DIABETES IN 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. This study addresses two specific aims: Aim 1. Identify genes that modify the iron-loading phenotype of hereditary hemochromatosis. Aim 2. Determine the mechanism(s) responsible for the glucose intolerance and clinically evident diabetes that affect patients with hemochromatosis.For Aim 1 we will utilize both new and previously ascertained pedigrees to define patterns of concordance for morbid complications due to iron overload among relatives (mainly sibling pairs) who have been identified either by phenotype or genotype to have hemochromatosis. These data will be used in conjunction with data obtained from specialized mouse strains to identify gene candidates which modify the phenotypic expression of hemochromatosis. Briefly, mouse genetics will be used to identify candidate genes and chromosomal regions believed to influence intestinal iron absorption. Hemochromatosis homozygote sibling sets concordant for disease related morbidity will be compared to determine if they share haplotypes in syntenic candidate regions identified in the mouse.Morbid complications due to iron overload will be defined clinically as: cirrhosis, hepatic fibrosis, elevated aminotransferase values in the absence of any identifiable cause other than iron overload, and radiographically confirmed hemochromatosis arthropathy of the metacarpal-phalangeal joints. In Aim 2 we will utilize newly acquired hemochromatosis pedigrees to determine the prevalence of glucose intolerance, impaired insulin secretion and clinically evident diabetes. We will determine if a defect in insulin secretion correlates with iron overload. We will then determine if diabetes occurs only when insulin resistance is superimposed on an iron-mediated defect in insulin secretion. Finally, we will determine the contribution of hepatic glucose production to the diabetes of hemochromatosis.