Dietary metabolite profiling brings new insight into the relationship between nutrition and metabolic risk: An IMI DIRECT study
Rebeca Eriksen,
Isabel Garcia Perez,
Joram M. Posma,
Mark Haid,
Sapna Sharma,
Cornelia Prehn,
Louise E. Thomas,
Robert W. Koivula,
Roberto Bizzotto,
Cornelia Prehn,
Andrea Mari,
Giuseppe N. Giordano,
Imre Pavo,
Jochen M. Schwenk,
Federico De Masi,
Konstantinos D. Tsirigos,
Søren Brunak,
Ana Viñuela,
Anubha Mahajan,
Timothy J. McDonald,
Tarja Kokkola,
Femke Rutter,
Harriet Teare,
Tue H. Hansen,
Juan Fernandez,
Angus Jones,
Chris Jennison,
Mark Walker,
Mark I. McCarthy,
Oluf Pedersen,
Hartmut Ruetten,
Ian Forgie,
Jimmy D. Bell,
Ewan R. Pearson,
Paul W. Franks,
Jerzy Adamski,
Elaine Holmes,
Gary Frost
Affiliations
Rebeca Eriksen
Section for Nutrition Research, Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, United Kingdom
Isabel Garcia Perez
Section for Nutrition Research, Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, United Kingdom
Joram M. Posma
Section of Bioinformatics, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College, London, United Kingdom; Health Data Research UK, London, United Kingdom
Mark Haid
Research Unit Molecular Endocrinology And Metabolism, Helmholtz Zentrum Muenchen, German Research Center for Environemental Health (GmbH), Neuherberg, Germany
Sapna Sharma
German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764 Neuherberg, Germany; Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Bavaria, Germany
Cornelia Prehn
Research Unit Molecular Endocrinology And Metabolism, Helmholtz Zentrum Muenchen, German Research Center for Environemental Health (GmbH), Neuherberg, Germany
Louise E. Thomas
Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London, United Kingdom
Robert W. Koivula
Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Radcliffe Department of Medicine, Oxford, United Kingdom
Roberto Bizzotto
Institute of Neuroscience - National Research Council, Padova, Italy
Cornelia Prehn
Research Unit Molecular Endocrinology And Metabolism, Helmholtz Zentrum Muenchen, German Research Center for Environemental Health (GmbH), Neuherberg, Germany
Andrea Mari
Institute of Neuroscience - National Research Council, Padova, Italy
Giuseppe N. Giordano
Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden
Imre Pavo
Eli Lilly Regional Operations GmbH, Vienna, Austria
Jochen M. Schwenk
Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH - Royal Institute of Technology, Stockholm, Sweden
Federico De Masi
Department of Health Technology, Technical University of Denmark, Kgs Lyngby and The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
Konstantinos D. Tsirigos
Department of Health Technology, Technical University of Denmark, Kgs Lyngby and The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
Søren Brunak
Department of Health Technology, Technical University of Denmark, Kgs Lyngby and The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark; Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, DK-2200 Copenhagen, Denmark
Ana Viñuela
Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
Anubha Mahajan
Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
Timothy J. McDonald
Medical School, Exeter, UK NIHR Exeter Clinical Research Facility, University of Exeter
Tarja Kokkola
Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
Femke Rutter
Department of Epidemiology and Biostatistics, Amsterdam Public Health Institute, Amsterdam UMC, locationVUMC, Amsterdam, Netherlands
Harriet Teare
Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
Tue H. Hansen
The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark
Juan Fernandez
Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
Angus Jones
Medical School, Exeter, UK NIHR Exeter Clinical Research Facility, University of Exeter
Chris Jennison
Department of Mathematical Sciences, University of Bath, Bath, United Kingdom
Mark Walker
Institute of Cellular Medicine (Diabetes), Newcastle University, Newcastle upon Tyne, United Kingdom
Mark I. McCarthy
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Radcliffe Department of Medicine, Oxford, United Kingdom; Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
Oluf Pedersen
The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark
Hartmut Ruetten
Sanofi-Aventis Deutschland GmbH, R&D, Frankfurt am Main, Germany
Ian Forgie
Population Health & Genomics, School of Medicine, University of Dundee, Dundee, United Kingdom
Jimmy D. Bell
Research Centre for Optimal Health, School of Life Sciences, University of Westminster, London, United Kingdom
Ewan R. Pearson
Population Health & Genomics, School of Medicine, University of Dundee, Dundee, United Kingdom
Paul W. Franks
Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden
Jerzy Adamski
Research Unit Molecular Endocrinology And Metabolism, Helmholtz Zentrum Muenchen, German Research Center for Environemental Health (GmbH), Neuherberg, Germany; Lehrstuhl für Experimentelle Genetik, Technische Universität München, 85350 Freising-Weihenstephan, Germany; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive, Singapore 117597, Singapore
Elaine Holmes
Section for Nutrition Research, Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, United Kingdom
Gary Frost
Section for Nutrition Research, Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, United Kingdom; NIHR Oxford Biomedical Research Centre, Churchill Hospital, Oxford, United Kingdom; Corresponding authors: Professor Gary Frost, Nutrition Research Section, Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, W12 0NN UK.
Summary: Background: Dietary advice remains the cornerstone of prevention and management of type 2 diabetes (T2D). However, understanding the efficacy of dietary interventions is confounded by the challenges inherent in assessing free living diet. Here we profiled dietary metabolites to investigate glycaemic deterioration and cardiometabolic risk in people at risk of or living with T2D. Methods: We analysed data from plasma collected at baseline and 18-month follow-up in individuals from the Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) cohort 1 n = 403 individuals with normal or impaired glucose regulation (prediabetic) and cohort 2 n = 458 individuals with new onset of T2D. A dietary metabolite profile model (Tpred) was constructed using multivariable regression of 113 plasma metabolites obtained from targeted metabolomics assays. The continuous Tpred score was used to explore the relationships between diet, glycaemic deterioration and cardio-metabolic risk via multiple linear regression models. Findings: A higher Tpred score was associated with healthier diets high in wholegrain (β=3.36 g, 95% CI 0.31, 6.40 and β=2.82 g, 95% CI 0.06, 5.57) and lower energy intake (β=-75.53 kcal, 95% CI -144.71, -2.35 and β=-122.51 kcal, 95% CI -186.56, -38.46), and saturated fat (β=-0.92 g, 95% CI -1.56, -0.28 and β=–0.98 g, 95% CI -1.53, -0.42 g), respectively for cohort 1 and 2. In both cohorts a higher Tpred score was also associated with lower total body adiposity and favourable lipid profiles HDL-cholesterol (β=0.07 mmol/L, 95% CI 0.03, 0.1), (β=0.08 mmol/L, 95% CI 0.04, 0.1), and triglycerides (β=-0.1 mmol/L, 95% CI -0.2, -0.03), (β=-0.2 mmol/L, 95% CI -0.3, -0.09), respectively for cohort 1 and 2. In cohort 2, the Tpred score was negatively associated with liver fat (β=-0.74%, 95% CI -0.67, -0.81), and lower fasting concentrations of HbA1c (β=-0.9 mmol/mol, 95% CI -1.5, -0.1), glucose (β=-0.2 mmol/L, 95% CI -0.4, -0.05) and insulin (β=-11.0 pmol/mol, 95% CI -19.5, -2.6). Longitudinal analysis showed at 18-month follow up a higher Tpred score was also associated lower total body adiposity in both cohorts and lower fasting glucose (β=-0.2 mmol/L, 95% CI -0.3, -0.01) and insulin (β=-9.2 pmol/mol, 95% CI -17.9, -0.4) concentrations in cohort 2. Interpretation: Plasma dietary metabolite profiling provides objective measures of diet intake, showing a relationship to glycaemic deterioration and cardiometabolic health. Funding: This work was supported by the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115,317 (DIRECT), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007–2013) and EFPIA companies.