OBJECTIVE To explore if oral insulin could delay onset of stage 3 type 1 diabetes (T1D) among patients with stage 1/2 who carry HLA DR4-DQ8 and/or have elevated levels of IA-2 autoantibodies (IA-2As). RESEARCH AND METHODS Next-generation targeted sequencing technology was used to genotype eight HLA class II genes (DQA1, DQB1, DRB1, DRB3, DRB4, DRB5, DPA1, and DPB1) in 546 participants in the TrialNet oral insulin preventative trial (TN07). Baseline levels of autoantibodies against insulin (IAA), GAD65 (GADA), and IA-2A were determined prior to treatment assignment. Available clinical and demographic covariables from TN07 were used in this post hoc analysis with the Cox regression model to quantify the preventive efficacy of oral insulin. RESULTS Oral insulin reduced the frequency of T1D onset among participants with elevated IA-2A levels (HR 0.62; P = 0.012) but had no preventive effect among those with low IA-2A levels (HR 1.03; P = 0.91). High IA-2A levels were positively associated with the HLA DR4-DQ8 haplotype (OR 1.63; P = 6.37 × 10−6) and negatively associated with the HLA DR7–containing DRB1*07:01-DRB4*01:01-DQA1*02:01-DQB1*02:02 extended haplotype (OR 0.49; P = 0.037). Among DR4-DQ8 carriers, oral insulin delayed the progression toward stage 3 T1D onset (HR 0.59; P = 0.027), especially if participants also had high IA-2A level (HR 0.50; P = 0.028). CONCLUSIONS These results suggest the presence of a T1D endotype characterized by HLA DR4-DQ8 and/or elevated IA-2A levels; for those patients with stage 1/2 disease with such an endotype, oral insulin delays the clinical T1D onset.

中文翻译：

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TrialNet 口服胰岛素预防试验 (TN07) 中 HLA DR4-DQ8 参与者重新审视第 3 期 1 型糖尿病的口服胰岛素延迟


目的 探讨口服胰岛素是否可以延缓携带 HLA DR4-DQ8 和/或 IA-2 自身抗体 (IA-2As) 水平升高的 1/2 期 1/2 期患者的 3 期 1 型糖尿病 (T1D) 发病。研究和方法 在 TrialNet 口服胰岛素预防性试验 (TN07) 中，使用下一代靶向测序技术对 546 名参与者的 8 个 HLA II 类基因（DQA1、DQB1、DRB1、DRB3、DRB4、DRB5、DPA1 和 DPB1）进行了基因分型。在治疗分配之前确定抗胰岛素自身抗体 (IAA)、GAD65 (GADA) 和 IA-2A 的基线水平。 TN07 中可用的临床和人口统计协变量用于此事后分析和 Cox 回归模型，以量化口服胰岛素的预防功效。结果 口服胰岛素可降低 IA-2A 水平升高的参与者发生 T1D 的频率（HR 0.62；P = 0.012），但对 IA-2A 水平低的参与者没有预防作用（HR 1.03；P = 0.91）。高 IA-2A 水平与 HLA DR4-DQ8 单倍型呈正相关（OR 1.63；P = 6.37 × 10−6），与含有 HLA DR7 的 DRB1*07:01-DRB4*01:01-DQA1* 呈负相关02:01-DQB1*02:02 扩展单倍型（OR 0.49；P = 0.037）。在 DR4-DQ8 携带者中，口服胰岛素延缓了 3 期 T1D 发病的进展（HR 0.59；P = 0.027），特别是如果参与者的 IA-2A 水平也很高（HR 0.50；P = 0.028）。结论 这些结果表明存在以 HLA DR4-DQ8 和/或 IA-2A 水平升高为特征的 T1D 内型；对于具有这种内型的 1/2 期疾病患者，口服胰岛素可延迟临床 T1D 发病。