University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
The Biostatistics Center, George Washington University, Rockville, MD 20852, USA.
J Clin Endocrinol Metab. 2024 Nov 18;109(12):3027-3035. doi: 10.1210/clinem/dgae376.
In the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, an intervention trial followed by an observational phase, half the participants reached the primary outcome [hemoglobin A1c (HbA1c) ≥ 8% for at least 6 months] within 4 years, which was associated with a decrease in C-peptide oral disposition index (oDI). We aimed to identify circulating microRNA (miRNA) species associated with a decline in beta cell function.
Following a preliminary survey of select participants using nCounter Human v3 miRNA Panel (NanoString Technologies), polymerase chain reaction analyses were carried out for 17 miRNAs from 365 participants from samples at baseline, 24, 60, 96, and 120 months.
Using a backward selection approach, 4 baseline miRNA log2 fold-changes independently predicted treatment failure; however, baseline HbA1c was higher in those with treatment failure. Three baseline miRNA log2 fold-changes remained significant predictors of this C-peptide oDI decline ≥20% (P < .05). Increased levels of miRNA-155 [odds ratio (OR): 1.2, 95% confidence interval (CI): 1.1-1.4] and miRNA-130b (OR:1.3, 95% CI: 1.0-1.7) were associated with oDI decline, while decreased levels of miRNA-126 (OR: 0.6, 95% CI: .4-.8) were associated with oDI decline. miRNA-122 was negatively correlated with C-peptide oDI at baseline and 24 months (R = 0.22, P < .01 and R = 0.19, P < .01, respectively) and positively correlated with proinsulin at baseline, 24, and 60 months (R = 0.26, P < 0.01, R = 0.26, P < .01, R = 0.18, P < .01, respectively).
The miRNA species associated with beta cell function are associated with alterations in cellular metabolism and apoptosis, suggesting that differences in baseline abundance may serve as circulating markers of beta cell dysfunction and provide potential mechanistic insights into the aggressive nature of youth-onset type 2 diabetes.
在青少年和青年 2 型糖尿病治疗选择（TODAY）研究中，一项干预试验后接着进行观察阶段，一半参与者在 4 年内达到主要结局[血红蛋白 A1c（HbA1c）≥8%至少持续 6 个月]，这与 C 肽口服处置指数（oDI）下降有关。我们旨在确定与胰岛β细胞功能下降相关的循环 microRNA（miRNA）种类。
在使用 nCounter Human v3 miRNA 面板（NanoString Technologies）对部分参与者进行初步调查后，对来自基线、24、60、96 和 120 个月样本的 365 名参与者进行聚合酶链反应分析了 17 种 miRNA。
使用向后选择方法，4 个基线 miRNA 的对数倍变化独立预测了治疗失败；然而，治疗失败的患者基线 HbA1c 更高。3 个基线 miRNA 的对数倍变化仍然是 C 肽 oDI 下降≥20%的显著预测因子（P<.05）。miRNA-155[比值比（OR）：1.2，95%置信区间（CI）：1.1-1.4]和 miRNA-130b（OR：1.3，95%CI：1.0-1.7）水平升高与 oDI 下降相关，而 miRNA-126（OR：0.6，95%CI：.4-.8）水平降低与 oDI 下降相关。miRNA-122 与基线和 24 个月时的 C 肽 oDI 呈负相关（R = 0.22，P<.01 和 R = 0.19，P<.01），与基线、24 个月和 60 个月时的前胰岛素呈正相关（R = 0.26，P<.01，R = 0.26，P<.01，R = 0.18，P<.01）。
与胰岛β细胞功能相关的 miRNA 种类与细胞代谢和细胞凋亡的改变有关，这表明基线丰度的差异可能作为胰岛β细胞功能障碍的循环标志物，并为青少年起病的 2 型糖尿病的侵袭性本质提供潜在的机制见解。
