title: Amino acids, lipid metabolites, and ferritin as potential mediators linking red meat consumption to type 2 diabetes.
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.
  
  
  METHODS
  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%).
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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).
authors.forename: Clemens
authors.identifier: http://orcid.org/0000-0001-7792-877X
authors.initials: C
authors.lastname: Wittenbecher
authors.affiliation: 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).
authors.forename: Kristin
authors.initials: K
authors.lastname: Mühlenbruch
authors.affiliation: 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).
authors.forename: Janine
authors.initials: J
authors.lastname: Kröger
authors.affiliation: 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).
authors.forename: Simone
authors.initials: S
authors.lastname: Jacobs
authors.affiliation: 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).
authors.forename: Olga
authors.initials: O
authors.lastname: Kuxhaus
authors.affiliation: 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).
authors.forename: Anna
authors.initials: A
authors.lastname: Floegel
authors.affiliation: 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).
authors.forename: Andreas
authors.initials: A
authors.lastname: Fritsche
authors.affiliation: 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).
authors.forename: Tobias
authors.initials: T
authors.lastname: Pischon
authors.affiliation: 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).
authors.forename: Cornelia
authors.initials: C
authors.lastname: Prehn
authors.affiliation: 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).
authors.forename: Jerzy
authors.initials: J
authors.lastname: Adamski
authors.affiliation: 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).
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Joost
authors.affiliation: 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).
authors.forename: Heiner
authors.initials: H
authors.lastname: Boeing
authors.affiliation: 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.
authors.forename: Matthias B
authors.initials: MB
authors.lastname: Schulze
mesh_terms: D000328:Adult; D000596:Amino Acids / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D015992:Body Mass Index; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000453:epidemiology*; D004032:Diet; D002149:Energy Intake; D005260:Female; D005293:Ferritins / Q000097:blood*; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D008019:Life Style; D016014:Linear Models; D050356:Lipid Metabolism / Q000502:physiology*; D008297:Male; D008460:Meat / Q000009:adverse effects*; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D016016:Proportional Hazards Models; D011446:Prospective Studies; D015203:Reproducibility of Results; D012307:Risk Factors
chemical_list: D000596:Amino Acids; D015415:Biomarkers; D005293:Ferritins
keywords: biomarkers; cohort study; metabolomics; red meat; type 2 diabetes mellitus