**4. Environmental factors**

During the last decades, the incidence of type 1 diabetes has increased significantly, reaching percentages of 3% annually worldwide. This increase suggests that besides genetic factors environmental perturbations (including viral infections) are also involved in the pathogenesis of type 1 diabetes.

with type 1 diabetes develop diabetes [49-50]. These observations are most likely explained by

Update of Type 1 Diabetes http://dx.doi.org/10.5772/55960 81

Islet Cell Autoantibodies (ICAs) were first detected in serum from patients with autoimmune polyendocrine deficiency; they have subsequently been identified in 70 to 80 percent of patients with newly diagnosed type 1 diabetes and in prediabetic subjects (American Diabetic Associa‐ tion 1997). Measurement of serum ICA by staining of frozen sections of human pancreas was the major screening test used to identify subjects at risk for clinical diabetes but currently, large studiesutilizeaseriesofradioassays forautoantibodies reactingwithspecific isletautoantigens. Children with type 1 diabetes who do not have islet-cell or other autoantibodies at presentation have a similar degree of metabolic decompensation as do children who have these antibodies, although those with more of the different types of antibodies appear to have the most accel‐ erated islet destruction and a higher requirement for exogenous insulin during the second year of clinical disease [51]. A few patients without obvious evidence of islet autoimmunity have been described in whom the onset of hyperglycemia was abrupt, glycosylated hemoglobin

values were normal, and serum pancreatic enzyme concentrations were high [52].

detect autoreactive T-lymphocytes are active areas of research.

Autoantibodies to biochemically characterized beta-cell autoantigens: Insulin Autoantibodies (IAA), Auto-antibodies to the tyrosine phosphatases IA-2, Glutamic Acid Decarboxylase Autoantibodies (GADA), and zinc transporter 8 autoantibody (ZnT8A) [53] help to define type 1 diabetes a, if measured prior to or shortly after initiation of insulin therapy. IAA are masked by antibodies induced by exogenous insulin and become very hard to measure after just 10 to 14 days of insulin therapy. ZnT8A tend to disappear quickly after diagnosis of diabetes, while GADA and IA-2A tend to persist longer, but are rarely seen more than 5 years after diagnosis. Testing for at least two of these autoantibodies at diagnosis is now considered standard of care in type 1 diabetes. Good commercial assays exist for IA-2A, GADA, and ZnT8A, with the former two recently harmonized [54]. IAA are low-affinity antibodies and harder to measure; however, high-quality non-radioactive assays for IAA are close to being commercially available [55]. The search for additional islet autoantibodies and assay that would reliably

The management of type 1 diabetes and modalities for prevention of complications has evolved, such that the majority of patients with excellent care and education should avoid major microvascular complications. The finding from the Diabetes Control and Complications Trial (DCCT) follow-up study of "metabolic memory", namely long term benefit from early intensive glucose management is very encouraging [56]. Intensive management and strict guidelines for lipid lowering and early introduction of renoprotective medications are the

environmental factors such as viruses and dietary antigens.

**5. Autoimmunity**

**6. Complications**

There is a number of environmental factors contribute to the marked global variation in the incidence of type 1 diabetes. Evidence suggests that the incidence is lower in the tropics compared with further north or south of the equator.

Assuming that the observation that there is a direct relationship between incidence of type 1 diabetes and equatorial distance, a number of environmental factors appear to be protective against the development of an autoimmune pathological process. Ultra violet radiation results in increased levels of vitamin D, which is an important modulator of the immune system. Detailed studies have shown not only that lower levels of circulating vitamin D predispose to autoimmunity, but that vitamin D supplementation may also reduce the risk of developing type 1 diabetes (vitamin D). Further data are required to establish the clinical utility and costeffectiveness of such interventions, including the demonstration of these positive effects over a longer period of time.

Other dietary considerations may also be important, with avoidance of cow's milk at an early age seemingly providing protection against autoimmunity. Again, it is unclear as to whether or not use of hydrolysed infant formulae instead of cow's milk for weaning will be of significant clinical benefit, as long-term prospective data of this type are lacking. However, the fact that cereal exposure at a young age may also provoke increased autoimmune activity reinforces the notion that antigen ingestion may affect immune system function.

The role for infectious agents in type 1 diabetes remains unclear, as there are variations on the hygiene hypothesis which suggest that certain infections may prove protective whereas others may be pathogenic. Certainly, evidence in animal models convincingly demonstrates an association between viral antigens and autoimmunity and human biopsies have shown viral particles in the pancreas of type 1 diabetes patients. However, there is a lack of data demon‐ strating a causal effect for viral infections. Furthermore, the intriguing prospect that parasitic infections may protect against type 1 diabetes requires further study, so that molecular mechanisms may be elucidated for therapeutic purposes.

Future research needs to be conducted on a large scale, with the inclusion of both randomised and prospective studies in order to establish the link between environmental factors and type 1 diabetes pathogenesis. In particular, long-term follow-up of infants is required to assess the true benefits of interventional trials. In addition, consideration of the interaction of genetics with environmental factors is necessary to complete the picture, as it is likely that both mechanisms are involved in determining geographical variation of disease [18, 48].

Environmental influences are another important factor in the development of type 1 diabetes. This has been illustrated in twin studies; less than 50 percent of monozygotic twins of probands with type 1 diabetes develop diabetes [49-50]. These observations are most likely explained by environmental factors such as viruses and dietary antigens.
