Towns Roberto, Pietropaolo Massimo
Laboratory of Immunogenetics, The Brehm Center for Diabetes Research, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan.
Drugs Future. 2011 Nov;36(11):847. doi: 10.1358/dof.2011.036.11.1710754.
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.
自身免疫性糖尿病的一个标志是存在针对神经内分泌蛋白的适应性反应。其中一种蛋白是谷氨酸脱羧酶（GAD）。虽然GAD广泛分布于神经内分泌组织中，但其在糖尿病中的具体意义与1型糖尿病（T1D）和部分2型糖尿病（T2D）中体液免疫和细胞免疫认识的进展并行，从胰岛自身抗体的开创性发现到作为诊断工具的生物测定法的开发和标准化，再到对GAD结构及其抗原决定簇的研究。GAD65自身抗体与其他替代体液生物标志物联合使用时可准确预测T1D的发生，并且它们被认为是最敏感和特异的生物标志物，可识别一部分临床诊断为成人隐匿性自身免疫性糖尿病（LADA）的T2D。我们和其他人提供的证据表明，GAD65自身抗体检测应成为临床诊断T2DM诊断评估的一部分，主要是因为它可预测LADA患者进展为需要胰岛素治疗的速度。最近，GAD已被用作“耐受性疫苗”以保留自身免疫性糖尿病患者的β细胞功能。虽然III期临床试验的结果并未证实I期和II期试验早期的前景，但在GAD应用于T1D和LADA治疗方面仍有许多未解决的问题和方法需要研究。
