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

Abstract

ObjectiveElevated 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.MethodsIn 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.ResultsSubjects 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).ConclusionsOur 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.

The Relationship between Dietary, Serum and Hair Levels of Minerals (Fe, Zn, Cu) and Glucose Metabolism Indices in Obese Type 2 Diabetic Patients

“…The relationship between T2DM and iron metabolism has gained interest both in research and clinical practice [ 15 , 56 ]. There was scientific evidence for the influence of elevated serum ferritin levels on IR and T2DM either because of increased body iron stores or due to inflammatory diseases [ 57 – 59 ].…”

“…Both mineral deficiency and excess have been reported in diabetic patients and in animal models of type 2 diabetes. For example, higher amounts of zinc and magnesium are excreted with urine [ 13 , 14 ], while iron accumulates in the body due to elevated ferritin levels in diabetes [ 15 , 16 ]. In type 1 diabetes, the elevated copper concentration and decreased zinc in serum were observed [ 13 , 17 ].…”

Molecular Fingerprints of Iron Parameters among a Population-Based Sample

“…One previous study has provided first indications of a metabolic pathway that can lead to impaired glucose metabolism in case of elevated ferritin concentrations. The authors speculated about an implication via the metabolic pathways of the amino acids sarcosine and citrulline [ 33 ]. However, the larger metabolite coverage of our approach further augments their observation to BCAA catabolites but it remains elusive if those observational results reflect causal mechanisms or are surrogates for tissue-specific pathways.…”

Regulatory Connections between Iron and Glucose Metabolism

“…Another study compared metabolites in serum samples of patients with metabolic syndrome (see below) and iron overload to control subjects, and to metabolic syndrome patients subjected to phlebotomy [ 31 ]. Interestingly, the concentrations of sarcosine, citrulline, methioninsulfoxide, and long-chain phosphatidylcholines were significantly altered between the groups, implying that iron may be involved in a multitude of metabolic pathways, some of which have not been previously reported.…”