. The chromosome location is given as well as a marker sequence. Note in this table that there are other autoimmune diseases that share the same marker. In addition, some of the loci have more than one marker. In this table, the following abbreviations are used: MS is used for multiple sclerosis; SLE represents systemic lupus erythematosus; RA indicates rheumatoid arthritis. While some of the type 1 patients may also develop these other diseases, this does not always happen.
|
Table 7.
Chromosomal Locations of Candidate Loci Identified for Type 1 Diabetes (49) |
| |
| Loci |
Location |
Marker |
Other autoimmune loci |
Marker |
|
| IDDM1 |
6p21 |
D6S426 |
MS
Asthma
Celiac Disease |
D6S273
D6S276
HLA-DQ |
| IDDM2 |
11p15.5 |
D11S922 |
SLE
Asthma
MS |
D11S922
D11S96
D11S922 |
| IDDM3 |
15q26 |
D15S107 |
SLE
Celiac Disease |
D15S127
D15S642, D15S207 |
| IDDM4 |
11q13 |
FGF3
D11S1296 |
Asthma |
FCER1B |
| IDDM5 |
6q25 |
D6S290 |
|
|
| IDDM6 |
18q21 |
D18S39 |
RA |
D18S57, D18S474 |
| IDDM7 |
2q31-33 |
D2S152 |
SLE |
D2S1391 |
| IDDM8 |
6q27 |
D68S64 |
SLE |
D6S1027 |
| IDDM9 |
3q21 |
D3S1303 |
RA |
D3S1267 |
| IDDM10 |
10p11-q11 |
D10S193 |
|
|
| IDDM11 |
14q24.3 |
D14S67 |
SLE |
D14S74 |
| IDDM12 |
2q33 |
D2S152
CTLA4 |
SLE
Thyroiditis |
D2S1391
CTLA4 |
| IDDM13 |
2q36 |
D2S301 |
RA |
D2S377, D2S2354 |
| 1q42 |
1q42 |
AGT |
SLE |
D1S103, D1S3462, D1S235 |
| Xp11.4 |
Xp11.4 |
DXS1068 |
RA
MS |
DXS1068
DXS1068 |
| Xp11.1 |
Xp11.1 |
DXS991 |
MS |
DXS991 |
|
|
|
Although these loci have been identified, specific mutations that phenotype as autoimunne diabetes have not been described in detail.
More than 100 genes encode the elements of the immune system. Mutation in almost any one of these genes could explain disturbed immune function, whether it is decreased resistance to common pathogens or increased immunoreactivity — as in one or more of the immune diseases.
The question of whether diet could affect the phenotypic expression of mutations in these genes has not been answered. Studies in animals subjected to pathogens have shown that their overall nutritional status can dictate their immune response. Additional studies of rodents with mutations in their immune system genes have been shown to respond to variations in their diets. NOD mice and BB rats are frequently studied because they develop type 1 diabetes due to an autoimmune destruction of their islet cells. Diabetes develops during puberty (60-90 days of age) and if untreated the animal will die. Additions of vitamin D (an immunosuppressent), the feeding of a protein free diet and using vitamin E supplements have prevented or delayed the onset of diabetes. (40-42) Autoimmune diabetes in the BB rat has been prevented or delayed by high protein diets, a purified amino acid diet, and a casein diet. (43-47) Both the NOD mouse and the BB rat are endogenously infected with retroviruses. If they are reared in pathogen free environments, the diabetes does not develop. (48) While these rodents have been useful in understanding the role of environmental factors in type 1 diabetes development, the results of the various dietary treatments have been contradictory.
The Finnish Hypothesis
How is the autoimmune reaction elicited? This is a question that has eluded countless researchers concerned with the various autoimmune diseases. In fact, with autoimmune diabetes, Finnish workers hypothesized that the early exposure of infants to milk other than their mother’s breast milk might be a factor in the development of the disease. As can be seen from Table 4, Finland has one of the highest prevalence rates of type 1 diabetes in children. Finland is exceeded in prevalence only by Sweden. Traditionally, Finnish mothers breast feed their young for periods as long as 2 years. Nonetheless, Finnish researchers proposed that proteins from cow’s milk might be triggers for autoimmunity. (50-52) The basis of this hypothesis was derived from several observations: 1. There was a rise in autoimmune disease in Finnish children coincident with the decline in breast feeding (duration and frequency). (53) 2. Antibodies to cow’s milk proteins were found in the bloods of children with autoimmune diabetes. (52,54) 3. Rats and mice that develop autoimmune diabetes did so when fed diets containing milkvproteins but were less likely to develop the disease when provided with a diet not containing milk proteins. (40-47,55-59)
How valid is this hypothesis? The initial reports from Finland (50,51) stimulated several subsequent research projects that in turn created doubt as to the validity of the original hypothesis. Vaarala et al., also from Finland, proposed that cow’s milk contains insulin that may serve as an antigen if it were absorbed by the infants mucosal cells. (57) Cow’s milk does contain minute amounts of insulin that is fairly similar to human insulin. Given that infants carrying a genetic tendency to lack antigen recognition specificity, consuming cow’s milk with its insulin could elicit an antigen response that subsequently could elicit an antibody response to the infant’s own insulin. Alternatively, this immune response could later be diverted into autoagressive immunity against the insulin producing ß cells. Others hypothesized that there were specific amino acid sequences in albumin in cow’s milk that could serve as an antigen. (52,58) The peptide ABBOS of the albumin was suggested to serve in this way. (52,58) The albumin in human milk and cow’s milk is quite similar, and again, this similarity coupled with the inherent lack of recognition specificity could give a false positive result when the sera from affected infants and children were tested after diabetes diagnosis. In this instance what appears to be an interaction between genes and dietary ingredients is not real. The technology used for determining the presence of antibodies to food constituents gives too many false positives because of the inherent error in the antibodies themselves. They lack specificity.
In addition to the lack of antibody recognition specificity in autoimmune diabetes, there is the question of gut closure. This question relates to how intact food proteins or peptides could escape digestion by the intestinal enzymes and cross the gut wall in sufficient amounts to serve as antigens.
Dietary proteins are fairly large molecules. Could such molecules pass through the intestinal mucosa undigested? The answer to this question depends on when gut closure occurs in the infant. The infant’s intestinal mucosa must be a bit leaky to allow the passage of IgA’s from breast milk that provide passive immunity to the infant. The colostrum and the first milk of the lactating mother provide these antibodies and these antibodies serve to reduce infectious disease in the infant. The transmittal of maternal antibodies to the infant is generally assumed to provide passive immunity for the first three months of life. Whether this passive immunity is direct through a continuous infusion of antibodies through the gut wall or whether this is an estimate based on the longevity of the antibodies is another consideration. Regardless of how the passive immunity is maintained, neonatologists generally assume that gut closure occurs fairly soon after birth.
Estimates range from 2 to 90 days. Do other intact proteins follow or accompany these antibodies? This is also subject to speculation.
If gut closure does not occur as soon as is estimated, there is the possibility that undigested or partly digested proteins could pass into the body and in turn could elicit an antibody reaction. Infants have been known to respond to proteins in their mother’s milk that came from the food she ate. However, the infant’s response is that of an allergic reaction (excess IgE production by the mucosal cells) characterized by diarrhea and abdominal discomfort. Could this explain autoimmunity? Not likely. There is a case on record of a mother who did not have gut closure giving birth to an infant who similarly did not have gut closure. (59) Neither the mother nor child developed autoimmune diabetes or any other autoimmune disease. There are other instances as well, that show that plasma antibodies to cow’s milk are increased even in the exclusively breast fed infant. (60) This suggests that it is not the early exposure to cow’s milk but that the autoimmune process produces antibodies that cross react to groups of similar proteins rather than to individual proteins.
Denial of the Cow’s Milk Hypothesis in Autoimmune Diabetes
Since the original papers were published suggesting a link between early cow’s milk exposure and subsequent autoimmune diabetes development, additional studies have been conducted in different regions of the world. Kostraba et al. using a case-control study design examined the hypothesis that early cow’s milk and solid food exposure increased the risk of autoimmune diabetes. (61) The study used 145 pairs of subjects matched for age, gender, and ethnicity. Relative to unexposed individuals (infants that were exclusively breast fed) early exposure to cow’s milk and solid food was strongly associated in individuals with a high-risk marker (OR 11.3,Cl1.2-102.0). These findings suggested that the foods provided the infant having this genetic marker could increase the risk of developing autoimmune diabetes. While the results of this study supported in part the suggestions of the Finnish workers, the study design did not allow for causality assignment. Furthermore, as mentioned above, the testing of sera from affected individuals has considerable error. Sera of autoimmune individuals will contain antibodies that lack specificity and therefore will react to similar proteins found in food. Thus, false positive responses will be found that cannot be used as proof that diet proteins triggered the autoimmune disease.
Abrams et al. followed two groups of infants from birth to age three. (62) Half of these infants were breast fed exclusively and half were provided a cow’s milk formula. The number of infants that subsequently developed autoimmune diabetes was the same in each group. These workers concluded that the feeding of cow’s milk formula was without effect on diabetes development. Ivarsson et al. measured antibodies to bovine serum albumin in children with newly diagnosed autoimmune diabetes and concluded that the levels of these antibodies were not sufficiently increased to explain the disease presence. (63) Atkinson et al. reached a similar conclusion using 210 newly diagnosed subjects and their first degree relatives who were diabetes free. (64) Some of the relatives had the same kind and amounts of antibodies in their sera while others had none. In addition, these workers also examined patients with other autoimmune diseases (thyroiditis and rheumatoid arthritis). Studies of these patients also did not reveal any significant differences in response to bovine serum albumin or to the ABBOS peptide.
A prospective study conducted by Couper et al. used 317 infants. (65) They showed that there was no association between the duration of breast feeding or the introduction of cow’s milk and the development of islet autoantibodies.
Several studies have been conducted in rodents (BB rats and NOD mice) that model autoimmune diabetes to determine whether autoimmune diabetes disease incidence could be reduced if these animals were never exposed to cow’s milk. (66,67) All the above studies showed that early exposure to cow’s milk (or absence of exposure) had no effect on disease development. NOD mice (66) and BB rats (67) fed either a standard ration containing some milk proteins or a purified ration that was milk protein-free were not different with respect to autoimmune diabetes development. Feeding the milk protein-free diet did not prevent diabetes development.
Although the evidence clearly refutes the idea that early exposure to cow’s milk "causes" autoimmune diabetes, the issue now before us is how do we explain the rise in autoimmune diabetes that has occurred with the decline of breast feeding. Is the real debate about mucosal immune function as suggested by Harrison and Honeyman? (68) These scientists suggest that impaired mucosal immune function might explain autoimmunity. They point out that the NOD mouse reared aseptically does not develop the disease as readily as do NOD mice reared normally. They also point out that breast milk contains a number of antibodies that provide some immunity to environmental pathogens that in turn could trigger autoimmunity. Lastly, they suggest that the gut mucosa as the first barrier for the immune system might be weak in those individuals prone to autoimmunity. All of these ideas are legitimate proposals and all will need further exploration before they can be accepted as explanations for autoimmune disease. Certainly genome-scale analysis of autoimmune patients and normal controls could be of assistance in identifying persons at risk. With so many candidate genes associated with immune system malfunction, this technology has potential for not only identifying persons at risk for disease development but also for the development of appropriate strategies to prevent or delay such development. Whether these strategies would involve dietary maneuvers cannot be predicted at this point. However, it should be pointed out once again that individuals with autoimmune diabetes are a very small segment of the population with diabetes and that their disease could be due to one or more mutations in the genes that encode the more than 100 proteins that are part of the immune system and that result in a loss in antibody recognition specificity.
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