Aims/hypothesis

We aimed to analyse TrialNet Anti-CD3 Prevention (TN10) data using oral minimal model (OMM)-derived indices to characterise the natural history of stage 2 type 1 diabetes in placebo-treated individuals, to describe early metabolic responses to teplizumab and to explore the predictive capacity of OMM measures for disease-free survival rate.

Methods

OMM-estimated insulin secretion, sensitivity and clearance and the disposition index were evaluated at baseline and at 3, 6 and 12 months post randomisation in placebo- and teplizumab-treated groups, and, within each group, in slow- and rapid-progressors (time to stage 3 disease >2 or \(\le\) 2 years). OMM metrics were also compared with the standard AUC C-peptide. Percentage changes in CD8⁺ T memory cell and programmed death-1 (PD-1) expression were evaluated in each group.

Results

Baseline metabolic characteristics were similar between 28 placebo- and 39 teplizumab-treated participants. Over 12 months, insulin secretion declined in placebo-treated and rose in teplizumab-treated participants. Within groups, placebo slow-progressors (n=14) maintained insulin secretion and sensitivity, while both declined in placebo rapid-progressors (n=14). Teplizumab slow-progressors (n=28) maintained elevated insulin secretion, while teplizumab rapid-progressors (n=11) experienced mild metabolic decline. Compared with rapid-progressor groups, insulin clearance significantly decreased between baseline and 3, 6 and 12 months in the slow-progressor groups in both treatment arms. In aggregate, both higher baseline insulin secretion (p=0.027) and reduced 12 month insulin clearance (p=0.045) predicted slower progression. A >25% loss of insulin secretion at 3 months had specificity of 0.95 (95% CI 0.86, 1.00) to identify rapid-progressors and correctly classified the 2 year risk for progression in 92% of participants, with a sensitivity of 0.19 (95% CI 0.08, 0.30). OMM-estimated insulin secretion outperformed AUC C-peptide to differentiate groups by treatment or to predict progression. Metabolic changes were paralleled by relative frequency of change in PD-1⁺ CD8⁺ T effector memory cells.

Conclusions/interpretation

OMM measures characterise the metabolic heterogeneity in stage 2 diabetes, identifying differences between rapid- and slow-progressors, and heterogeneous impacts of immunotherapy, suggesting the need to account for these differences when designing and interpreting clinical trials.

Graphical Abstract

中文翻译：

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2 期 1 型糖尿病中 β 细胞功能和胰岛素清除率的轨迹：自然病程和对 teplizumab 的反应

 目标/假设

我们旨在使用口服最小模型 （OMM） 衍生的指数分析 TrialNet 抗 CD3 预防 （TN10） 数据，以描述安慰剂治疗个体 2 期 1 型糖尿病的自然病程，描述对 teplizumab 的早期代谢反应，并探索 OMM 措施对无病生存率的预测能力。

 方法

在基线和随机分组后 3 、 6 和 12 个月评估安慰剂和 teplizumab 治疗组以及每组内缓慢和快速进展者（达到 3 期疾病 >2 或 \（\le\） 2 年的时间）的胰岛素分泌、敏感性和清除率以及处置指数。还将 OMM 指标与标准 AUC C 肽进行了比较。评估每组 CD8⁺ T 记忆细胞和程序性死亡-1 （PD-1） 表达的百分比变化。

 结果

28 名接受安慰剂治疗的参与者和 39 名接受 teplizumab 治疗的参与者之间的基线代谢特征相似。在 12 个月内，安慰剂治疗参与者的胰岛素分泌下降，而 teplizumab 治疗参与者的胰岛素分泌增加。在各组中，安慰剂缓慢进展者 （n=14） 维持胰岛素分泌和敏感性，而安慰剂快速进展者 （n=14） 均下降。Teplizumab 进展缓慢者 （n=28） 维持较高的胰岛素分泌，而 teplizumab 快速进展者 （n=11） 出现轻度代谢下降。与快速进展组相比，两个治疗组的缓慢进展组在基线和 3 、 6 和 12 个月之间胰岛素清除率显著降低。总的来说，较高的基线胰岛素分泌 （p=0.027） 和 12 个月胰岛素清除率降低 （p=0.045） 都预示着较慢的进展。A 3 个月时胰岛素分泌损失的 >25% 特异性为 0.95 （95% CI 0.86， 1.00），用于识别快速进展者，并正确分类了 92% 参与者的 2 年进展风险，敏感性为 0.19 （95% CI 0.08， 0.30）。OMM 估计的胰岛素分泌优于 AUC C 肽，以按治疗区分各组或预测进展。代谢变化与 PD-1 ⁺ CD8 ⁺ T 效应记忆细胞的相对变化频率平行。

结论/解释

OMM 测量表征了 2 期糖尿病的代谢异质性，确定了快速进展和缓慢进展之间的差异，以及免疫治疗的异质性影响，这表明在设计和解释临床试验时需要考虑这些差异。

 图形摘要