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Type 1 diabetes, or Insulin Dependent Diabetes Mellitus (IDDM), is a disease
characterized by “auto-destruction” of the pancreatic beta cells that produce insulin.
Overtime, your body silently destroys these cells creating an insulin deficiency.
IDDM appears to stem from an inherited defect in the immune system, triggered by
some environmental stimuli. The exact cause of the disease is still unknown;
however, scientists have isolated a few factors that may be related to development of
the disease. The purpose of this review is to provide insight on where research is
headed and what we already know about the progression of IDDM.
Genetics. Recent mapping of the human genome has opened many areas to explore
in the field of diabetes research. Animal models and large population studies have led
to some possible genetic links. The major histocompatibility complex (MHC) on
chromosome 6 is a regulator of immune response because it recognizes “self” and
“not-self” things in the body. If something is seen as foreign, the MHC will stimulate
antibody production. Genes encoded on the MHC are associated with IDDM,
particularly the human leukocyte antigen (HLA) class II alleles, DQ and DR (1).
Although the HLA-DQ locus appears to be the best single marker for susceptibility
among Caucasians, at least 40% of family-related diabetes cases have combinations
of both DQ and DR alleles (2,3). DQ and DR alleles are almost always found
together on a chromosome and the risk is associated with them not being in
equilibrium. Many combinations have been documented, some showing both
increased and decreased susceptibility, however it has been difficult to determine the
contribution of HLA-DQ independent of DR. The insulin gene region at chromosome
11 is also associated with IDDM risk.
Studies conducted in the 1970’s established an HLA association and contribution of
IDDM while comparing siblings with the disease (4,5,6). When comparing the
relationship between family members, results are inconsistent. Current estimates
suggest that HLA is 40-50% related to genes passed down by family members (7,5).
The risk of developing IDDM for a twin of someone who already has the disease is
about 70%, and this rises depending on the specific HLA alleles that the twins share
(8). When comparing the risk of developing the disease for first-degree relatives vs.
the US population, the risk is 1/20 and 1/300, respectively (1). Research in the area
of HLA has been extremely difficult. Definitive answers cannot be drawn because
not everyone holding these “susceptible” genes develops IDDM. Actually, less than
10% of genetically susceptible individuals progress to diabetes, implying that other
factors are responsible for progression of the disease. Researchers have explored
these other factors, particularly environmental factors such as early introduction of
cow’s milk, dysregulation of the gut immune system, viral infections, drinking water
and a number of others.
Cow’s Milk Several population studies have found a link between exposure to cow’s
milk and increased risk for IDDM in genetically susceptible individuals. A few
studies have also shown an increased risk for infants exposed to cow’s milk or cow’
s milk based formulas within the first 3 months, and also later in life. It has been
found that infants fed cow’s milk had increased levels of bovine insulin anti-bodies
compared to those that were breast-fed (9,10,11). Bovine insulin is found in the milk
of cows. The antibodies binding to bovine insulin appear to cross-react with human
insulin (9,10). Bovine insulin is considered immunogenic because it differs from
human insulin by 3 amino acids.
Insulin-specific antibodies (ISA), those specific for IDDM, and increased T cell
levels from exposure to cow’s milk have been found in those carrying diabetes
associated HLA risk alleles. Of all the studies to date however, levels of insulin
binding antibodies seem to decrease as the child approaches 9-18 months. This
suggests that the infant is building a tolerance to dietary antigens (12). However,
Vaarala et al. discovered that infants who developed ISA’s, also had increased levels
of bovine insulin antibodies, suggesting that insulin specific immune responses in
children prone to develop autoimmunity cannot be prevented (12). Other studies
have found bovine insulin antibody levels to decrease when human insulin was
presented in the body.
Early weaning (2-3 months) from breast milk has been shown to increase the risk
for IDDM. Maternal milk contains colostrum, a light fluid that contains a variety of
protective factors for the infant. Infants have an immature and easily penetrable gut
system allowing food, in this case cow’s milk, to easily cross into the bloodstream.
The gut system works in one of two ways: it will either accept (build tolerance to)
or reject (develop immunity to) food and its dietary components (13). Several cow’s
milk proteins have been shown to be related to IDDM such as bovine albumin, beta-
lactoglobulin, and beta casein (14,15,16)
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.
Other Environmental Factors. Recent studies have found a positive association
between zinc levels in drinking water and protection against diabetes. Magnesium
levels in tap water have been shown to be related to diabetes protection as well,
however conflicting evidence resides with this. The protections that zinc may
provide is unclear. Despite possible relationships with heavy metals and diabetes,
more research must be done to ascertain the actual relationship.
Of all the evidence presented here, researchers have been unable to find the exact
cause for development of IDDM. What we do know is that genetically susceptible
individuals have an increased risk for diabetes. As displayed here, researchers have
located genes that seem to predispose individuals to diabetes. Genes are not enough
however, because not everyone who has these genes develops diabetes.
Environmental factors are another part of the picture. Whether it is milk proteins,
viral infections, or impaired gut function, those with genetic susceptibility tend to
develop the disease after exposure to these. Identifying which factor is responsible
has been difficult because exact mechanisms of the body are still unclear and tests to
determine these things may not be specific or have not yet been developed. Plus,
isolating one factor is not reasonable because there are a lot of overlaps in immune
functions and genetics. All in all, research is headed in the right direction, but for
now there is still no known cause for IDDM.
References
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Insulin Dependent Diabetes. Annual Review of Medicine. 1998; 49: 397-405.
2. Nepom G.T. Immunogenics and IDDM. Diabetes Review. 1993; 1: 93-103.
3. Pugliese A, Eisenbarth G.S. Human Type 1 Diabetes Mellitus: Genetic
Susceptibility and Resistance. In Type 1 Diabetes: Molecular, Cellular, and Clinical
Immunology, ed. G.S. Eisenbarth, K.J. Lafferty. New York: Oxford University
Press. 1996; pp.
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Antibodies and Tissue Antibodies in Patients with Diabetes Mellitus. Diabetes. 1973;
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6. Thomsen M, Platz P, Andersen OO et al. MLC Typing in Juvenile Diabetes
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Disease. American Journal of Human Genetics. 1987; 40: 1-14.
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Chronic Beta Cell Autoimmunity in Identical Twins of Patients with Type 1 Diabetes.
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10. Vaarala O, et al. Cow Milk Feeding Induces Antibodies to Insulin in Children-A
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Infants at Genetic Risk for Type 1 Diabetes. Diabetes. 1999; 48: 1389-1394.
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Immunology Today. 1998; 19: 173-181.
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Patients with Newly Diagnosed IDDM. Diabetes. 1996; 45: 178-182.
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Diabetes. Diabetes. 2000; 49: 912-917.
19. Vaarala O. The Gut Immune System and Type 1 Diabetes. Annals of the New
York Academy of Sciences. 2002; 958: 39-46.
20. Menser M.A., et al. Rubella Infection and Diabetes Mellitus. Lancet. 1978; 1: 57-
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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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