This application is being made in response to PA-09-133, Pilot and Feasibility Clinical Research Grants in Diabetes, Endocrine and Metabolic Diseases. It will be a collaborative effort among the members of the Southwest/MountainWest CTSA Consortium, the Universities of Utah (parent site), Colorado, and New Mexico. The trial is a novel application to humans of a safe adjunct treatment for type 2 diabetes and prediabetes that was developed and validated by us in animal models: Phlebotomy to reduce iron stores. It is generally assumed that overeating engenders diabetes risk principally through caloric excess. There is increasing evidence, however, that specific components of the diet may also impart risk. Excess iron, for example, has been shown in numerous epidemiologic and experimental studies to be strongly associated with diabetes risk. Our data in animal models, validated in a small human sample, suggest that iron depletion of subjects with dietary iron overload should be beneficial to diabetes risk through two independent mechanisms, conferring increased insulin secretory capacity while at the same time increasing insulin sensitivity. We will test this hypothesis by lowering iron stores in a cohort of individuals with impaired glucose tolerance and diabetes controlled on metformin and/or DPP-4 inhibitor therapy. Subjects will be recruited who are in the highest quartile of normal ferritin with no known cause for secondary elevation, and will donate blood until ferritin falls to the lowest quartile of normal. They will be assessed befoe and after for measures of insulin secretory capacity, insulin sensitivity, glucose metabolism, and markers of metabolic syndrome. It is hoped that this limited trial will provide data to guide futue trials to establish dose- responsiveness, duration, and universality for this novel adjunct therapy for prediabetes and type 2 diabetes. In addition, we hope to demonstrate the potential power of the CTSA consortium in rapidly translating the latest findings in biomedical research into useful clinical findings. PUBLIC HEALTH RELEVANCE: The proposal will test a safe, simple, and even societally beneficial treatment, blood donation, for a disease that is becoming a worldwide epidemic. While we acknowledge that diabetes is a heterogeneous disease with many contributing factors, and that the current protocol only addresses individuals with iron overload (arbitrarily defined as the top quartile, i.e. 25% of that population), epidemiologic data suggest the impact on the general population of diabetics is could be substantial.