Insulin Dependent Diabetes Mellitus

Diabetes Mellitus is a group of diseases in which the body fails to maintain normal glucose levels either because the body does not produce enough insulin (type 1) or because the cells of the body do not respond to the insulin that is produced (type 2). Type 1 diabetes is also known as Insulin Dependent Diabetes Mellitus (IDDM) as it requires patients to inject insulin.

IDDM is characterised by progressive infiltration of immune cells into the Islets of the pancreas and autoantibody production leading to autoimmune destruction of the insulin producing pancreatic Islet cells. Primary damage in IDDM is caused by a cellular immune response in which CD4+ Th1 helper T cells activate in situ CD8+ cytotoxic T cells directed against the beta cells. Clinical symptoms of diabetes occur when over 90% of an individual’s beta cells are destroyed. Autoantibody production pre dates the development of clinical symptoms. Antibodies are developed against most components of beta cells, including Insulin, Glutamic Acid Decarboxylase (GAD) and Islet-cell Antigen2 (IA-2).

IDDM is a polygenic disease where the concordance rate in twins is 30 – 50%. An as yet unknown trigger is required for genetically susceptible individuals to develop the condition. Environmental factors such as diet and viral infection have been shown to be associated with an increased incidence of IDDM. The HLA system contributes approximately 50% of the heritable risk of IDDM and is the most important susceptibility genetic region and has been named IDDM1. The next most important genetic region is the Insulin gene region on chromosome 11, which is thought to contribute approximately 10% of the heritable risk. This region has been named IDDM2. An additional 15 genes located on different chromosomes, with variable but small effects have been described and named IDDM3 – IDDM17.

More than 90% of Caucasian patients with IDDM carry the haplotypes DRB1*03:01, DQA1*05:01, DQB1*02:01 (DR17, DQ2) or DRB1*04:01, DQA1*03:01, DQB1*03:02 (DR4, DQ8), particularly where the age of onset is less than 15. Patients heterozygous for these haplotypes carry a greater susceptibility risk. The critical residues are thought to be DQ alpha Arg-52, DQ beta Asp-57 and DQ beta Arg-74. Absence of DQ beta Asp-57 and DQ beta Arg-74 is strongly associated with IDDM. Resistance to IDDM is conferred by some DQ6 alleles. DQA1*01:02, DQB1*06:02 confers protection in Caucasian populations.

Genetic testing is useful as an aid to diagnosis of IDDM. In addition, as IDDM is characterised by a variable length silent period before overt disease, genetic testing for disease susceptibility genes in siblings of IDDM patients may be a useful measure.

Do you or someone you know suffer from Diabetes or are you a researcher working in this area? Please join the conversation. Leave a comment. Thanks.


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