Glycolysis/gluconeogenesis- and tricarboxylic acid cycle-related metabolites, Mediterranean diet, and type 2 diabetes

Marta Guasch-Ferré; José L Santos; Miguel A Martínez-González; Clary B Clish; Cristina Razquin; Dong Wang; Liming Liang; Jun Li; Courtney Dennis; Dolores Corella; Carlos Muñoz-Bravo; Dora Romaguera; Ramón Estruch; José Manuel Santos-Lozano; Olga Castañer; Angel Alonso-Gómez; Luis Serra-Majem; Emilio Ros; Sílvia Canudas; Eva M Asensio; Montserrat Fitó; Kerry Pierce; J Alfredo Martínez; Jordi Salas-Salvadó; Estefanía Toledo; Frank B Hu; Miguel Ruiz-Canela

doi:10.1093/ajcn/nqaa016

Glycolysis/gluconeogenesis- and tricarboxylic acid cycle-related metabolites, Mediterranean diet, and type 2 diabetes

Am J Clin Nutr. 2020 Apr 1;111(4):835-844. doi: 10.1093/ajcn/nqaa016.

Authors

Marta Guasch-Ferré^{1

2

3}, José L Santos⁴, Miguel A Martínez-González^{1

5

6}, Clary B Clish⁷, Cristina Razquin^{5

6}, Dong Wang¹, Liming Liang⁸, Jun Li¹, Courtney Dennis⁷, Dolores Corella^{6

9}, Carlos Muñoz-Bravo¹⁰, Dora Romaguera^{6

11}, Ramón Estruch^{6

12}, José Manuel Santos-Lozano^{6

13}, Olga Castañer^{6

14}, Angel Alonso-Gómez^{6

15}, Luis Serra-Majem^{6

16}, Emilio Ros^{6

17}, Sílvia Canudas^{2

6}, Eva M Asensio⁹, Montserrat Fitó^{6

14}, Kerry Pierce⁷, J Alfredo Martínez^{6

18}, Jordi Salas-Salvadó^{2

6}, Estefanía Toledo^{5

6}, Frank B Hu^{1

3}, Miguel Ruiz-Canela^{5

6}

Affiliations

¹ Department of Nutrition, Harvard TH Chan School of Public Health, Boston, MA, USA.
² Human Nutrition Unit, Faculty of Medicine and Health Sciences, Pere Virgili Health Research Institute, Rovira i Virgili University, Reus, Spain.
³ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁴ Department of Nutrition, Diabetes and Metabolism, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
⁵ Department of Preventive Medicine and Public Health, IdiSNA (Health Research Institute of Navarra), University of Navarra, Pamplona, Spain.
⁶ The Spanish Biomedical Research Center in Physiopathology of Obesity and Nutrition, Health Institute Carlos III, Madrid, Spain.
⁷ Broad Institute of MIT and Harvard University, Cambridge, MA, USA.
⁸ Department of Biostatistics, Harvard TH Chan School of Public Health, Boston, MA, USA.
⁹ Department of Preventive Medicine, University of Valencia, Valencia, Spain.
¹⁰ Department of Public Health and Psychiatry, University of Málaga, Málaga, Spain.
¹¹ Health Research Institute of the Balearic Islands (IdISBa), University Hospital Son Espases, Mallorca, Spain.
¹² Department of Internal Medicine, Department of Endocrinology and Nutrition Biomedical Research Institute August Pi Sunyer (IDI-BAPS), Hospital Clinic, University of Barcelona, Barcelona, Spain.
¹³ Department of Family Medicine, Primary Care Division of Sevilla, San Pablo Health Center, Sevilla, Spain.
¹⁴ Cardiovascular and Nutrition Research Group, Hospital del Mar Research Institute (IMIM), Barcelona, Spain.
¹⁵ Bioaraba Health Research Institute; Osakidetza Baseque Health Service, Araba University Hospital; Unibersity of the Basque Country UPV/EHU; Vitoria-Gasteiz, Spain.
¹⁶ Research Institute of Biomedical and Health Sciences (IUIBS), University of Las Palmas de Gran Canaria and Service of Preventive Medicine, Complejo Hospitalario Universitario Insular Materno Infantil (CHUIMI), Canary Health Service, Las Palmas de Gran Canaria, Spain.
¹⁷ Lipid Clinic, Department of Endocrinology and Nutrition Biomedical Research Institute August Pi Sunyer (IDI-BAPS), Hospital Clinic, University of Barcelona, Barcelona, Spain.
¹⁸ Department of Nutrition, Food Sciences, and Physiology, Center for Nutrition Research, University of Navarra, Pamplona, IMDEA Food, Madrid, Spain.

Abstract

Background: Glycolysis/gluconeogenesis and tricarboxylic acid (TCA) cycle metabolites have been associated with type 2 diabetes (T2D). However, the associations of these metabolites with T2D incidence and the potential effect of dietary interventions remain unclear.

Objectives: We aimed to evaluate the association of baseline and 1-y changes in glycolysis/gluconeogenesis and TCA cycle metabolites with insulin resistance and T2D incidence, and the potential modifying effect of Mediterranean diet (MedDiet) interventions.

Methods: We included 251 incident T2D cases and 638 noncases in a nested case-cohort study within the PREDIMED Study during median follow-up of 3.8 y. Participants were allocated to MedDiet + extra-virgin olive oil, MedDiet + nuts, or control diet. Plasma metabolites were measured using a targeted approach by LC-tandem MS. We tested the associations of baseline and 1-y changes in glycolysis/gluconeogenesis and TCA cycle metabolites with subsequent T2D risk using weighted Cox regression models and adjusting for potential confounders. We designed a weighted score combining all these metabolites and applying the leave-one-out cross-validation approach.

Results: Baseline circulating concentrations of hexose monophosphate, pyruvate, lactate, alanine, glycerol-3 phosphate, and isocitrate were significantly associated with higher T2D risk (17-44% higher risk for each 1-SD increment). The weighted score including all metabolites was associated with a 30% (95% CI: 1.12, 1.51) higher relative risk of T2D for each 1-SD increment. Baseline lactate and alanine were associated with baseline and 1-y changes of homeostasis model assessment of insulin resistance. One-year increases in most metabolites and in the weighted score were associated with higher relative risk of T2D after 1 y of follow-up. Lower risks were observed in the MedDiet groups than in the control group although no significant interactions were found after adjusting for multiple comparisons.

Conclusions: We identified a panel of glycolysis/gluconeogenesis-related metabolites that was significantly associated with T2D risk in a Mediterranean population at high cardiovascular disease risk. A MedDiet could counteract the detrimental effects of these metabolites.This trial was registered at controlled-trials.com as ISRCTN35739639.

Keywords: glycolysis metabolites; insulin resistance; metabolomics; tricarboxylic acid cycle metabolites; type 2 diabetes.

Publication types

Randomized Controlled Trial
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Aged, 80 and over
Case-Control Studies
Citric Acid Cycle*
Cohort Studies
Diabetes Mellitus, Type 2 / diet therapy*
Diabetes Mellitus, Type 2 / metabolism
Diabetes Mellitus, Type 2 / physiopathology
Diet, Mediterranean*
Female
Gluconeogenesis*
Glycolysis*
Humans
Male
Middle Aged

Associated data

ISRCTN/ISRCTN35739639

Abstract

Publication types

MeSH terms

Associated data

Grants and funding