Abstract
Fanconi anemia (FA) is a rare genetic disorder characterized by congenital abnormalities, bone marrow failure, and cancer predisposition. Approximately 80% of individuals with FA exhibit metabolic abnormalities, including failure to thrive and increased diabetes risk. Current management relies on physical examinations and glucose tolerance tests, which lack dynamic metabolic assessment. We used stable isotope labeling with(13)C(6)-glucose to track nutrient metabolism in individuals with FA. Unlike controls, persons with FA showed no postprandial increase in energy expenditure, sustained hyperglycemia accompanied by elevated glycolysis, and a markedly higher ketogenic response supporting a shift toward lipid utilization. Hormonal analysis revealed secretion of pancreatic hormones and ghrelin in individuals with FA, while incretins were unaffected. These results reflect a profound alteration in substrate utilization involving glucose intolerance, insulin resistance, and β-cell dysfunction. This innovative approach provides unprecedented insights into FA pathophysiology, which will inform more targeted nutritional and therapeutic interventions for this complex disorder.