GAD-65 autoantibodies and their role as biomarkers of type 1 diabetes and latent autoimmune diabetes in adults (LADA)

Abstract

One of the hallmarks of autoimmune diabetes is the presence of adaptive responses directed to neuroendocrine proteins. One of these proteins is glutamic acid decarboxylase (GAD). While GAD is widely distributed in neuroendocrine tissues, its specific significance in diabetes has paralleled the advances in understanding humoral and cellular immunity in Type 1 diabetes (T1D) and in a subset of Type 2 diabetes (T2D), going from the seminal discoveries of islet autoantibodies to the development and standardization of bioassays as diagnostic tools, to studies on the structure of GAD and its antigenic determinants. GAD65 autoantibodies can accurately predict T1D development in combination with other surrogate humoral biomarkers and they are considered the most sensitive and specific biomarker which identifies a subset of clinically diagnosed T2D termed Latent Autoimmune Diabetes in Adults (LADA). We and others provided evidence indicating that GAD65 autoantibody detection should be part of the diagnostic assessment for clinically diagnosed T2DM mainly because it predicts the rate of progression to insulin requirement in patients affected by LADA. More recently GAD has been used as a "tolerogenic vaccine" to preserve beta cell function in autoimmune diabetes. While the results of Phase III clinical trials did not substantiate the earlier promise of Phase I and II trials, there are still many unanswered questions and approaches that need to be investigated in the applications of GAD in the therapy of T1D and LADA.