Aspetti immunologici e genetici del diabete autoimmune latente dell’adulto (LADA)

The presence of islet cell autoantibodies (ICA), and especially of glutamic acid decarboxylase autoantibodies (GAD65Ab), in patients with non-insulin-dependent diabetes mellitus identifies the so-called latent autoimmune diabetes in the adult (LADA). LADA patients have an increased risk for developing insulin deficiency, and in 60-80% of cases the exogenous insulin therapy must be started within 5-6 years. GAD65Ab identify a subgroup of type 2 diabetic (T2DM) patients with low body mass index (BMI) at the time of diagnosis. The presence of GAD65Ab at high titres and directed against COOH-terminal epitopes of the autoantigen, or the presence of both GAD65Ab and ICA, discriminates patients with clinical characteristics very similar to those of a slowly progressive form of type 1 diabetes (T1DM). On the other hand, the presence of low levels GAD65Ab, in the absence of ICA or other immune markers, such as IA-2 antibodies, characterizes a subgroup of patients with clinical characteristics almost indistinguishable from those of typical T2DM patients. The autoimmune origin of LADA is also demonstrated by the increased frequency of thyroid and adrenal autoantibodies, as compared to GAD65Ab-negative T2DM patients, and by the strong genetic association with HLA-DR3-DQ2, -DR4-DQ8 and the polymorphisms of the MHC class I chain-related A (MICA) and CTLA-4 genes. Metabolic studies have shown the coexistence of insulin resistance and insulin secretion defect supporting the hypothesis that LADA may be the result of the interaction of a genetic background predisposing for islet autoimmunity and a genetic background predisposing for T2DM.