Genome-wide Association Study: Fetal Hemoglobin Phenotypes in Sickle Cell Disease

Project Summary/Abstract It is estimated that type II diabetes (T2D) affects 5-8% of adults. Also recognized is a transitional group of individuals whose glucose levels are above normal, yet not high enough to be considered diabetes. Defined as "pre-diabetes," these individuals are either have impaired fasting glucose (IFG;fasting glucose 100-125 mg/dl), impaired glucose tolerance (IGT;2-h glucose 140-199 mg/dl) or both. Two unifying features associated with pre-diabetes is a strong link to obesity and physical inactivity, the antithesis of which also positively influences IFG/IGT and obesity, representing an important standard-of-care therapy. While contemporary exercise guidelines for various diseases processes recommend exercise intensity ranges from 40-85% of maximal aerobic exercise capacity, the authors of the recently updated Physical Activity and Public Health from the American College of Sports Medicine and the American Heart Association recognize that few studies have examined the effects of exercise intensity. This same group acknowledges that, "...there is some indication that vigorous-intensity activities may have greater benefit for reducing cardiovascular disease and premature mortality than moderate-intensity physical activity..." Accumulating research shows that interval training (INT) produces greater changes in exercise capacity, mitochondrial biogenesis, skeletal muscle enzymatic markers associated with carbohydrate metabolism, aerobic metabolism and fat oxidation than AER. INT involves short exposures (15s - 2 min) of high exercise intensity (~95% VO2max) followed by a recovery period (~50% VO2max) of equal or longer duration. Several reports have shown INT to be safe and effective than traditional AER in clinical patients including those with peripheral artery disease, intermittent claudication, coronary artery disease, congestive heart failure, asthma, COPD, and the elderly (>75y). Further, the recent publication of the lay press book, The South Beach Diet Supercharged: Faster Weight Loss and Better Health for Life has brought INT into the public limelight despite the paucity of clinical studies attesting to the books purported benefits. The Insulin Sensitivity using Aerobic Interval Conditioning (ISAIC) trial will compare traditional AER to INT in sedentary, overweight/obese men and women with pre-diabetes. This study will provide information that may enhance current physical activity recommendations for individuals who are overweight/obese and have pre-diabetes. The primary outcome for ISAIC is insulin sensitivity (ISens). The secondary outcome for ISAIC is maximal cardiorespiratory fitness (VO2max/peak). Tertiary outcomes will include sub-maximal indices of cardiorespiratory fitness, anthropometry, and specific mechanistic markers associated with glycolysis, aerobic metabolism, -oxidation, and mitochondrial biogenesis inclusive of PGC-1 , GLUT4, hexokinase, citrate synthase, beta-hydroxyacyl CoA dehydrogenase, and the serine phosphorylation of insulin receptor substrate-1.