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Study of Circulating Prohepcidin in Association with Insulin Sensitivity and Changing Iron Stores

Department of Diabetes, Endocrinology and Nutrition (J.M.F.-R., J.M.M., F.O., W.R.), University Hospital of Girona "Dr Josep Trueta" and CIBER Fisiopatología de la Obesidad y Nutrición CB06/03/010, 17007 Girona, Spain; Department of Transfusion Science (F.E.), San Filippo Neri Hospital, 00149 Rome, Italy; and Department of Hepatogastroenterology and Nutrition (M.M.), Bambino Gesù Hospital, 00165 Rome, Italy

Address all correspondence and requests for reprints to: J. M. Fernández-Real, M.D., Ph.D., Unit of Diabetes, Endocrinology and Nutrition, Hospital de Girona "Dr. Josep Trueta", Ctra. França s/n, 17007 Girona, Spain. E-mail: jmfernandezreal.girona.ics{at}gencat.cat.

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.

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