Metabolomic profiling identifies potential pathways involved in the interaction of iron homeostasis with glucose metabolism

• Published in: Molecular metabolism (Germany) Vol. 6; no. 1; pp. 38 - 47
• Main Authors: Stechemesser, Lars, Eder, Sebastian K, Wagner, Andrej, Patsch, Wolfgang, Feldman, Alexandra, Strasser, Michael, Auer, Simon, Niederseer, David, Huber-Schönauer, Ursula, Paulweber, Bernhard, Zandanell, Stephan, Ruhaltinger, Sandra, Weghuber, Daniel, Haschke-Becher, Elisabeth, Grabmer, Christoph, Rohde, Eva, Datz, Christian, Felder, Thomas K, Aigner, Elmar
• Format: Journal Article
• Language: English
• Published: Germany Elsevier 01.01.2017
• Subjects: Endocrinology & Metabolism; Original; Hyperferritinemia; C-reactive protein; Akt/PKB; glucose transporter 1; alanine aminotransferase; DIOS; ALT; Glucose; oGTT; TNF; CDP; plasmalogens; RBC; VLDL; gamma-glutamyl transpeptidase; with iron overload; WHO; Iron overload; WHR; high density lipoproteins; World Health Organization; IL; body mass index; phosphatidylethanolamine N-methyltransferase; T2D; without iron overload; very low-densitylipoproteins; IR; glycine N-methyltransferase; HOMA-IR; PCOS; MetS; dysmetabolic iron overload syndrome; FoxO1; CRP; Metabolomics; NAFLD; non-alcoholic fatty liver disease; oral glucose tolerance test; glycogen synthase kinase 3β; MRI; magnet resonance imaging; waist hip ratio; Metabolic syndrome; polycystic ovary syndrome; HDL; LDL; phosphatidylcholine; type 2 diabetes mellitus; interleukin; PC_E; insulin resistance; HIF1α; BMI; Fe; hypoxia-inducible factor 1α; GLUT1; AST; homeostatic model assessment-insulin resistance; Cytidinediphosphat; forkhead transcription factor O1; aspartate aminotransferase; GNMT; Akt/protein kinase B; GSK3β; PC; tumor necrosis factor; GGT; low density lipoproteins; PEMT; red blood count; oGTT, oral glucose tolerance test; WHR, waist hip ratio; LDL, low density lipoproteins; VLDL, very low-densitylipoproteins; Akt/PKB, Akt/protein kinase B; GGT, gamma-glutamyl transpeptidase; BMI, body mass index; NAFLD, non-alcoholic fatty liver disease; MRI, magnet resonance imaging; PEMT, phosphatidylethanolamine N-methyltransferase; WHO, World Health Organization; GNMT, glycine N-methyltransferase; PC_E, plasmalogens; Fe, with iron overload; ALT, alanine aminotransferase; HOMA-IR, homeostatic model assessment-insulin resistance; PC, phosphatidylcholine; TNF, tumor necrosis factor; Fe, without iron overload; GSK3β, glycogen synthase kinase 3β; MetS, metabolic syndrome; T2D, type 2 diabetes mellitus; HDL, high density lipoproteins; DIOS, dysmetabolic iron overload syndrome; RBC, red blood count; HIF1α, hypoxia-inducible factor 1α; IL, interleukin; PCOS, polycystic ovary syndrome; CRP, C-reactive protein; FoxO1, forkhead transcription factor O1; AST, aspartate aminotransferase; CDP, Cytidinediphosphat; IR, insulin resistance; GLUT1, glucose transporter 1
• ISSN: 2212-8778; 2212-8778
• DOI: 10.1016/j.molmet.2016.10.006

Abstract Objective 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. Methods 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. Results 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). Conclusions 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.