GLUCOSE AND INSULIN ABNORMALITIES IN FANCONI ANEMIA

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。先前的研究已经证实范可尼贫血（FA）和糖尿病（DM）之间存在关联。Swift等人（Science 1972）报道了FA患儿亲属中糖尿病患病率的增加。最近，Wajnrajch等人（儿科2001）报道了25%的FA患者口服葡萄糖耐量试验（OGTT）异常，72%的患者表现出胰岛素抵抗；然而，患者没有根据bmt前后或雄激素治疗进行分层。雄激素、BMT和应激可与OGTT异常有关。作者还将这些异常与补体组联系起来，发现补体组FA-G有胰岛素抵抗的趋势。然而，FA-C的突变位于编码一种被认为与2型糖尿病相关的蛋白质的区域，而不是FA-G （Rothschild et al, Genomics 1995）。因此，我们计划在OGTT的基础上，通过胰岛素修饰频繁取样静脉葡萄糖耐量试验（FSIGT）进一步明确FA中胰岛素和葡萄糖异常，提供胰岛素分泌和敏感性的病理生理信息。我们也将能够确定雄激素和互补组对胰岛素和葡萄糖异常的贡献。这些结果将使我们能够更好地预测FA患者是否会发展为糖尿病。随着越来越多的FA患儿进入成年期，这一认识变得越来越重要。如果发现与补体群相关，我们就可以假设，杂合的父母和可能的兄弟姐妹患糖尿病的风险也会增加。

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. Previous studies have demonstrated an association between Fanconi anemia (FA) and diabetes mellitus (DM). Swift et al (Science 1972) reported an increased prevalence of diabetes in relatives of children with FA. More recently, Wajnrajch et al (Pediatrics 2001) reported abnormalities in oral glucose tolerance testing (OGTT) in 25% of patients with FA with 72% of patients manifesting resistance to insulin action; however, the patients were not stratified based on pre- or post-BMT or androgen therapy. Androgens, BMT and stress can be associated with abnormalities in OGTT. The authors also correlated these abnormalities with complementation group and found a trend toward insulin resistance in the complementation group FA-G. However, it is the mutation for FA-C that lies in the region encoding a protein thought to be associated with type 2 DM, not FA-G (Rothschild et al, Genomics 1995). Therefore, we plan to further define the insulin and glucose abnormalities in FA through insulin-modified frequently sampled iv glucose tolerance test (FSIGT) in addition to OGTT to provide pathophysiologic information about insulin secretion and sensitivity. We will also be able to determine the contribution of androgens and complementation groups to the insulin and glucose abnormalities. These results will enable us to better predict the FA patients who will develop diabetes. This knowledge has become important now that many more children with FA are living into adulthood. If an association with a complentation group is found, we could then hypothesize that the heterozygous parents and possibly siblings would be at increased risk for DM as well.