Improving clinical utility of GAD65 autoantibodies by electrochemiluminescence assay and clinical phenotype when identifying autoimmune adult-onset diabetes,Diabetologia

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Improving clinical utility of GAD65 autoantibodies by electrochemiluminescence assay and clinical phenotype when identifying autoimmune adult-onset diabetes
Diabetologia ( IF 8.4 ) Pub Date : 2021-07-16 , DOI: 10.1007/s00125-021-05492-6
Yong Gu _{1,

2} , Xiaofan Jia _{1,

3} , Tanwi Vartak ₄ , Dongmei Miao ₁ , Fran Dong ₁ , Samuel T Jerram ₄ , Marian Rewers ₁ , Assiamira Ferrara ₅ , Jean M Lawrence ₆ , Liping Yu ₁ , R David Leslie ₄ ,

Affiliation

Aims/hypothesis

It is important to differentiate the two major phenotypes of adult-onset diabetes, autoimmune type 1 diabetes and non-autoimmune type 2 diabetes, especially as type 1 diabetes presents in adulthood. Serum GAD65 autoantibodies (GADA) are the most sensitive biomarker for adult-onset autoimmune type 1 diabetes, but the clinical value of GADA by current standard radiobinding assays (RBA) remains questionable. The present study focused on the clinical utility of GADA differentiated by a new electrochemiluminescence (ECL) assay in patients with adult-onset diabetes.

Methods

Two cohorts were analysed including 771 diabetic participants, 30–70 years old, from the Action LADA study (n = 6156), and 2063 diabetic participants, 20–45 years old, from the Diabetes in Young Adults (DiYA) study. Clinical characteristics of participants, including requirement of early insulin treatment, BMI and development of multiple islet autoantibodies, were analysed according to the status of RBA-GADA and ECL-GADA, respectively, and compared between these two assays.

Results

GADA was the most prevalent and predominant autoantibody, >90% in both cohorts. GADA positivity by either RBA or ECL assay significantly discriminated clinical type 1 from type 2 diabetes. However, in both cohorts, participants with ECL-GADA positivity were more likely to require early insulin treatment, have multiple islet autoantibodies, and be less overweight (for all p < 0.0001). However, clinical phenotype, age at diagnosis and BMI independently improved positive predictive value (PPV) for the requirement of insulin treatment, even augmenting ECL-GADA. Participants with GADA detectable by RBA, but not confirmed by ECL, had a phenotype more similar to type 2 diabetes. These RBA-GADA positive individuals had lower affinity GADA compared with participants in which GADA was confirmed by ECL assay.

Conclusions/interpretation

Detection of GADA by ECL assay, given technical advantages over RBA-GADA, identified adult-onset diabetes patients at higher risk of requiring early insulin treatment, as did clinical phenotype, together allowing for more accurate clinical diagnosis and management.

Graphical abstract

中文翻译：

在识别自身免疫性成人发病糖尿病时，通过电化学发光测定和临床表型提高 GAD65 自身抗体的临床效用

目标/假设

区分成人发病糖尿病的两种主要表型很重要，即自身免疫性 1 型糖尿病和非自身免疫性 2 型糖尿病，尤其是当 1 型糖尿病出现在成年期时。血清 GAD65 自身抗体 (GADA) 是成人发病的自身免疫性 1 型糖尿病最敏感的生物标志物，但目前标准放射结合试验 (RBA) 对 GADA 的临床价值仍然值得怀疑。本研究的重点是通过一种新的电化学发光 (ECL) 分析区分 GADA 在成人糖尿病患者中的临床应用。

方法

分析了两个队列，包括来自 Action LADA 研究 ( n = 6156)的 771 名 30-70 岁的糖尿病参与者，以及来自青年糖尿病 (DiYA) 研究的 2063 名 20-45 岁的糖尿病参与者。分别根据 RBA-GADA 和 ECL-GADA 的状态分析参与者的临床特征，包括早期胰岛素治疗的要求、BMI 和多种胰岛自身抗体的发展，并在这两种检测之间进行比较。

结果

GADA 是最普遍和最主要的自身抗体，在两个队列中均 > 90%。RBA 或 ECL 检测的 GADA 阳性显着区分临床 1 型和 2 型糖尿病。然而，在这两个队列中，ECL-GADA 阳性的参与者更有可能需要早期胰岛素治疗，有多种胰岛自身抗体，并且超重较少（所有p < 0.0001）。然而，临床表型、诊断年龄和 BMI 独立地提高了胰岛素治疗需求的阳性预测值 (PPV)，甚至增加了 ECL-GADA。RBA 可检测到 GADA 的参与者，但 ECL 未证实，其表型与 2 型糖尿病更相似。与通过 ECL 测定证实 GADA 的参与者相比，这些 RBA-GADA 阳性个体的 GADA 亲和力较低。