β Cell death and dysfunction during type 1 diabetes development in at-risk individuals
β Cell death and dysfunction during type 1 diabetes development in at-risk individuals
复制标题
DOI：
10.1172/jci78142
复制
发表时间：
2015-03-01
影响因子：
15.9
通讯作者：
Palmer, Jerry P.
中科院分区：
文献类型：
--
作者：
Herold, Kevan C.;Usmani-Brown, Sahar;Palmer, Jerry P.
资金来源的作用：来自NIH的资金用于支持参与的临床中心和协调中心。资助来源未参与数据的收集和分析。作为1型糖尿病（T1D）特征的β细胞杀伤被认为在患者临床表现为代谢失代偿前几年就开始了；然而，这种疾病的主要病理过程尚未被测量。在这里，我们用一种检测β细胞来源的未甲基化胰岛素（INS） DNA的方法来测量β细胞死亡。使用这种方法，我们进行了一项观察性研究，包括来自TrialNet途径预防研究中有T1D发生风险的2个队列的50名参与者和4名接受胰岛自体移植的受试者。在高危受试者中，进展为T1D的患者INS未甲基化DNA的平均水平与健康对照组相比略有升高。在进展为T1D的高危个体中，观察到的非甲基化INS DNA的增加与胰岛素分泌的减少有关，这表明非甲基化INS DNA的变化表明β细胞被杀死。T1D高风险受试者的INS DNA未甲基化水平高于健康对照组，也高于高危进展组和高危非进展组的INS DNA未甲基化水平，随访4年。胰岛素分泌动力学的评估也能区分出发展为显性疾病的高危受试者和未发展为显性疾病的高危受试者。我们的结论是，测量未甲基化的INS DNA的血液测试可以作为t1d相关自身免疫导致的活跃β细胞杀伤的标记。综上所述，这些数据支持了β细胞死亡在T1D诊断前的几年中零星发生，并且在围诊断期更为强烈的概念。
Role of the funding source: Funding from the NIH was used for support of the participating clinical centers and the coordinating center. The funding source did not participate in the collection or the analysis of the data.BACKGROUND. The beta cell killing that characterizes type 1 diabetes (T1D) is thought to begin years before patients present clinically with metabolic decompensation; however, this primary pathologic process of the disease has not been measured.METHODS. Here, we measured beta cell death with an assay that detects beta cell-derived unmethylated insulin (INS) DNA. Using this assay, we performed an observational study of 50 participants from 2 cohorts at risk for developing T1D from the TrialNet Pathway to Prevention study and of 4 subjects who received islet autotransplants.RESULTS. In at-risk subjects, those who progressed to T1D had average levels of unmethylated INS DNA that were elevated modestly compared with those of healthy control subjects. In at-risk individuals that progressed to T1D, the observed increases in unmethylated INS DNA were associated with decreases in insulin secretion, indicating that the changes in unmethylated INS DNA are indicative of beta cell killing. Subjects at high risk for T1D had levels of unmethylated INS DNA that were higher than those of healthy controls and higher than the levels of unmethylated INS DNA in the at-risk progressor and at-risk nonprogressor groups followed for 4 years. Evaluation of insulin secretory kinetics also distinguished high-risk subjects who progressed to overt disease from those who did not.CONCLUSION. We conclude that a blood test that measures unmethylated INS DNA serves as a marker of active beta cell killing as the result of T1D-associated autoimmunity. Together, the data support the concept that beta cell killing occurs sporadically during the years prior to diagnosis of T1D and is more intense in the peridiagnosis period.