We thank Valenti et al. (1) for their interest in our study and valuable comments. As they state, heterozygous H63D gene mutation is the most common mutation of the hemochromatosis (HFE) gene. Even though we reported one carrier alone of this mutation (2), we believe that diagnostic and therapeutic approaches in patients with clinical features of iron overload are not based on genetic testing so much as on clinical judgment, iron tests, and occurrence of metabolic comorbidities. Several authors, including Valenti et al. (3), have observed the utility of phlebotomies to ameliorate insulin sensitivity and secretion in healthy blood donors and in insulin-resistant phenotypes with clinical features of liver iron depot, normal transferrin and saturation, and high ferritin—hence, independently of whether subjects are carriers of HFE gene mutation.

It is hard to believe that a nonintensive nutritional counsel can cause a weight loss that remains stable for as long as 2 years. Conversely, the fall of insulin levels, following the iron depletion, might have favored the loss and the maintenance of body weight. In keeping with this hypothesis, Valenti et al. (3) observed insulin resistance ameliorating independently of body weight in iron-depleted patients. They claim no amelioration of insulin secretion, measured as homeostasis model assessment of β-cell function, following iron depletion in patients with nonalcoholic fatty liver disease (3). Again, our results are in agreement with their study; neither levels of C-peptide (Table 1 in ref. 2) nor homeostasis model assessment of β-cell function (data not shown) changed significantly after treatment (2). We observed that the secretion after the glucose load, an index of the first-phase insulin secretion, improved. These data suggest that iron is implicated in the potentiation of glucose-induced insulin release. We are not back to leaches, but the interaction between insulin and iron remains an intriguing topic that deserves further investigation through controlled studies varying lifestyle and iron intake and depletion.

1.
Valenti L, Dongiovanni P, Francanzani AL, Fargion S: Bloodletting ameliorates insulin sensitivity and secretion in parallel to reducing liver iron in carriers of HFE gene mutations (Letter).
Diabetes Care
31
:
e18
,
2008
. DOI:10.2337/dc07-2181
2.
Equitani F, Fernadez-Real JM, Menichella G, Koch M, Calvani M, Nobili V, Mingrone G, Manco M: Bloodletting ameliorates insulin sensitivity and secretion in parallel to reducing liver iron in carriers of HFE gene mutations.
Diabetes Care
31
:
3
–8,
2008
3.
Valenti L, Fracanzani AL, Dongiovanni P, Bugianesi E, Marchesini G, Manzini P, Vanni E, Fargion S: Iron depletion by phlebotomy improves insulin resistance in patients with nonalcoholic fatty liver disease and hyperferritinemia: evidence from a case-control study.
Am J Gastroenterol
102
:
1251
–1258,
2007