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.
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