Effect of Iron Chelation Therapy on Glucose Metabolism in Non-Transfusion-Dependent Thalassemia

Background: Increased intestinal iron absorption has been shown in non-transfusion-dependent thalassemia (NTDT) and thus results in mild to moderate iron excess. Therefore, these patients should theoretically have increased risks of pre-diabetes and diabetes. However, there have been no studies addressing insulin and glucose metabolism in these patients. We, therefore, hypothesize that NTDT with iron excess may have impaired β-cell function and reduced insulin sensitivity and their improvements may occur following iron chelation therapy.

Objective: To assess insulin sensitivity and β-cell function in NTDT with iron excess pre- and post-iron chelation therapy.

Study design: non-randomized open-labelled prospective cohort study

Patients:

Inclusion criteria: NTDT patients, aged older than 10 years who have had serum ferritin >300 ng/mL and/or transferrin saturation ≥70% and/or liver iron (Fe) concentration (LIC) of at least 5 mg Fe per gram of dry weight.

Exclusion criteria: Known case of type I or type II DM and taking medications affecting glucose metabolism or iron chelation therapy within one month prior to study.

Methods: The complete patient histories were obtained and physical examinations were performed initially and at 3- and 6-month follow-up. Deferasirox at the dose of 10 mg/kg was prescribed daily to the studied patients for 6 months. Iron status indicators including serum ferritin, serum iron, total iron biding capacity (TIBC), transferrin saturation, non-transferrin-binding iron (NTBI) and hepcidin were determined pre- and 6-month post-chelation. For assessment of glucose metabolism, an oral glucose tolerance test (OGTT) and serum adiponectin were determined pre- and 6-month post-chelation. During an OGTT, serum insulin and plasma glucose at 0, 30, 60, 90 and 120 min were obtained. Insulin resistance, insulin sensitivity and β-cell function indices including homeostatic model assessment-insulin resistance (HOMA-IR), whole body insulin sensitivity index (WBISI) and disposition index (WBISI x insulinogenic index), were calculated. Also, MRI of the heart, liver and pancreas were monitored pre- and 6-month post-chelation.

Results: Ten patients (7 males) with a median age of 17.4 years enrolled in the study. Seven patients were b-thalassemia /Hb E disease of either b⁰ or b⁺ thalassemia genes and three patients were non-deletion type of Hb H disease with Hb Constant Spring or Hb Pakse. One of these three patients had additional Hb E resulting in AE Bart's disease. The severity of the thalassemia diseases was classified using a scoring system for b-thal/HbE revealing severe (n=1), moderate (n=6) and mild (n=3) degrees.

For iron status indicators, the median pre-chelation serum ferritin was significantly higher than that of post-chelation (551.4 vs. 486.1 ng/mL, p=0.049). Also, the median pre-chelation TIBC was significantly lower than that of post-chelation (211.5 vs. 233.5 µg/dL, p=0.006). The median pre-chelation NTBI was higher than that of post-chelation (6.2 vs 4.0 µM, p =0.068) but no statistical significance. Also, the median pre-chelation hepcidin was lower than that of post-chelation but no statistical significance.

For glucose metabolism, the median pre-chelation serum adiponectin was not different from that of post-chelation (46.41 vs. 48.77 ng/mL, p=0.508). All patients had normal glucose tolerance both pre- and post-chelation with no significant changes of body mass index during the 6-month period. However, there was a significant reduction of fasting plasma glucose after iron chelation (85.0 vs.79.5 mg/dL, p =0.045). In comparison between pre- and post-chelation, there were trends towards decreasing insulin resistance index expressed as HOMA-IR (0.8 vs. 0.2, p =0.219) and increasing insulin sensitivity indices expressed as WBISI (11.5 vs. 19.8, p =0.105). Also, there was a trend towards improving β-cell function expressed as disposition index (5.1 vs. 6.2, p=0.064). MRI revealed no significant changes of iron accumulation in liver, pancreas and myocardium following 6-month iron chelation therapy. No adverse effects following oral iron chelation therapy were detected.

Conclusions: There was a trend towards improving insulin sensitivity and β-cell function following 6-month iron chelation therapy. Longer term of iron chelating agent treatment may demonstrate a significant beneficial effect on glucose metabolism.