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The recent discovery of hepcidin, the key iron regulatory hormone, has changed our view of iron metabolism, which in turn is long known to be linked with insulin resistant states, including type 2 diabetes mellitus and the Metabolic Syndrome (MetS). Serum ferritin levels are often elevated in MetS (Dysmetabolic hyperferritinemia - DHF), and are sometimes associated with a true mild-to-moderate hepatic iron overload (dysmetabolic iron overload syndrome - DIOS). However, the pathophysiological link between iron and MetS remains unclear. This study was aimed to investigate, for the first time, the relationship between MetS and hepcidin at population level. We measured serum hepcidin levels by Mass Spectrometry in 1,391 subjects from the Val Borbera population, and evaluated their relationship with classical MetS features. Hepcidin levels increased significantly and linearly with increasing number of MetS features, paralleling the trend of serum ferritin. In multivariate models adjusted for relevant variables including age, C-Reactive Protein, and the HFE C282Y mutation, ferritin was the only significant independent predictor of hepcidin in males, while in females MetS was also independently associated with hepcidin. Overall, these data indicate that the fundamental iron regulatory feedback is preserved in MetS, i.e. that hepcidin tends to progressively increase in response to the increase of iron stores. Due to recently discovered pleiotropic effects of hepcidin, this may worsen insulin resistance and contribute to the cardiovascular complications of MetS.

There is an error in the affiliation list for author Ginevra Biino. The following are the correct affiliations for this author: 1) Institute of Molecular Genetics, National Research Council of Italy, Pavia, Italy 2) Institute of Population Genetics, National Research Council of Italy, Sassari, Italy

Abstract 348 Background and Aims: Hepcidin is a 25 amino acid hormone mainly produced by the liver in response to increased plasma or tissue iron to homeostatically down-regulate absorption and recycling of the metal from duodenum and macrophages, respectively. Hepcidin expression is also upregulated by inflammation. Dysmetabolic hyperferritinemia is among the commonest causes of increased serum ferritin levels encountered in clinical practice, but its pathophysiology remains unclear. Indeed, the Metabolic Syndrome (MS) that affects near 20–25% of western adults, is characterized by subclinical inflammation, which hampers the interpretation of serum ferritin as a marker of body iron stores. We recently measured serum hepcidin levels in the large Val Borbera (VB) population to evaluate their genetic determinants (Traglia et al. J Med Genet 2011). Taking advantage of this survey, we investigated for the first time the relationships between hepcidin, ferritin, C-Reactive Protein (CRP) and MS phenotypes at population level. Subjects and Methods: Serum hepcidin-25 levels measured by Mass Spectrometry were analyzed in 941 subjects for whom complete data allowing classification of MS according to NLHBI criteria (fasting glucose ≥100 mg/dl or antidiabetes medication; blood pressure ≥135/85 mmHg or antihypertensive medication; triglycerides ≥150 mg/dl; HDL cholesterol Main Results: Serum hepcidin-25 levels increased linearly with the increasing number of MS traits in males (ANOVA: F=6.8, P=0.009) and, even more strongly, in females (ANOVA: F=35.2, P Conclusions: Hepcidin levels are strongly associated with MS features at population level, independently of subclinical inflammation. This association appears to reflect a response to increasing iron stores in males, while in females some MS traits may directly influence hepcidin levels. Disclosures: No relevant conflicts of interest to declare.