Diabetes Care Publish Ahead of Print published online ahead of print
October 24, 2007
DOI: 10.2337/dc07-0939

Clinical Care/Education/Nutrition/Psychosocial Research
Original Research

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
1 Transfusion Medicine, SanFilippo Neri Hospital, Rome, Italy
2 Section of Diabetes, Endocrinology, and Nutrition, University
Hospital, Girona, Spain
3 Liver Unit, SanFilippo Neri Hospital, Rome, Italy
4 Department of Internal Medicine, Catholic University, Rome, Italy
5 Department 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@tiscali.it

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.

Abbreviations: 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

Published online October 24, 2007
Diabetes Care 31:3-8, 2008
DOI: 10.2337/dc07-0939
(c) 2008 by the American Diabetes Association

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