**2. Type 1 diabetes mellitus**

### **2.1 Background**

Type 1 diabetes mellitus is the most common endocrinopathy to have clinical onset in childhood or adolescence, with varied pathogenesis, clinical appearance and outcome, and seriously affects patients' and families' life. A combination of genetic, environmental and immunological factors exerts to a T-cell mediated autoimmune process targeted against insulin-producing -cells in the pancreatic islet of Langerhans (Daneman, 2006).

Autoimmune Disorders Associated to Type 1 Diabetes Mellitus in Children and Adolescents 5

In 1990 Baekkeskov and co-workers reported that the 64,000 M (R) molecule previously defined as an antigenic target of Type 1 diabetes was the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD) (Baekkeskow et al., 1990). GAD is not expressed exclusively on -cells, but also in other islet cells. Anti-GAD autoantibodies (GADA) can be detected both by RIA or by ELISA. The prevalence of anti-GAD autoantibodies positivity is 84%, and is positively related to age and female sex. Their peak level can be reached after diabetes diagnosis and persist longer than anti-islet cell antibodies, making them a useful

In 1994 a cDNA coding a 548 aminoacid protein named ICA-512 was described as a major target of humoral immunity by screening an islet c-DNA expression library with patients' sera (Rabin et al., 1994). Moreover it has been reported that IA-2, a 979 aminoacid transmembrane protein of the tyrosine phosphatase family, is a major autoantigen in type 1 diabetes. IA-2 is a intrinsic membrane protein of secretory granules neuroendocrine cells, like pancreatic islets. IA-2 autoantibodies (IA-2A) can be detected by RIA as well as by ELISA. Recently a not radio-isotopic method (time-resolved immunofluorometric assay (TR-IFMA) showed comparable results with RIA. The prevalence of IA-2A has been reported

Recently the cation efflux transporter 8 (ZnT8) has been identified as a novel target autoantigen in patients with type 1 diabetes. Autoantibodies to ZnT8 (ZnT8 A) are detectable in about 70% of newly diagnosed patients, independent of age (Achenbach et al., 2009). Patients presenting with a single islet cell autoantibody were also positive for ZnT8 A, suggesting that they could be a marker for type 1 diabetes risk stratification. Three variants of ZnT8 A have been recognized: 1) ZnT8RA (arginine 325 zinc transporter 8 autoantibody), 2) ZnT8WA (tryptophan 325 zinc transporter 8 autoantibody), 3) ZnT8QA (glutamine 325 zinc transporter 8 autoantibody). These 3 ZnT8 variants precede T1DM clinical onset and

Diagnosis of type 1 diabetes is based on symptoms of hyperglycemia: polyuria, polydipsia, with mild symptoms up to severe ketoacidosis. After intravenous fluid, insulin and salt replacement for metabolic imbalance recovery, treatment of type 1 diabetes consists of lifelong substitutive subcutaneous insulin therapy, together with correct dietary habits, selfmanagement of the disease and regular physical activity, as result of a prolonged educational intervention starting at the time of clinical diagnosis (Maffeis & Pinelli, 2008, Bangstad et al., 2007). Recognition, management and prevention of hypoglycemic episodes as well as hyperglycemic spikes is mandatory. Continuous education implementation starting at the time of clinical diagnosis, designed for children, adolescents and their

The most serious problem related to pediatric type 1 diabetes is the risk, even in young adulthood, of microvascular and macrovascular complications, i.e. retinopathy, nephropathy, neuropathy, cardiovascular and cerebrovascular diseases (Donaghue et al., 2007). The key role of good glycaemic control to prevent diabetes-related complications has been firmly established by the Diabetes Control and Complications Trial Study, which demonstrated the protective role of intensive insulin treatment (DCCT, 1993). Sustained

about 73%, and no correlation with age was found (Tsirogianni et al., 2009).

are all detectable by radio-binding assay (Andersson et al., 2011).

parents, is necessary thereafter (Weinzimer et al., 2005).

marker especially for adult patients.

**2.4 Diagnosis and treatment** 

**2.5 Follow-up** 
