Amino acids, lipid metabolites, and ferritin as potential mediators linking red meat consumption to type 2 diabetes

Clemens Wittenbecher; Kristin Mühlenbruch; Janine Kröger; Simone Jacobs; Olga Kuxhaus; Anna Floegel; Andreas Fritsche; Tobias Pischon; Cornelia Prehn; Jerzy Adamski; Hans-Georg Joost; Heiner Boeing; Matthias B Schulze

doi:10.3945/ajcn.114.099150

Amino acids, lipid metabolites, and ferritin as potential mediators linking red meat consumption to type 2 diabetes

Am J Clin Nutr. 2015 Jun;101(6):1241-50. doi: 10.3945/ajcn.114.099150. Epub 2015 May 6.

Affiliations

¹ From the Department of Molecular Epidemiology (CW, KM, JK, SJ, OK, and MBS), Department of Pharmacology (H-GJ), and the Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany (A Floegel and HB); the German Center for Diabetes Research, Neuherberg, Germany (CW, KM, JK, OK, A Fritsche, JA, H-GJ, and MBS); the Department of Internal Medicine, Division of Endocrinology, Diabetology, Nephrology, Vascular Disease and Clinical Chemistry, University of Tübingen, Tübingen, Germany (A Fritsche); the Molecular Epidemiology Group, Max Delbrueck Center for Molecular Medicine Berlin-Buch, Berlin, Germany (TP); the Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany (CP and JA); and the Chair of Experimental Genetics, Technical University München, Freising-Weihenstephan, Germany (JA).
² From the Department of Molecular Epidemiology (CW, KM, JK, SJ, OK, and MBS), Department of Pharmacology (H-GJ), and the Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany (A Floegel and HB); the German Center for Diabetes Research, Neuherberg, Germany (CW, KM, JK, OK, A Fritsche, JA, H-GJ, and MBS); the Department of Internal Medicine, Division of Endocrinology, Diabetology, Nephrology, Vascular Disease and Clinical Chemistry, University of Tübingen, Tübingen, Germany (A Fritsche); the Molecular Epidemiology Group, Max Delbrueck Center for Molecular Medicine Berlin-Buch, Berlin, Germany (TP); the Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany (CP and JA); and the Chair of Experimental Genetics, Technical University München, Freising-Weihenstephan, Germany (JA). mschulze@dife.de.

PMID: 25948672
DOI: 10.3945/ajcn.114.099150

Abstract

Background: Habitual red meat consumption was consistently related to a higher risk of type 2 diabetes in observational studies. Potentially underlying mechanisms are unclear.

Objective: This study aimed to identify blood metabolites that possibly relate red meat consumption to the occurrence of type 2 diabetes.

Design: Analyses were conducted in the prospective European Prospective Investigation into Cancer and Nutrition-Potsdam cohort (n = 27,548), applying a nested case-cohort design (n = 2681, including 688 incident diabetes cases). Habitual diet was assessed with validated semiquantitative food-frequency questionnaires. Total red meat consumption was defined as energy-standardized summed intake of unprocessed and processed red meats. Concentrations of 14 amino acids, 17 acylcarnitines, 81 glycerophospholipids, 14 sphingomyelins, and ferritin were determined in serum samples from baseline. These biomarkers were considered potential mediators of the relation between total red meat consumption and diabetes risk in Cox models. The proportion of diabetes risk explainable by biomarker adjustment was estimated in a bootstrapping procedure with 1000 replicates.

Results: After adjustment for age, sex, lifestyle, diet, and body mass index, total red meat consumption was directly related to diabetes risk [HR for 2 SD (11 g/MJ): 1.26; 95% CI: 1.01, 1.57]. Six biomarkers (ferritin, glycine, diacyl phosphatidylcholines 36:4 and 38:4, lysophosphatidylcholine 17:0, and hydroxy-sphingomyelin 14:1) were associated with red meat consumption and diabetes risk. The red meat-associated diabetes risk was significantly (P < 0.001) attenuated after simultaneous adjustment for these biomarkers [biomarker-adjusted HR for 2 SD (11 g/MJ): 1.09; 95% CI: 0.86, 1.38]. The proportion of diabetes risk explainable by respective biomarkers was 69% (IQR: 49%, 106%).

Conclusion: In our study, high ferritin, low glycine, and altered hepatic-derived lipid concentrations in the circulation were associated with total red meat consumption and, independent of red meat, with diabetes risk. The red meat-associated diabetes risk was largely attenuated after adjustment for selected biomarkers, which is consistent with the presumed mediation hypothesis.

Keywords: biomarkers; cohort study; metabolomics; red meat; type 2 diabetes mellitus.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Amino Acids / blood*
Biomarkers / blood
Body Mass Index
Cross-Sectional Studies
Diabetes Mellitus, Type 2 / blood*
Diabetes Mellitus, Type 2 / epidemiology*
Diet
Energy Intake
Female
Ferritins / blood*
Follow-Up Studies
Humans
Incidence
Life Style
Linear Models
Lipid Metabolism / physiology*
Male
Meat / adverse effects*
Middle Aged
Multicenter Studies as Topic
Proportional Hazards Models
Prospective Studies
Reproducibility of Results
Risk Factors

Substances

Amino Acids
Biomarkers
Ferritins