**3. Epidemiology**

In 2010, about 215,000 people younger than 20 years of age had diabetes (type 1 or type 2) in the United States. A 2011 Centers for Disease Control and Prevention (CDC) report estimates that nearly 26 million Americans have diabetes. Diabetes affects 8.3% of

Role of Vitamin D in the Pathogenesis and Therapy of Type 1 Diabetes Mellitus 405

of these 2 types, DR4-DQ8/DR3-DQ2, carries the highest risk and type 1 diabetes mellitus occurs at a very early age in this population. First-degree relatives of the patients who carry the highest risk haplotype combination also have a higher risk of developing diabetes mellitus as compared to the relatives of diabetes patients who do not have this haplotype and who

Another HLA haplotype (DR15-DQ6) might have protective properties, and is found in a much larger percentage in the general population (20%) as compared to less than 1% in

HLA haplotypes appear to have an association with islet autoantibodies. Glutamic acid decarboxylase (GAD) antibodies are more frequent in patients with HLA DR3-DQ2, whereas insulin auto-antibodies (IAA) and protein tyrosine phosphatase-like protein antibodies (IA-2 antibodies) are more frequent in patients with HLA DR4-DQ8. Patients that do not have these

Another key genetic factor is the insulin gene (INS), with different forms of the promoter region conferring either protection or increased susceptibility to autoimmune diabetes mellitus (Bennett et al., 1995). The insulin gene contributes 10% to the genetic susceptibility in developing autoimmune diabetes (Bell et al., 1984). The risk of developing diabetes depends on the expression of the insulin protein in the thymus which can cause a defective central tolerance to the insulin molecule. The degree of immune tolerance may be reflected by the less common presence of insulin autoantibodies (IAA) in patients or relatives who

Fig. 1. Antigen Presenting Cell. The activation of the T-cell by various stimuli (antigens), is brought by major histocompatibility complex (MHC-HLA II). This figure shows also, inhibitors of T-cell activation: cytotoxic T lymphocyte antigen 4 (CTLA-4) and lymphoid

tyrosine phosphatase (LYP).

develop type 1 diabetes mellitus later in life (Gillespie et al., 2002).

patients with type 1 diabetes mellitus (Eisenbarth & Gottlieb, 2004).

haplotypes are less likely to develop islet autoantibodies (Achenbach et al., 2005).

have the protective INS class I/III or III/III genotypes (Vafiadis et al., 1997).

Americans of all ages and 11.3% of adults aged 20 years and older, according to the National Diabetes Fact Sheet for 2011. About 27% of those with diabetes (approximately 7 million Americans) do not know they have the disease. 1 in every 400 children and adolescents has type 1 diabetes.

Type 1 diabetes mellitus continues to be highly prevalent in many countries, with an overall annual increase estimated at 3% (International Diabetes Federation [IDF] 2010). Worldwide, it is more common in males than in females, with a ratio of 1.5.

The 4th edition of the IDF Diabetes Atlas, released in 2009 at the 20th World Diabetes Congress, estimated that in 2010, 285 million people would have diabetes (6.4% of world's adult population). The same forum predicts that by 2030, 438 million people will have diabetes world-wide. Type 1 diabetes in children is estimated at 480,000 patients worldwide in 2010, and the number of newly diagnosed cases per year is 75,800 (IDF 2010).
