Bloodletting Ameliorates Insulin Sensitivity and Secretion in Parallel to Reducing Liver Iron in Carriers of HFE Gene Mutations

Abstract

OBJECTIVE -To clarify the pathogenesis of diabetes associated with mutations of the hemochromatosis (HFE) gene, 17 carriers, 9 normal glucose tolerant (NGT) and 8 diabetic, were evaluated in an interventional trial. RESEARCH DESIGN AND METHODS-At enrollment and after a 2-year bloodletting period, euglycemic-hyperinsulinemic clamp, oral glucose tolerance test (OGTT), liver histology (nonalcoholic fatty liver disease activity score [NAS]), and liver iron content (LIC) were assessed.RESULTS -NGT subjects had significantly higher baseline insulin sensitivity (P Յ 0.001), secretion, and insulinogenic index (calculated from the OGTT) (P Յ 0.0001 for both) and lower LIC (P ϭ 0.004) and NAS (P ϭ 0.02) than diabetic patients. Baseline LIC correlated negatively with insulin secretion (NGT r 0 ϭ Ϫ0.676, P Յ 0.0001; diabetes r 0 ϭ Ϫ0.589, P ϭ 0.02) and insulin sensitivity (M value) (NGT r 0 ϭ Ϫ0.597, P ϭ 0.009; diabetes r 0 ϭ Ϫ0.535, P ϭ 0.03) and positively with NAS (diabetes r 0 ϭ 0.649, P ϭ 0.007) and triglycerides (NGT r 0 ϭ 0.563, P ϭ 0.015). At month 24, circulating iron was reduced by 179 Ϯ 26% in NGT and 284 Ϯ 54% in diabetic subjects. Insulin secretion (NGT 20 Ϯ 4%; diabetes 33 Ϯ 7%) and insulin sensitivity (NGT 25 Ϯ 5%; diabetes 18 Ϯ 3%) increased. LIC decreased in both groups (NGT 126 Ϯ 42%; diabetes 61 Ϯ 13%), and NAS ameliorated (NGT 65.1 Ϯ 6.5 vs. 38.1 Ϯ 6.83; P Յ 0.0001; diabetes 2.1 Ϯ 10.7 vs. 69.9 Ϯ 10; P Յ 0.0001).CONCLUSIONS -Iron depletion ameliorates insulin secretion and sensitivity in NGT and diabetic carriers of HFE gene mutations. This amelioration occurs in parallel with decreased LIC and improved NAS. These results justify glucose tolerance testing and prophylactic iron depletion in asymptomatic carriers as well.

Body iron stores and the risk of type 2 diabetes in middle-aged men

“…He found that lowering sF from 75 to 38 mg/l led to 37 and 19% reduction in 2-h plasma insulin and glucose concentrations respectively in ten healthy individuals. Also, a few controlled interventional studies have demonstrated the positive effect of iron depletion on insulin resistance (31,32), which could be more pronounced in subjects with elevated baseline sF than in those with relatively normal baseline sF (31). These studies (29,30) suggest that maintaining the sF below high normal could possibly prove useful in reducing the prevalence of T2DM.…”

Iron in fatty liver and in the metabolic syndrome: A promising therapeutic target

“…Phlebotomy led to decreased HbA1c levels, heightened insulin secretion and insulin sensitivity in a randomized controlled study in 28 patients with T2D and increased ferritin levels and stable body weight [148]. In addition, ID improved insulin release in an uncontrolled study in 17 carriers of HFE mutations with steatosis [149]. Regular blood donation was also associated with increased insulin sensitivity in 21 frequent donors compared to 66 healthy subjects, suggesting that stored iron impacts negatively on insulin action even in healthy people [150].…”

Early interplay of intra-hepatic iron and insulin resistance in children with non-alcoholic fatty liver disease

“…In keeping with the role of intra-parenchymal iron accumulation in insulin metabolism, in vivo studies have demonstrated that the depletion of intra-hepatic iron deposits is effective in improving insulin resistance in individuals with siderosis and features of the metabolic syndrome, and also by ameliorating inflammation [16,17].…”