Bloodletting Ameliorates Insulin Sensitivity and Secretion in Parallel to Reducing Liver Iron in Carriers of HFE Gene Mutations
- Francesco Equitani, MD1,
- Josè Manuel Fernandez-Real, MD2,
- Giacomo Menichella, MD1,
- Maurizio Koch, MD3,
- Menotti Calvani, MD4,
- Valerio Nobili, MD5,
- Geltrude Mingrone, MD, PHD4 and
- Melania Manco, MD, PHD5
- 1Transfusion Medicine, SanFilippo Neri Hospital, Rome, Italy
- 2Section of Diabetes, Endocrinology, and Nutrition, University Hospital, Girona, Spain
- 3Liver Unit, SanFilippo Neri Hospital, Rome, Italy
- 4Department of Internal Medicine, Catholic University, Rome, Italy
- 5Department of Hepato-Gastroenterology and Nutrition, Bambino Gesù Hospital and Research Institute, Rome, Italy
- Address correspondence and reprint requests to Melania Manco, MD, PhD, Department of Hepato-Gastroenterology and Nutrition, Bambino Gesù Hospital and Research Institute, S. Onofrio 4 square, 00165 Rome, Italy, E-mail: melaniamanco{at}tiscali.it
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 ≤ 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.
- ALT, alanine aminotransferase
- AST, aspartate aminotransferase
- FFM, free fat mass
- HH, type 1 hereditary hemochromatosis
- IGI, insulinogenic index
- LIC, liver iron content
- NAFLD, nonalcoholic fatty liver disease
- NAS, nonalcoholic fatty liver disease activity score
- NGT, normal glucose tolerant
- NMR, nuclear magnetic resonance
- OGTT, oral glucose tolerance test
Footnotes
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Published ahead of print at http://care.diabetesjournals.org on 24 October 2007. DOI: 10.2337/dc07-0939. Clinical trial reg. no. NCT00440986, clinicaltrials.gov.
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.
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- Accepted September 16, 2007.
- Received May 17, 2007.
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