Type 1 Diabetes Mellitus and Possible Causes of It

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 Glucofort 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)

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