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Randomized Controlled Trial
. 2024 Sep 1;47(9):1597-1607.
doi: 10.2337/dc23-2441.

Circulating Metabolite Biomarkers of Glycemic Control in Youth-Onset Type 2 Diabetes

Zsu-Zsu Chen  1 , Chang Lu  2   3 , Jonathan M Dreyfuss  2 , Gaurav Tiwari  1 , Xu Shi  1 , Shuning Zheng  1 , Danielle Wolfs  2 , Laura Pyle  4 , Petter Bjornstad  4 , Laure El Ghormli  5 , Robert E Gerszten  1 , Elvira Isganaitis  2
Affiliations
Randomized Controlled Trial

Circulating Metabolite Biomarkers of Glycemic Control in Youth-Onset Type 2 Diabetes

Zsu-Zsu Chen et al. Diabetes Care. .

Abstract

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.

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Conflict of interest statement

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

Figures

None
Graphical abstract
Figure 1
Figure 1
A and B: Baseline circulating compound associations with future glycemic failure risk in the TODAY study after 36 months of follow-up. Volcano plots showing HR of glycemic failure during 36 months of follow-up in the TODAY study for every 1 SD increase in the relative concentration of the compound. Cox proportional hazards models were used, adjusted for age, sex, race/ethnicity, and treatment group as categorical variables and BMI as a continuous variable in A and additionally adjusted for HbA1c in B. Gray horizontal line designated q < 0.05 level of significance. BHB, β-hydroxybutyrate; CAR, carnitine; PC, phosphatidylcholine; Phe, phenylalanine; Lac, lactate; Val, valine.
Figure 2
Figure 2
A and B: Association of glycemic failure risk metabolites with measures of glycemia, insulin, and β-cell function. C-index, C-peptide index; CPEP, fasting C-peptide; INS, fasting insulin.
Figure 3
Figure 3
A–D: ROC curves for clinical and metabolomic prediction models of treatment failure.
See this image and copyright information in PMC

References

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