OBJECTIVE We aimed to identify metabolites associated with loss of glycemic control in youth-onset type 2 diabetes. RESEARCH DESIGN AND METHODS We measured 480 metabolites in fasting plasma samples from the TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) study. Participants (N = 393; age 10–17 years) were randomly assigned to metformin, metformin plus rosiglitazone, or metformin plus lifestyle intervention. Additional metabolomic measurements after 36 months were obtained in 304 participants. Cox models were used to assess baseline metabolites, interaction of metabolites and treatment group, and change in metabolites (0–36 months), with loss of glycemic control adjusted for age, sex, race, treatment group, and BMI. Metabolite prediction models of glycemic failure were generated using elastic net regression and compared with clinical risk factors. RESULTS Loss of glycemic control (HbA1c ≥8% or insulin therapy) occurred in 179 of 393 participants (mean 12.4 months). Baseline levels of 33 metabolites were associated with loss of glycemic control (q < 0.05). Associations of hexose and xanthurenic acid with treatment failure differed by treatment randomization; youths with higher baseline levels of these two compounds had a lower risk of treatment failure with metformin alone. For three metabolites, changes from 0 to 36 months were associated with loss of glycemic control (q < 0.05). Changes in d-gluconic acid and 1,5-AG/1-deoxyglucose, but not baseline levels of measured metabolites, predicted treatment failure better than changes in HbA1c or measures of β-cell function. CONCLUSIONS Metabolomics provides insight into circulating small molecules associated with loss of glycemic control and may highlight metabolic pathways contributing to treatment failure in youth-onset diabetes.

中文翻译：

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青年发病 2 型糖尿病患者血糖控制的循环代谢生物标志物


目的 我们的目的是确定与青年发病的 2 型糖尿病血糖失控相关的代谢物。研究设计和方法 我们测量了 TODAY（青少年 2 型糖尿病的治疗选择）研究中的空腹血浆样本中的 480 种代谢物。参与者（N = 393；年龄 10-17 岁）被随机分配到二甲双胍、二甲双胍加罗格列酮或二甲双胍加生活方式干预组。 36 个月后，对 304 名参与者进行了额外的代谢组学测量。 Cox模型用于评估基线代谢物、代谢物与治疗组的相互作用以及代谢物的变化（0-36个月），并根据年龄、性别、种族、治疗组和BMI调整血糖控制的丧失。使用弹性网络回归生成血糖衰竭的代谢预测模型，并与临床危险因素进行比较。结果 393 名参与者中有 179 名出现血糖失控（HbA1c ≥8% 或胰岛素治疗）（平均 12.4 个月）。 33 种代谢物的基线水平与血糖控制丧失相关（q < 0.05）。己糖和黄嘌呤酸与治疗失败的关联因治疗随机化而异；这两种化合物基线水平较高的青少年单独使用二甲双胍治疗失败的风险较低。对于三种代谢物，0 至 36 个月的变化与血糖控制丧失相关 (q < 0.05)。 d-葡萄糖酸和 1,5-AG/1-脱氧葡萄糖的变化（而非测量代谢物的基线水平）比 HbA1c 或 β 细胞功能的变化更能预测治疗失败。 结论 代谢组学可以深入了解与血糖失控相关的循环小分子，并可能突出导致青年糖尿病治疗失败的代谢途径。