title: Study of circulating prohepcidin in association with insulin sensitivity and changing iron stores.
abstract: BACKGROUND
  Liver synthesizes hepcidin in response to iron overload, leading to down-regulation of duodenal iron absorption. The pathophysiology of type 2 diabetes is associated with increased iron stores. We aimed to study circulating prohepcidin in association with insulin sensitivity and parameters of glucose and iron metabolism.
  
  
  METHODS
  Serum prohepcidin was evaluated in three cohorts: 1) a cross-sectional study (cohort 1, men from the general population; n = 135); 2) after decreasing iron stores in men with "high-ferritin" type 2 diabetes (cohort 2; n = 13); and 3) after decreasing iron stores in men carrying HFE gene mutations (cohort 3; n = 16). Insulin sensitivity was measured using either the minimal model or the clamp technique.
  
  
  RESULTS
  Circulating prohepcidin correlated significantly with glycated hemoglobin (P < 0.0001), fasting glucose (P = 0.002), triglycerides (P = 0.007), high-density lipoprotein-cholesterol (P = 0.01), ferritin (P = 0.01), and soluble transferrin receptor concentration (P = 0.001) in subjects from cohort 1. Prohepcidin decreased significantly after iron depletion in patients with type 2 diabetes (P = 0.04) (cohort 2) and in carriers of HFE gene mutations (P = 0.03) (cohort 3). In the latter subjects, the change in serum prohepcidin after iron depletion was associated with the change in both fasting glucose transferrin (r = 0.58; P = 0.02) and saturation (r = 0.68; P = 0.005). The changes in insulin sensitivity were associated with those of liver iron content (r = -0.64; P = 0.007) and with those of serum prohepcidin (r = -0.50; P = 0.04) (cohort 3).
  
  
  CONCLUSIONS
  These associations suggest that circulating prohepcidin concentration is pathophysiologically associated with parameters of glucose and iron metabolism. A failure to increase prohepcidin synthesis is hypothesized to contribute to iron-induced disorders of glucose metabolism.
authors.affiliation: Department of Diabetes, Endocrinology and Nutrition, University Hospital of Girona Dr Josep Trueta and CIBER Fisiopatología de Obesidad y Nutrición CB06/03/010, 17007 Girona, Spain. jmfernandezreal.girona.ics@gencat.cat
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Fernández-Real
authors.forename: Francesco
authors.initials: F
authors.lastname: Equitani
authors.forename: José María
authors.initials: JM
authors.lastname: Moreno
authors.forename: Melania
authors.initials: M
authors.lastname: Manco
authors.forename: Francisco
authors.initials: F
authors.lastname: Ortega
authors.forename: Wifredo
authors.initials: W
authors.lastname: Ricart
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000097:blood* / Q000502:physiology; D015992:Body Mass Index; D008076:Cholesterol, HDL / Q000097:blood; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D005293:Ferritins / Q000097:blood; D005947:Glucose / Q000378:metabolism; D006442:Glycated Hemoglobin / Q000032:analysis; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D007501:Iron / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D011498:Protein Precursors / Q000097:blood* / Q000502:physiology
chemical_list: D023181:Antimicrobial Cationic Peptides; D008076:Cholesterol, HDL; D005293:Ferritins; D005947:Glucose; D006442:Glycated Hemoglobin; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I; D007328:Insulin; D007501:Iron; D008565:Membrane Proteins; D011498:Protein Precursors; C103673:HFE protein, human; C517652:hemoglobin A1c protein, human