Type Diabetes Mellitus

Type 1 diabetes mellitus (DM) is a disease of multifactorial autoimmune causation. Worldwide, there is a marked geographic variation in prevalence. The overall lifetime risk in Caucasian subjects is approximately 0-4%. Type 1 DM is caused by an interaction between environmental factors and an inherited genetic predisposition. In twin studies, a significant genetic contribution is suggested by a concordance value for type 1 DM of 30-50%. The risk to a first-degree relative is approximately 5%. The high discordance rate supports the notion that type 1 DM is multifactorial in etiology. Environmental triggers may account for up to two-thirds of the disease susceptibility.

About 20 different regions of the human genome have been found to have some degree of linkage with type 1 DM. To date, the strongest linkage has been with genes encoded in the human leukocyte antigen (HLA) region located within the major histocompatibility complex (MHC), the contribution of which to disease risk is now designated IDDM1. This appears to be the most powerful determinant of genetic susceptibility to the disease, accounting for approximately 40% of familial inheritance. More than 90% of patients who develop type 1 DM have either DR3, DQ2 or DR4, DQy haplotypes, whereas fewer than 40% of normal controls have these haplotypes. DR3-DR4 heterozygosity is highest in children who develop diabetes before the age of 5 years (50%) and lowest in adults presenting with type 1 diabetes (20-30%) compared with an overall US population prevalence of 2.4%. Specific polymorphisms of the DQB1 gene encoding the p-chain of class II DQ molecules predispose to diabetes in Caucasians but not in Japanese. In contrast, the HLS-DQ6 molecule protects against the disease. HLA antigens (classes I and II) are cell-surface glycoproteins that play a crucial role in presenting autoantigen peptide fragments to T lymphocytes and thus initiating an immune response. Polymorphisms in the genes encoding specific peptide chains of the HLA molecules may therefore modulate the ability of p-cell-derived antigens to trigger an autoimmune response against the p-cell.

Only one non-HLA gene has been identified with certainty and that is the insulin gene (INS) region on chromosome 11p5.5, now designated IDDM2. Population studies of Caucasian type 1 diabetic subjects and non-diabetic controls initially showed a positive association between alleles within the INS region and disease susceptibility. However, recent genome screens have provided conflicting data regarding the role of the INS gene region (IDDM2). It is thought that INS and HLA act independently in the causation of type 1 diabetes and that the INS gene region (IDDM2) accounts for 10% of familial clustering.

The most likely environmental factor implicated in the causation of type 1 DM is viral infection. Numerous viruses attack the pancreatic p-cell either directly through a cytolytic effect or by triggering an autoimmune attack against the p-cell. Evidence for a viral factor in etiology has come from animal models and, in humans, from observation of seasonal and geographic variations in the onset of the disease. In addition, patients newly presenting with type 1 DM may exhibit serologic evidence of viral infection. Viruses that have been linked to human type 1 DM include mumps, Coxsackie B, retroviruses, rubella, cytomegalovirus and Epstein-Barr virus. Bovine serum albumin, a major constituent of cow's milk, has been implicated as a cause of type 1 DM in children exposed at an early age, but definitive proof is lacking and this remains controversial. Nitrosamines (found in smoked and cured meats) may be diabetogenic as may chemicals known to be toxic to pancreatic p-cells, including alloxan, streptozotocin and the rat poison Vacor. Recent reports suggesting that early ingestion of cereal or gluten increases the risk of type 1 diabetes remain to be confirmed.

Type 1 DM is associated with autoimmune destruction of the p-cells of the endocrine pancreas. Examination of islet tissue obtained from pancreatic biopsy or at postmortem from patients with recent-onset type 1 DM confirms a mononuclear cell infiltrate (termed insulitis) with the presence of CD4 and CD8 T lymphocytes, B lymphocytes and macrophages suggesting that these cells have a role in the destruction of p-cells. Although the precise mechanism of such an insult has not been elucidated it seems likely that an environmental factor, such as a viral infection, in a subject with an inherited predisposition to the disease, triggers the damaging immune response. This results in aberrant expression of class II MHC antigen by pancreatic p-cells. T lymphocytes recognize antigen-presenting cells and are activated, producing cytokines such as interleukin (IL)-2, interferon (IFN)y and tumor necrosis factor (TNF)-a. This generates a clone of T lymphocytes that carry receptors specific to the presented antigen. Such T-helper cells assist B lymphocytes to produce antibodies directed against the p-cell. Such antibodies include islet cell antibodies (ICA) directed against cytoplasmic components of the islet cells. ICA presence may precede the development of type 1 DM. Some subjects may develop ICA temporarily and not go on to develop the disease, but persistence of ICA leads to progressive p-cell destruction associated with the chronic inflammatory cell infiltrate termed 'insulitis'. Type 1 DM ensues. Other antibodies associated with type 1 DM are islet cell-surface antibodies (present in 30-60% of newly diagnosed type 1 DM patients), insulin autoantibodies (IAA) and antibodies to an isoform of glutamic acid decarboxylase (GAD).

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