We appreciate the opportunity to respond to the letter from Yaqiong Liu and Tao Li (1) and are pleased that our work (2), in which we analyzed associations of plasma metabolites with glycemic control and β-cell function in youth-onset type 2 diabetes (T2D), garnered their interest. While Liu and Li commended our study for being “comprehensive and well-conducted,” they asked questions about our methodology and interpretation of our findings, which we are happy to clarify.

Liu and Li correctly observe that dietary patterns can influence both the plasma metabolome and glycemic control and, as such, may be viewed as a confounder. Because our samples were collected in the context of the TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) study, a randomized controlled trial that included a lifestyle intervention with diet and exercise, we were able to account, in part, for diet by including the treatment randomization in all our statistical models. It should also be noted that in the TODAY study neither the lifestyle intervention nor prospectively assessed diet and physical activity measures had a strong impact on glycemic control (3,4). The randomized design also allowed us to identify metabolites for which the association with treatment failure differed by treatment randomization, which highlights compounds that may predict response to lifestyle intervention and may be more sensitive to dietary patterns. Finally, as discussed in our limitations section, we report metabolite associations, but further studies will be needed to clarify if the circulating metabolites cause these associations independent of other factors such as diet.

Our analyses also included metabolites measured at both baseline and 3-year time points to examine the associations and predictive utility of changes in metabolite levels (see Supplementary Tables 7–9). We reported that changes in d-gluconic acid and 1,5-anhydroglucitol over 3 years predicted treatment failure better than changes in clinical measures such as HbA1c, C-peptide oral disposition index, or C-peptide index alone. As such, we respectfully disagree with Liu and Li’s comment that our study “does not provide . . . evidence regarding how these biomarkers change over time . . . .” However, we agree with Liu and Li that it would be of great interest to analyze longer-term changes in these markers (beyond 3 years) and potential associations with the accelerated onset of microvascular and macrovascular complications reported in youth-onset T2D (5).

We also agree that including an external validation cohort would have strengthened our analysis. As discussed in our methods section, we internally validated our prediction models using a 60% to 40% split-sample and 10-fold cross-validation design. However, given the unique design of the TODAY study, which included the largest cohort of youth-onset T2D to date and included both a randomized controlled trial phase and up to 15 years of detailed follow-up, including oral glucose tolerance tests and measures of β-cell function, there were no comparable validation cohorts. We hope that the publication of our data will allow other research groups to test the external validity of our findings.

Finally, we agree with Liu and Li that carefully designed follow-up studies will be essential before our findings can be translated to clinical applications.

Funding. This project was supported by U01 DK061230 (E.I.), K23 DK127073 (Z.-Z.C.), T32DK007260 (C.L.), and P30DK036836 (J.M.D. and E.I.).

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

Handling Editors. The journal editor responsible for overseeing the review of the manuscript was Steven E. Kahn.

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