Abstract

Objective: To clarify the pathogenesis of diabetes associated with mutations of the haemochromatosis gene (HFE), 17 carriers, 9 with normal glucose tolerance (NGT) and 8 with diabetes (DM) were evaluated in an interventional trial.

Design and methods: At enrolment and after 2-year blood letting period, euglycemic-hyperinsulinemic-clamp (EHC), oral glucose tolerance test (OGTT), liver histology (NAS-score) and iron content (LIC) were assessed.

Results: NGT had significantly higher baseline insulin sensitivity (P≤0.001), secretion and insulinogenic index (IGI, calculated from the OGTT) (P≤0.0001 for both), lower LIC (P=0.004) and NAS-score (P=0.02) than DM patients.

Results: Baseline LIC correlated negatively with insulin secretion (NGT r₀=−0.676; P≤0.0001; DM r₀=−0.589; P=0.02); insulin sensitivity (M value) (NGT r₀=−0.597; P=0.009; DM r₀=−0.535; P=0.03); and positively with NAS (DM r₀=0.649; P=0.007) and triglycerides (NGT r₀=0.563; P=0.015).

Results: At month 24, circulating iron was reduced by 179±26 % in NGT and 284±54% in DM patients. Insulin secretion (NGT by 20±4%; DM 33±7%) and insulin sensitivity (25±5% NGT; 18±3% DM) increased. LIC decreased in both groups (by 126±42% and 61±13%), and NAS-score ameliorated (NGT 65.1±6.5 vs. 38.1±6.83; P≤0.0001; DM 2.1±10.7 vs. 69.9±10; P≤0.0001).

Conclusions: Iron depletion ameliorates insulin secretion and sensitivity in NGT and DM carriers of HFE gene mutations. This occurs in parallel to decreased LIC and improved NAS-score. These results would justify glucose tolerance testing and prophylactic iron depletion in asymptomatic carriers too.