Kinetics of Human Homocysteine Metabolism

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DESCRIPTION (provided by applicant):The goal of this proposal is to address the hypothesis that type II diabetes (DM2) patients with poor glycemic control have higher levels of basal homocysteine (Hcy) due to impaired Hcy metabolism. The level of Hcy measured in plasma is the balance between its rate of production from methionine, via transmethylation (TM), and disposal, through remethylation (RM) back to methionine or transulfuration (TS) to cystathionine. Previous research supports the notion that elevated Hcy is a strong, independent risk factor for cardiovascular disease (CVD), particularly in DM2. Thus, studies addressing the cause(s) of the elevated Hcy levels in DM2 have important implications for CVD risk management in this population. I will quantify the kinetics of Hcy metabolism in patients and controls on the General Clinical Research Center (GCRC) using isotopically labeled methionine and leucine, and analysis using gas chromatography/mass spectrometry (GC/MS). Patients and controls will be matched for age and sex, and all subjects will have normal plasma folate and B vitamin levels, as established by direct measurement. I will also address the hypothesis that improved glycemic control, achieved through insulin therapy, decreases basal Hcy levels by altering the rate of Hcy production and/or disposal in DM2 patients who initially have poor glycemic control. Stable isotope kinetics and GC/MS analysis will also be used to address this hypothesis. Level of glycemic control will be assessed by direct measurement of glycated hemoglobin (HbA,c). The career development plan includes: 1) supervised training to learn the assessment of 1-carbon metabolism using isotopically labeled substrates, 2) supervised clinical training in the Diabetes Center, Shands Medical Plaza at the University of Florida, in the diagnosis and management of DM2 patients, to culminate with my application to become a Certified Diabetes Educator, 3) formal didactic coursework (K30 Fellowship), and 4) continuing professional education (i.e., American Diabetes Association Postgraduate Course). This period of supervised research and clinical training, with guidance and support from the GCRC, the Division of Endocrinology and Metabolism, and the Department of Food Science and Human Nutrition, is vital to enhance my understanding of human metabolic regulation in both diseased and healthy states. The specific research proposed in this application will allow me to obtain novel data on the kinetics of Hcy metabolism in DM2 that will evolve into a formal R01 application during year 02 of this K01 award, to facilitate my transition to an independent, federally funded investigator. This is directly related to my long-term goal of applying laboratory techniques to GCRC-based, mechanistically oriented studies of the effects of metabolic perturbations (e.g., exercise training and pharmacotherapy) on diabetes prevention and therapy.