High prevalence of abnormal glucose homeostasis secondary to decreased insulin secretion in individuals with hereditary haemochromatosis

Abstract

Aims/hypothesis: The prevalence and mechanisms of diabetes in hereditary haemochromatosis are not known. We therefore measured glucose tolerance, insulin secretory capacity and insulin sensitivity in adults with haemochromatosis.Subjects and methods: Subjects recruited from referrals to a haemochromatosis clinic underwent OGTT and frequently sampled IVGTT. A chart review of former clinic patients was also performed. Results: The prevalence of diabetes (23%) and IGT (30%) was increased in haemochromatosis compared with matched control subjects (0% diabetes and 14% IGT). Subjects with haemochromatosis and diabetes were overweight (14%) or obese (86%). The prevalence of diabetes, as determined by chart review of fasting glucose values, in subjects who had haemochromatosis and were in the 40-79 years age range was 26%. Overall, patients with haemochromatosis and control subjects had similar values for acute insulin response to glucose and insulin sensitivity. However, patients with haemochromatosis and IGT had a 68% decrease in acute insulin response to glucose (p<0.02) compared with those with NGT. They were not insulin-resistant, exhibiting instead a 62% increase in insulin sensitivity (NS). Haemochromatosis subjects with diabetes exhibited further declines in acute insulin response to glucose, insulin resistance, or both.Conclusions/interpretation: Diabetes and IGT are common in haemochromatosis, justifying screening for diabetes and therapeutic phlebotomy. The major abnormality associated with IGT is decreased insulin secretory capacity. Diabetes is usually associated with obesity and concomitant insulin resistance.

Iron and glucose homeostasis: new lessons from hereditary haemochromatosis

“…In the same study, six haemochromatosis patients with diabetes had more markedly reduced AIRg, but, in addition, had decreased Si. Thus, all of the findings of Hramiak et al were consistent with those reported by McClain et al in the current issue [5]. Apparently conflicting results, however, were obtained in two earlier studies, in which non-diabetic haemochromatosis patients were found by OGTT or IVGTT to have persistent hyperinsulinaemia with normal or elevated serum glucose [8,9].…”

“…The current work by McClain et al [5] clearly shows that reduced insulin secretory responses can be an early component of impaired glucose tolerance in haemochromatosis. Their findings that insulin sensitivity may actually be increased in this setting are interesting and are supported by their animal studies.…”

“…Differences between the findings in these patients and those in the respective studies of Hramiak and McClain are thus not readily explained. Interestingly, close examination of the data presented by the McClain group (see [5] Fig. 2) reveals a marked trend toward increased AIRg and DI in haemochromatosis patients with normal glucose tolerance, though this is not associated with changes in Si.…”

“…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].…”

Mechanisms Linking Glucose Homeostasis and Iron Metabolism Toward the Onset and Progression of Type 2 Diabetes

“…Patients with HH cannot respond with increased insulin secretion because of the primary impairment of b-cells. Insulin-secretory abnormalities improve with phlebotomy in this context (63).…”