DIABETES IN HEMOCHROMATOSIS

血色病中的糖尿病

• 批准号: 7604950
• 负责人: JAMES P KUSHNER
• 金额: $ 20.59万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7604950
• 关键词: Address; Affect; Candidate Disease Gene; Cirrhosis; Computer Retrieval of Information on Scientific Projects Database; Data; Defect; Diabetes Mellitus; Disease; Funding; Gene-Modified; Genetic; Genotype; Glucose Intolerance; Grant; Haplotypes; Hemochromatosis; Hepatic; Hereditary hemochromatosis; Homozygote; Institution; Insulin Resistance; Intestines; Iron; Iron Overload; Joints; Liver Fibrosis; Mediating; Metacarpal bone; Morbidity - disease rate; Mouse Strains; Mus; Patients; Pattern; Phenotype; Prevalence; Relative (related person); Research; Research Personnel; Resources; Siblings; Source; Transaminases; United States National Institutes of Health; absorption; acquired hemochromatosis; genetic pedigree; glucose production; insulin secretion

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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 这项研究有两个具体目标： 目标 1. 识别改变遗传性血色素沉着症铁负荷表型的基因。目标 2. 确定影响血色素沉着病患者的葡萄糖耐受不良和临床明显糖尿病的机制。对于目标 1，我们将利用新的和先前确定的谱系来定义已通过表型或基因型鉴定患有血色素沉着病的亲属（主要是兄弟姐妹对）中因铁超载引起的并发症的模式。这些数据将与从特殊小鼠品系获得的数据结合使用，以确定改变血色素沉着症表型表达的候选基因。简而言之，小鼠遗传学将用于识别被认为影响肠道铁吸收的候选基因和染色体区域。将比较与疾病相关发病率一致的血色素沉着病纯合子同胞集，以确定它们是否在小鼠中鉴定的同线候选区域中共享单倍型。铁超载引起的并发症将在临床上定义为：肝硬化、肝纤维化、在除铁超载之外没有任何可识别原因的情况下转氨酶值升高，并经放射学证实 掌指关节血色素沉着性关节病。在目标 2 中，我们将利用新获得的血色素沉着病谱系来确定葡萄糖耐受不良、胰岛素分泌受损和临床明显糖尿病的患病率。我们将确定胰岛素分泌缺陷是否与铁超载相关。然后，我们将确定是否仅当胰岛素抵抗叠加铁介导的胰岛素分泌缺陷时才会发生糖尿病。最后，我们将确定肝葡萄糖生成对血色素沉着症糖尿病的贡献。