Metabolomics analysis of type 2 diabetes remission identifies 12 metabolites with predictive capacity: a CORDIOPREV clinical trial study

Marina Mora-Ortiz, Juan F Alcala-Diaz, Oriol Alberto Rangel-Zuñiga, Antonio Pablo Arenas-de Larriva, Fernando Abollo-Jimenez, Diego Luque-Cordoba, Feliciano Priego-Capote, Maria M Malagon, Javier Delgado-Lista, Jose M Ordovas, Pablo Perez-Martinez, Antonio Camargo, Jose Lopez-Miranda, Marina Mora-Ortiz, Juan F Alcala-Diaz, Oriol Alberto Rangel-Zuñiga, Antonio Pablo Arenas-de Larriva, Fernando Abollo-Jimenez, Diego Luque-Cordoba, Feliciano Priego-Capote, Maria M Malagon, Javier Delgado-Lista, Jose M Ordovas, Pablo Perez-Martinez, Antonio Camargo, Jose Lopez-Miranda

Abstract

Background: Type 2 diabetes mellitus (T2DM) is one of the most widely spread diseases, affecting around 90% of the patients with diabetes. Metabolomics has proven useful in diabetes research discovering new biomarkers to assist in therapeutical studies and elucidating pathways of interest. However, this technique has not yet been applied to a cohort of patients that have remitted from T2DM.

Methods: All patients with a newly diagnosed T2DM at baseline (n = 190) were included. An untargeted metabolomics approach was employed to identify metabolic differences between individuals who remitted (RE), and those who did not (non-RE) from T2DM, during a 5-year study of dietary intervention. The biostatistical pipeline consisted of an orthogonal projection on the latent structure discriminant analysis (O-PLS DA), a generalized linear model (GLM), a receiver operating characteristic (ROC), a DeLong test, a Cox regression, and pathway analyses.

Results: The model identified a significant increase in 12 metabolites in the non-RE group compared to the RE group. Cox proportional hazard models, calculated using these 12 metabolites, showed that patients in the high-score tercile had significantly (p-value < 0.001) higher remission probabilities (Hazard Ratio, HR, high versus low = 2.70) than those in the lowest tercile. The predictive power of these metabolites was further studied using GLMs and ROCs. The area under the curve (AUC) of the clinical variables alone is 0.61, but this increases up to 0.72 if the 12 metabolites are considered. A DeLong test shows that this difference is statistically significant (p-value = 0.01).

Conclusions: Our study identified 12 endogenous metabolites with the potential to predict T2DM remission following a dietary intervention. These metabolites, combined with clinical variables, can be used to provide, in clinical practice, a more precise therapy.

Trial registration: ClinicalTrials.gov, NCT00924937.

Keywords: Diabetes; Insulin resistance; Metabolomics; Prospective human study.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
CORDIOPREV study design
Fig. 2
Fig. 2
O-PLS DA analysis loading and score plot calculated using all spectra as a matrix of independent variables and diabetic remission as the predictor
Fig. 3
Fig. 3
Adjusted Cox for the analysis of the patient risk scored grouped in tertiles. a Survival probability chart overtime (expressed in months). b Hazard ratio of the risk score for the three tertiles and the covariables
Fig. 4
Fig. 4
ROCs were obtained for the clinical variables and in combination with the metabolites or glycated haemoglobin (HbA1c)

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