Bloodletting ameliorates insulin sensitivity and secretion in parallel to reducing liver iron in carriers of HFE gene mutations

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 ≤ 0.001), secretion, and insulinogenic index (calculated from the OGTT) (P ≤ 0.0001 for both) and lower LIC (P = 0.004) and NAS (P = 0.02) than diabetic patients. Baseline LIC correlated negatively with insulin secretion (NGT r₀ = -0.676, P ≤ 0.0001; diabetes r₀ = -0.589, P = 0.02) and insulin sensitivity (M value) (NGT r₀ = -0.597, P = 0.009; diabetes r₀ = -0.535, P = 0.03) and positively with NAS (diabetes r₀ = 0.649, P = 0.007) and triglycerides (NGT r₀ = 0.563, P = 0.015). At month 24, circulating iron was reduced by 179 ± 26% in NGT and 284 ± 54% in diabetic subjects. Insulin secretion (NGT 20 ± 4%; diabetes 33 ± 7%) and insulin sensitivity (NGT 25 ± 5%; diabetes 18 ± 3%) increased. LIC decreased in both groups (NGT 126 ± 42%; diabetes 61 ± 13%), and NAS ameliorated (NGT 65.1 ± 6.5 vs. 38.1 ± 6.83; P ≤ 0.0001; diabetes 2.1 ± 10.7 vs. 69.9 ± 10; P ≤ 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.