STUDIES IN HEREDITARY HEMOCHROMATOSIS

遗传性血色病的研究

• 批准号: 7376469
• 负责人: JAMES P KUSHNER
• 金额: $ 23.04万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7376469
• 关键词: genes; glucose tolerance test; human; insulin; insulin sensitivity /resistance; iron poisoning; liver; pancreatic islet function

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.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。遗传性血色病是一种常染色体隐性遗传病，是北方欧洲血统的高加索人中最常见的遗传性疾病之一。当完全渗透时，由于铁过载，疾病引起器官损伤，但渗透通常是不完全的。我们小组最近的一项研究表明修饰基因影响血色病的表型表达（New Eng J Med 2000，343：1529-35）。我们计划通过对犹他州血色病家系的系谱分析来定位和鉴定修饰基因。作为NIH资助的一项独立但相关的研究（NIH-RO 1-DK 062106）的一部分，正在小鼠品系中鉴定候选基因座。 糖尿病是铁超载的常见并发症。本项目的第二个目的是确定血色素沉着症相关的糖尿病是否是由于胰岛素分泌受损，胰岛素抵抗，或两者兼而有之。该项目的这一部分得到了另一项NIH资助（RO 1-DKI 59512）的支持，该资助涉及动物模型和人类受试者。人类方案利用C282 Y HFE突变纯合子的受试者，该突变导致大多数血色素沉着症病例。一旦通过正常的口服葡萄糖耐量试验排除了糖尿病的存在，受试者就进行频繁取样的静脉内葡萄糖耐量试验以确定胰腺胰岛素分泌。然后使用高胰岛素血正常葡萄糖钳夹技术测定胰岛素敏感性。然后将胰岛素敏感性（或抗性）与通过肝活检确定的肝的显微解剖结构相关联。在人类身上的结果与在老鼠身上的结果相似。胰腺胰岛素分泌减少，因为铁超载发生，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相关，胰岛素抵抗与胰腺胰岛素产生减少相结合，导致糖尿病。