Type 1 Diabetes Mellitus and Possible Causes of It

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A study by Karjalainen et al. in 1992 was conducted to assess whether bovine serum albumin (BSA) was a trigger for IDDM (14). Researchers measured the levels of anti-BSA and anti-ABBOS (specific part of the albumin protein) antibodies in the serum of children with newly diagnosed IDDM, children without IDDM, and blood donors’ (14). Antibodies that react to the ABBOS also react with a beta cell surface protein that may represent a target for autoimmune attack (14). All children in the study with IDDM had the highest amount of both antibodies, especially ABBOS, compared to the children without IDDM and blood donors’ (14). Antibody levels declined after one or two years of exposure to cow’s milk (14). This suggests that albumin has a section that is capable of reacting with “beta-cell specific surface proteins”, which could contribute to islet cell dysfunction because of molecular mimicry (14). What is molecular mimicry?

When an antigen is present in the body, T cells latch onto a short segment, consisting of about 10 amino acids. T cells then present the antigen to macrophages that engulf it and break it down into smaller protein fragments. The macrophages bring the fragments to the cell surface where capable T cells can bind to it. This activates the T cells, leading to stimulation in other areas to attack all proteins with similar amino acid segments. Bovine serum albumin has a short amino acid sequence similar to a beta cell surface receptor ICA69 (17) and beta casein shares a similar sequence with a glucose transporter. If molecular mimicry occurs here, then presentation of BSA or beta casein in the body would lead to autoimmune destruction.

Contrary to Karjalainen et al.’s study, Vaarala et al. found no association with BSA, but did find an increased risk for newly diagnosed IDDM with beta-lactoglobulin, another cow’s milk protein (15). A study conducted by Cavallo et al. found an association with increased risk of newly diagnosed IDDM with beta casein, another milk protein (16). However, no differences were noted with BSA and other proteins assessed (16). Despite these conflicting results, it does appear that some form of “cross-reactivity” may occur with cow’s milk proteins and islet-cell antigens, leading to “auto-attack” of the beta cells.

The role of cow’s milk related to IDDM is not clear. The hypothesis of molecular mimicry has been questioned. Few studies have found a link between cellular immunity to BSA and IDDM. A recent study found that reactivities to beta casein were similar between newly diagnosed individuals with IDDM, their immediate relatives without the disease, and non-related healthy subjects. One confounding factor of the previous study was the lack of appropriately matched subjects, because researchers failed to use HLA matched relatives. Also, when comparing breast-feeding vs. cow milk formula, it is unclear at what point there is an increased risk, as well as the actual amount needed to induce an immune response. Despite all of the evidence presented here, exposure to cow’s milk and risk for IDDM is only suggestive because the exact cause is unknown (18).

Viral Infections Viral infections have been considered to be “more” responsible for diabetes development, than milk proteins. Identifying the exact virus responsible has been extremely daunting for several reasons. Individuals are exposed to many viral infections within their lifetime. Although IDDM is primarily a juvenile disease, by the time the disease is diagnosed, children have been exposed to many viruses. Thus, pinpointing the exact one would be every difficult, if not impossible to link. Another problem is that immunological damage often occurs after the virus is gone, leaving no trace of the virus responsible. However, large population studies, as well as human and mice studies, have led to some possible viruses responsible.

Coxsackie B Virus Coxsackie B virus is an enterovirus, a virus part of a group of picornaviruses, related to those that cause polio. Several studies have found that after or with exposure to Coxsackie B that individuals developed IDDM. Also, large population studies have found antibodies against the virus in children with newly diagnosed IDDM. Coxsackie B viruses have been isolated from the pancreas in children who have developed IDDM very rapidly. Plus, inducing certain mouse strains with the virus has caused these mice to develop the disease.

Molecular mimicry has been postulated in the case of Coxsackie B virus. The virus increases the expression of an enzyme GAD in the pancreas. GAD is a highly potent autoantigen of the autoimmune response in humans and mice models. Coxsackie B and GAD share a similar sequence that may lead to cross reactivity.

Other, but not limited to, factors that may be responsible for Coxsackie B and IDDM are altered immune system regulation because of viral infection, altered memory of the T cells causing them to forget which are “self” and “not self” in the presence of viral infection, and persistent infection of the beta cells because of viral antigens expressed within them.

Although this all sounds promising, several other studies have not found conflicting results such as no difference in Coxsackie B antibodies between those with IDDM and those without it, along with no differences in prevalence and amount of antibodies responsible.

Rubella Virus About 12-20% of fetal infected individuals with rubella will develop diabetes within 5-20 years (19,20). In some adults, development of diabetes has occurred after infection with rubella. Although this poses a threat to genetically susceptible individuals, vaccination programs have decreased the amount of rubella cases.

Cytomegalovirus (CMV) There have been individual case reports of children developing IDDM after exposure to CMV. There have been recent studies done showing that newly diagnosed individuals with IDDM were recently exposed to CMV. It has been suggested that molecular mimicry may be partly responsible because CMV proteins share a resemblance with a protein in the islet cells of the pancreas. Pak et al. discovered that about 20% of individuals with IDDM have CMV DNA in the islet cells (21). Despite all this evidence however, a large Swedish study found no correlation between CMV infection and risk for IDDM (22). Besides all of this, vaccinations against the virus have lowered the prevalence of CMV infections.

Epstein-Barr Virus (EBV) Individual cases have been noted where those infected with EBV develop diabetes. However, IDDM development as a result of EBV infection is probably not responsible for the disease in the majority of subjects. Little research and single cases are not enough to consider this a major cause.

Other Viruses There have been reports of individuals developing IDDM after exposure to influenza, hepatitis A, varicella zoster, mumps, measles, rotavirus, polio, and Coxsackie A virus.

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Chris Theberge is the founder of the Nutrition and Food Web Archive, NutriWeb Designs, and Dietitian Designs. Visit http://www.nafwa.org for free nutrition and food-related resources.

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