MITOCHODRIAL DYSFUNCTION IN OBESITY AND DIABETES IN BLOOD

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Obesity is a well recognized public health problem in the U.S. and the magnitude of excess weight is greater among racial/ethnic minority populations such as Native Hawaiians (NHs) and Pacific Peoples (PPs). In Hawai'i, the overall percentage reported to be overweight or obese was 50% in 2003. Concurrent with the epidemic of overweight and obesity in the U.S., is the alarming rates of obesity-related diseases such as diabetes mellitus. NHs and Filipino (who are PPs) populations have diabetes at rates of ~8.0%. Recent evidence has shown organ specific mitochondrial (mt) energetic alterations in individuals diagnosed with Type II diabetes and/or obesity. Insulin resistance in the elderly and in children of parents with Type II diabetes has been associated with decreased ATP production in skeletal muscle. Similar decreases in ATP levels have been observed in the livers of obese individuals compared to non-obese. Additionally, subsarcolemmal muscle mt are decreased in either obese or diabetic individuals compared to lean subjects. This corresponds with decreases in mtDNA and oxidative phosphorylation enzyme activities. Furthermore, depletion of mtDNA has been noted in peripheral blood mononuclear cells (PBMCs) of healthy insulin resistant young adults. Additionally, Type II diabetes and/or obesity has been associated with increased mt oxidative stress in PBMCs and plasma. Currently, there is no minimally invasive method to study mt dysfunction in diabetes and/or obesity. We hypothesize that a mitochondrial phenotype of diabetes and/or obesity may be studied in PBMCs of individuals. We also hypothesize that a pre-diabetic phenotype may be detectable in PBMCs of insulin resistant individuals. In a longitudinal approach, we propose to study mitochondrial function in PBMCs in 100 obese NHs and PPs undergoing a 16-week weight loss intervention at baseline, immediately following the intervention (week 16) and after 1-year of follow-up. We believe that mitochondrial parameters will improve as a result of weight-loss and correspond to an improvement in the pre-diabetic phenotype. We intend to evaluate at baseline, 4 months, and 16 months PBMC mtDNA copies/cell, OXPHOS protein/enzyme activity using a novel immunological assay, and mitochondrial oxidative damage (8- oxodeoxyguanine). Phenotype characteristics will be obtained by evaluating body mass index (BMI) and metabolic parameters (fasting insulin, glucose, and cholesterol). The significance of the proposed study lies in the fact that obesity and diabetes are major public health issues particularly in minority populations. Understanding the mechanisms contributing to obesity and diabetes may provide clues to intervention and treatment to improve morbidity and mortality.