Centre for Diabetes and Metabolic Medicine, Blizard Institute, Queen Mary, University of London, London, UK.
Diabetes. 2012 May;61(5):1192-8. doi: 10.2337/db11-0971. Epub 2012 Mar 6.
In type 1 diabetes, diabetes-associated autoantibodies, including islet cell antibodies (ICAs), reflect adaptive immunity, while increased serum N(ε)-carboxymethyl-lysine (CML), an advanced glycation end product, is associated with proinflammation. We assessed whether serum CML and autoantibodies predicted type 1 diabetes and to what extent they were determined by genetic or environmental factors. Of 7,287 unselected schoolchildren screened, 115 were ICA(+) and were tested for baseline CML and diabetes autoantibodies and followed (for median 7 years), whereas a random selection (n = 2,102) had CML tested. CML and diabetes autoantibodies were determined in a classic twin study of twin pairs discordant for type 1 diabetes (32 monozygotic, 32 dizygotic pairs). CML was determined by enzyme-linked immunosorbent assay, autoantibodies were determined by radioimmunoprecipitation, ICA was determined by indirect immunofluorescence, and HLA class II genotyping was determined by sequence-specific oligonucleotides. CML was increased in ICA(+) and prediabetic schoolchildren and in diabetic and nondiabetic twins (all P < 0.001). Elevated levels of CML in ICA(+) children were a persistent, independent predictor of diabetes progression, in addition to autoantibodies and HLA risk. In twins model fitting, familial environment explained 75% of CML variance, and nonshared environment explained all autoantibody variance. Serum CML, a glycotoxin, emerged as an environmentally determined diabetes risk factor, in addition to autoimmunity and HLA genetic risk, and a potential therapeutic target.
在 1 型糖尿病中，包括胰岛细胞抗体 (ICA) 在内的与糖尿病相关的自身抗体反映了适应性免疫，而血清 N(ε)-羧甲基赖氨酸 (CML) 的增加，一种晚期糖基化终产物，与前炎症有关。我们评估了血清 CML 和自身抗体是否可以预测 1 型糖尿病，以及它们在多大程度上受到遗传或环境因素的影响。在筛查的 7287 名未选择的学龄儿童中，有 115 名 ICA(+)，他们接受了基线 CML 和糖尿病自身抗体检测，并进行了随访（中位时间为 7 年），而随机选择（n=2102）则进行了 CML 检测。在经典的双胞胎研究中，对 1 型糖尿病不一致的双胞胎（32 对同卵双胞胎，32 对异卵双胞胎）进行了 CML 和糖尿病自身抗体的测定。CML 通过酶联免疫吸附试验测定，自身抗体通过放射免疫沉淀测定，ICA 通过间接免疫荧光测定，HLA Ⅱ类基因分型通过序列特异性寡核苷酸测定。ICA(+)和糖尿病前期的学龄儿童以及糖尿病和非糖尿病双胞胎的 CML 均升高（均 P<0.001）。ICA(+)儿童中 CML 水平升高是糖尿病进展的另一个独立预测因子，除了自身抗体和 HLA 风险外。在双胞胎模型拟合中，家庭环境解释了 CML 变异的 75%，非共享环境解释了所有自身抗体的变异。血清 CML，一种糖毒素，除了自身免疫和 HLA 遗传风险外，还是一个环境决定的糖尿病危险因素，也是一个潜在的治疗靶点。
