Iron and glucose homeostasis: new lessons from hereditary haemochromatosis.

Interest in the relationship between systemic iron stores and glucose homeostasis has existed since the early descriptions of hereditary haemochromatosis [1, 2]. Diabetes is also prevalent in transfusional iron overload and African iron overload, which resembles haemochromatosis clinically but has a different genetic mechanism. These findings, and studies showing that glucose intolerance in iron overload states can sometimes be prevented or ameliorated by iron removal, have left little doubt that increased tissue iron can contribute to glucose intolerance and diabetes. The actual prevalence of diabetes in haemochromatosis is unknown, with a broad range of estimates reported by different studies. Prevalence assessments have been confounded by selection bias, in that diabetes is considered a diagnostic feature of haemochromatosis. To date, studies of the mechanism(s) of haemochromatosis-associated diabetes have been limited. Thus, discussions of its pathogenesis have drawn heavily on findings in transfusional iron overload, and have been influenced by extensive and elegant studies of type 2 diabetes [3, 4]. In this issue of Diabetologia, McClain et al. provide a combined report of an extensive chart review and a prospective study of newly diagnosed patients with haemochromatosis, to address both the prevalence and mechanism of impaired glucose tolerance and diabetes in this disorder [5]. First, the McClain group reviewed the records of 505 haemochromatosis homozygotes seen at the University of Utah between 1975 and 1999. Records were included in the study if patients were aged >40 years (because of the age dependence of diabetes), and if adequate information was available to determine the presence or absence of diabetes by either fasting glucose values (137 patients) or unambiguous history (135 patients). The prevalence of diabetes was 26% as determined by fasting glucose and 20% as determined by history alone. Both figures were close to the 23% prevalence of diabetes in the subsequent prospective study (see below). Among patients whose fasting blood glucose had been recorded, those with diabetes were heavily iron loaded. Seventy-two percent had biopsy-proven cirrhosis and 16% had moderate fibrosis, compared with a 40% prevalence of cirrhosis or fibrosis in patients without diabetes. Among 46 clinically unselected patients in whom haemochromatosis had been identified through family screening or screening at blood donation, 6 (13%) had given a history of diabetes. Next, McClain et al. recruited 30 haemochromatosis patients over a 6-year period from among referrals to the Hemochromatosis Research Clinic at the University of Utah. Fourteen of the patients’ relatives who did not have haemochromatosis served as control subjects. All study participants underwent an OGTT, and a frequently sampled IVGTTwas performed the following day. About half of the patients with haemochromatosis had normal glucose tolerance, and the rest had overt diabetes or varying degrees of glucose intolerance, impaired fasting glucose, or both. The patients with normal glucose tolerance did not differ significantly from control subjects in either acute insulin response to glucose (AIRg) or insulin sensitivity (Si). In contrast, those with impaired glucose tolerance had significantly decreased AIRg, a marked tendency towards increased Si, and an overall reduction in the mean J. G. Wilson (*) G. V. (Sonny) Montgomery, Department of Veterans Affairs Medical Center, 1500 E. Woodrow Wilson Avenue, Jackson, MS 39216, USA e-mail: james.wilson1@med.va.gov Tel.: +1-601-3641225 Fax: +1-601-3641390