This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Hypotheses: 1. A defect in adipocyte differentiation in the setting of caloric excess/obesity is responsible for the variability in insulin-mediated glucose uptake (IMGU) observed in overweight/obese individuals. 2. The insulin-resistant (IR) subgroup of obese individuals will demonstrate abnormalities in adipocyte differentiation/terminal function that improve in association with insulin sensitization via interventions targeting adipose tissue, but these changes will not be seen in insulin-sensitive controls who experience no change in insulin sensitivity with the same interventions. Goals: IR, present in 25-50% of US adults, increases the risk for diabetes mellitus by up to 24-fold, and cardiovascular disease (CVD) by up to 4-fold. A major contributor to the high prevalence of IR is increasing obesity among US adults. While body mass is positively correlated with IR, the physiologic mechanism linking adiposity to IR is not understood. For example, not all obese individuals are IR, nor are all lean individuals insulin-sensitive. Experimental Design: The first visit (screening) will be to determine if a patient qualifies for the study based on age, height, weight, and medical history. Participants will have height, weight measured and blood pressure and heart rate taken and a lab test to check glucose level and hematocrit (to check for anemia). The second visit will be the insulin sensitivity test. This test will determine if a patient qualifies to participate in this study. At this time lipid levels as well as liver and kidney function will be measured. Those who are IR or insulin sensitive (IS) will qualify for the study. This test will be repeated at the end of the study for the qualifying participants. For those who qualify, an eight-hour meal profile will be done on another day. After an overnight fast (12-14 hrs) an IV catheter will be placed in one arm for blood draws. After the fasting sample is drawn the patient will receive a standardized breakfast and four hours later lunch. Blood draws will be once/hr for 8 hrs for insulin, glucose, free fatty acid (FFA), and lipoproteins among other things related to IR. A separate blood test for a lipid profile will be done at the time of the meal profile. This test will be repeated at the end of the study. For those who qualify, a fat cell biopsy will be done at the beginning and end of the study. After the induction of local anesthesia, a 1-cm incision will be made with a scalpel in the peri-umbilical region, and approximately 1-2 g of superficial subcutaneous adipose tissue will be removed. For those who qualify, a single picture, cross-sectional CT scan of the abdomen at the level of the umbilicus, will be done before and at the end of the study to quantify subcutaneous (SC) versus visceral distribution of fat before and after intervention. Brachial Artery Vasodilation test may be done before and after the study if equipment is available to us at the time of this study. This is a noninvasive test using an ultrasound probe used to image the brachial artery. Once all baseline studies are complete the study participant will be randomized to receive either a weight-loss program or started on Pioglitazone. If started on Pioglitazone the starting dose will be 30 mg daily for one month and then the dose will be increased to 45 mg daily for the remainder of the study (2 more months) Once intervention is started the participant will come in to the GCRC every two weeks for three months, or more frequently if needed, to have their weight and blood pressure measured, and be seen by one of Dr. Reaven's associates. If they are in the weight loss intervention they will also meet with the research dietitian. A lab test to measure liver function (ALT) will be done once per month.
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