Antidiabetic Drugs

Archive for the ‘Type 1 diabetes’ Category

Immunobiology researchers from Yale University have identified an antigen that triggers development of Type I diabetes. Though Type 1 diabetes is classified as an autoimmune disease, the agent that stimulates the immune system to attack the pancreas hasn’t been identified until now.

Researchers used NOD (non-obese diabetic) mice for their studies, because mice have a version of Type I diabetes that’s extremely similar to the human version of this disease. For both mice and humans, the major contributing factor for the disease is genetic and involves a defect in an area called the major histocompatibility complex (MHC).

Through an unknown mechanism, the beta cells of the pancreas, which are responsible for making insulin, are attacked by the body as if they are foreign tissue. Defensive cells of the immune system, called CD8 T lymphocytes react to an antigen on the beta cells. The reaction takes the form of an attack, eventually destroying the beta cells, and thereby eliminating the body’s ability to make insulin.

Type I diabetes accounts for approximately 10 percent of all cases of diabetes and usually begins in childhood. Type II diabetes, which is much more common, is not an autoimmune disease but a dysfunction in the metabolism of glucose (sugar). Those with Type I need to take replacement insulin, whereas those with Type II diabetes may or may not need insulin.

While the cells that carry out the destruction had been identified previously, the antigen that sets off the reaction had not. Previous researchers proposed that the offending agent is insulin itself or one of its chemical precursors.

Now that the antigen has been identified, researchers hope to investigate the possibility of using it to desensitize the body, similar to the way allergy shots work. If this can be achieved, it may become possible to prevent Type I diabetes.

Insulin-dependent diabetes mellitus (IDDM) is a chronic debilitating disease that afflicts more than 1 million Americans. It is caused by the autoimmune destruction of the pancreatic insulin-producing apparatus, and can be detected months or even years before the onset of symptoms by the presence of autoantibodies directed against the pancreatic beta cell, the islet cell, insulin itself, or against glutamic acid decarboxylase or the insulinoma-associated islet tyrosine phosphatases. How the autoimmune attack is triggered is not known, although toxins, viruses (congenital rubella, mumps, coxsackievirus, cytomegalovirus) and foods (sugar, coffee, soy, wheat, and cow’s milk) have all been implicated.

According to Desmond Schatz and Noel Maclaren (University of Florida College of Medicine, Gainesville), the cow’s milk hypothesis has been one of the most persistent. It is based on the assumption that the early introduction of cow’s milk formula to the infant’s diet – prior to gut maturation – would result in sufficient absorption of intact protein to “immunize” the infant and direct an autoimmune attack against the islets. This hypothesis has been given so much publicity that it has changed infant feeding practices, with the result that increasing numbers of infants are becoming malnourished. Cow’s milk is a valuable source of nutrients for infants and children all over the world, said Schatz and Maclaren, so replacing milk with alternative diets is not a practice that should be recommended without good scientific evidence that cow’s milk increases the subsequent risk of insulin-dependent diabetes mellitus. And so far, the evidence has been less than adequate. Indeed, the best study to date indicates that cow’s milk does not increase the risk of insulin-dependent diabetes mellitus (IDDM). Norris et al studied 253 children (aged 9 months to 7 years) from 171 families of insulin-dependent diabetes mellitus patients involved in the Diabetes Autoimmunity Study in the Young (DAISY). They found that early exposure to cow’s milk or other dietary proteins was not associated with the development of pancreatic beta-cell autoantibodies, which predict the development of diabetes.

Since a prolonged period of subclinical beta-cell autoimmunity (BCA) precedes the onset of insulin-dependent diabetes mellitus (IDDM), Norris et al screened the children for BCA markers before any of them had developed diabetes symptoms. BCA was defined as elevated levels (at the 99th percentile of normal controls) of insulin autoantibody (IAA), glutamic acid decarboxylase autoantibody (GAA), or insulinoma-associated islet tyrosine phosphatase autoantibody (ICA). In previous studies, BCA screening was shown to be a reliable technique for predicting diabetes. For example, in one group of patients the cumulative risk of insulin-dependent diabetes mellitus (IDDM) after 10 years was 84% in patients with IAA compared with 23% in IAA-negative relatives, and the risk was 60% for patients with GAA compared with 15% for GAA-negative relatives.

Norris et al detected BCA in 18 children. For comparison purposes, 153 unrelated autoantibody-negative children were selected from the DAISY cohort as controls. There were no differences between cases and controls regarding exposure to cow’s milk, or foods containing cow’s milk, or other proteins (cereal, fruit, vegetable, or meat) by the ages of 3 months or 6 months. The only difference was that children with BCA were breast-fed for a slightly longer period than controls (median duration 10 versus 8 months). Another interesting finding was a lack of association between the genetic risk of insulin-dependent diabetes mellitus (IDDM) and beta-cell autoimmunity (BCA) and cow’s milk exposure.

According to the investigators, the data show that BCA was not associated with infant dietary exposure to cow’s milk in this cohort. “The results are likely generalizable to any population-based group of offspring and siblings of people with insulin-dependent diabetes mellitus (IDDM). Such groups have been targeted for primary prevention of insulin-dependent diabetes mellitus (IDDM) through elimination of cow’s milk in the initial 6 months of life.” However, “Our observations suggest that the etiological role of infant dietary exposures may be more complex than previously thought, and that avoidance of cow’s milk may not be effective in the prevention of BCA, or possibly insulin-dependent diabetes mellitus.”

Several investigators have suggested that insulin-dependent diabetes mellitus (IDDM) children have a generalized failure to develop tolerance to dietary antigens. A case in point is an infant in a cow’s milk avoidance group who developed beta-cell autoantibodies (IAA, GAA, and ICA) prior to 9 months of age. On exposure to cow’s milk at age 9 months, the infant developed an abnormally strong humoral and cellular immune response against beta- lactoglobulin and casein. and went on to develop insulin-dependent diabetes mellitus at 14 months of age. According to Norris et al, this case suggests that the failure to develop tolerance to dietary antigens is unrelated the infant’s age at exposure to these antigens. In animal studies conducted by Schatz and Maclaren, feeding increased quantities of bovine serum albumin or skim milk powder had little or no effect on the incidence of diabetes in mice, although feeding the animals soy or wheat had some effect.

Currently two major long-term studies of relatives of patients with insulin-dependent diabetes mellitus (IDDM) are underway in Europe and North America. Infants at risk of developing IDDM will be randomized to receive either breast milk or formula with or without cow’s milk, and follow-up will be long enough to ascertain the role of cow’s milk in IDDM. “If these studies prove conclusive, only then can we pronounce a guilty verdict,” said Schatz and Maclaren. “In the meantime, avoidance of cow’s milk on the basis of increased diabetes risk should not be advised.”