title: Metabolomic profiling identifies potential pathways involved in the interaction of iron homeostasis with glucose metabolism.
abstract: Elevated serum ferritin has been linked to type 2 diabetes (T2D) and adverse health outcomes in subjects with the Metabolic Syndrome (MetS). As the mechanisms underlying the negative impact of excess iron have so far remained elusive, we aimed to identify potential links between iron homeostasis and metabolic pathways.
  
  
  
  In a cross-sectional study, data were obtained from 163 patients, allocated to one of three groups: (1) lean, healthy controls (n = 53), (2) MetS without hyperferritinemia (n = 54) and (3) MetS with hyperferritinemia (n = 56). An additional phlebotomy study included 29 patients with biopsy-proven iron overload before and after iron removal. A detailed clinical and biochemical characterization was obtained and metabolomic profiling was performed via a targeted metabolomics approach.
  
  
  
  Subjects with MetS and elevated ferritin had higher fasting glucose (p < 0.001), HbA1c (p = 0.035) and 1 h glucose in oral glucose tolerance test (p = 0.002) compared to MetS subjects without iron overload, whereas other clinical and biochemical features of the MetS were not different. The metabolomic study revealed significant differences between MetS with high and low ferritin in the serum concentrations of sarcosine, citrulline and particularly long-chain phosphatidylcholines. Methionine, glutamate, and long-chain phosphatidylcholines were significantly different before and after phlebotomy (p < 0.05 for all metabolites).
  
  
  
  Our data suggest that high serum ferritin concentrations are linked to impaired glucose homeostasis in subjects with the MetS. Iron excess is associated to distinct changes in the serum concentrations of phosphatidylcholine subsets. A pathway involving sarcosine and citrulline also may be involved in iron-induced impairment of glucose metabolism.
authors.affiliation: First Department of Medicine, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria.
authors.forename: Lars
authors.initials: L
authors.lastname: Stechemesser
authors.affiliation: First Department of Medicine, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria; Obesity Research Unit, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria.
authors.forename: Sebastian K
authors.initials: SK
authors.lastname: Eder
authors.affiliation: First Department of Medicine, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria.
authors.forename: Andrej
authors.initials: A
authors.lastname: Wagner
authors.affiliation: Department of Pharmacology and Toxicology, Paracelsus Medical University, Strubergasse 21, 5020 Salzburg, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Patsch
authors.affiliation: First Department of Medicine, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria; Obesity Research Unit, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Feldman
authors.affiliation: First Department of Medicine, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Strasser
authors.affiliation: Department of Laboratory Medicine, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria.
authors.forename: Simon
authors.initials: S
authors.lastname: Auer
authors.affiliation: Department of Internal Medicine, Hospital Oberndorf, Paracelsusstrasse 37, 5110 Oberndorf, Austria; Department of Cardiology, University Heart Center Zurich, University of Zurich, Raemistrasse 100, 8091 Zurich, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Niederseer
authors.affiliation: Department of Internal Medicine, Hospital Oberndorf, Paracelsusstrasse 37, 5110 Oberndorf, Austria.
authors.forename: Ursula
authors.initials: U
authors.lastname: Huber-Schönauer
authors.affiliation: First Department of Medicine, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Paulweber
authors.affiliation: First Department of Medicine, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria.
authors.forename: Stephan
authors.initials: S
authors.lastname: Zandanell
authors.affiliation: First Department of Medicine, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria.
authors.forename: Sandra
authors.initials: S
authors.lastname: Ruhaltinger
authors.affiliation: Obesity Research Unit, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria.
authors.forename: Daniel
authors.initials: D
authors.lastname: Weghuber
authors.affiliation: Department of Laboratory Medicine, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Haschke-Becher
authors.affiliation: Department of Blood Group Serology and Transfusion Medicine, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Grabmer
authors.affiliation: Department of Blood Group Serology and Transfusion Medicine, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria.
authors.forename: Eva
authors.initials: E
authors.lastname: Rohde
authors.affiliation: Obesity Research Unit, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria; Department of Internal Medicine, Hospital Oberndorf, Paracelsusstrasse 37, 5110 Oberndorf, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Datz
authors.affiliation: Obesity Research Unit, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria; Department of Laboratory Medicine, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria.
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Felder
authors.affiliation: First Department of Medicine, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria; Obesity Research Unit, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria. Electronic address: e.aigner@salk.at.
authors.forename: Elmar
authors.initials: E
authors.lastname: Aigner
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D002956:Citrulline / Q000097:blood / Q000378:metabolism; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D005260:Female; D005293:Ferritins / Q000032:analysis / Q000097:blood / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006706:Homeostasis; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology; D007501:Iron / Q000097:blood / Q000378:metabolism*; D008297:Male; D024821:Metabolic Syndrome / Q000378:metabolism; D055432:Metabolomics / Q000379:methods; D008875:Middle Aged; D009765:Obesity / Q000097:blood; D012521:Sarcosine / Q000097:blood / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D002956:Citrulline; D005293:Ferritins; D007501:Iron; D005947:Glucose; D012521:Sarcosine
keywords: +Fe, with iron overload; ALT, alanine aminotransferase; AST, aspartate aminotransferase; Akt/PKB, Akt/protein kinase B; BMI, body mass index; CDP, Cytidinediphosphat; CRP, C-reactive protein; DIOS, dysmetabolic iron overload syndrome; FoxO1, forkhead transcription factor O1; GGT, gamma-glutamyl transpeptidase; GLUT1, glucose transporter 1; GNMT, glycine N-methyltransferase; GSK3β, glycogen synthase kinase 3β; Glucose; HDL, high density lipoproteins; HIF1α, hypoxia-inducible factor 1α; HOMA-IR, homeostatic model assessment-insulin resistance; Hyperferritinemia; IL, interleukin; IR, insulin resistance; Iron overload; LDL, low density lipoproteins; MRI, magnet resonance imaging; MetS, metabolic syndrome; Metabolic syndrome; Metabolomics; NAFLD, non-alcoholic fatty liver disease; PC, phosphatidylcholine; PCOS, polycystic ovary syndrome; PC_E, plasmalogens; PEMT, phosphatidylethanolamine N-methyltransferase; RBC, red blood count; T2D, type 2 diabetes mellitus; TNF, tumor necrosis factor; VLDL, very low-densitylipoproteins; WHO, World Health Organization; WHR, waist hip ratio; oGTT, oral glucose tolerance test; −Fe, without iron overload