STUDIES IN HEREDITARY HEMOCHROMATOSIS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。遗传性血色素沉着症是一种常染色体隐性遗传性状，是北欧高加索人后裔中最常见的遗传性疾病之一。当完全渗透时，由于铁超载，疾病引起器官损伤，但渗透通常不完全。我们小组最近的一项研究表明，修饰基因影响血色素沉着症的表型表达（New Eng J Med 2000, 343:1529-35）。我们计划通过对犹他州血色素沉着症家族的系谱分析来绘制和鉴定修饰基因。候选基因座正在小鼠品系中进行鉴定，这是一项独立但相关的NIH资助研究（NIH- ro1 - dk062106）的一部分。糖尿病是铁超载的常见并发症。该项目的第二个目标是确定与血色素沉着症相关的糖尿病是由于胰岛素分泌受损，胰岛素抵抗，还是两者兼而有之。该项目的这一部分由另一项NIH拨款（RO1-DKI59512）支持，该拨款涉及动物模型和人类受试者。人类方案使用了C282Y HFE突变纯合的受试者，该突变导致大多数血色素沉着症。一旦通过正常的口服葡萄糖耐量试验排除糖尿病的存在，受试者进行频繁取样的静脉葡萄糖耐量试验以确定胰腺胰岛素分泌。然后使用高胰岛素正糖钳技术测定胰岛素敏感性。胰岛素敏感性（或抵抗）与肝脏显微解剖相关联，由肝活检确定。在人类身上的结果与在老鼠身上的结果相似。当铁超载发生时，胰腺胰岛素分泌减少，但这不足以引起糖尿病。当肝脏组织学正常时，胰岛素敏感性似乎增强。肝纤维化或肝硬化的存在与胰岛素抵抗有关，再加上胰腺胰岛素分泌减少，导致糖尿病。

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.