STUDIES IN HEREDITARY HEMOCHROMATOSIS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Hereditary hemochromatosis is transmitted as an autosomal recessive trait and is among the most common inherited diseases in Caucasians of Northern European descent. When fully penetrant, the disease causes organ damage due to iron overload but penetrance is often incomplete. A recent study by our group suggests that modifier genes influence phenotypic expression of hemochromatosis (New Eng J Med 2000, 343:1529-35). We plan to map and then identify modifier genes through pedigree analyses of Utah families with hemochromatosis. Candidate loci are being identified in mouse strains as part of a separate but related NIH funded study (NIH-RO1-DK062106). Diabetes is a common complication of iron overload. A second objective of this project is to determine if the diabetes associated with hemochromatosis is due to impaired insulin secretion, to insulin resistance, or to both. This portion of the project is supported by another NIH grant (RO1-DKI59512) which addresses both animal models and human subjects. The human protocol utilizes subjects homozygous for the C282Y HFE mutation causitive for most cases of hemochromatosis. Once the presence of diabetes has been excluded by a normal oral glucose tolerance test, subjects undergo a frequently sampled intravenous glucose tolerance test to determine pancreatic insuin secretion. Insulin sensitivity is then determined using the hyperinsulinemic euglycemic glucose clamp technique. Insulin sensitivity (or resistance) is then correlated with the microanatomy of the liver as determined by liver biopsy. The results in humans have paralled the results in mice. Pancreatic insulin secretion diminishes as iron overload occurs but this insufficient to cause diabetes. When liver histology is normal, insulin sensitivity appears to be enhanced. The presence of hepatic fibrosis or cirrhosis is associated with insulin resistance which, coupled with diminished pancreatic insulin production, leads to diabetes.