WHAT ARE THE UNIQUE BENEFITS OF PIOGLITAZONE COMPARED TO WEIGHT LOSS

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 假设： 1. 在热量过量/肥胖的情况下脂肪细胞分化的缺陷是导致在超重/肥胖个体中观察到的胰岛素介导的葡萄糖摄取（IMGU）的可变性的原因。 2. 肥胖个体的胰岛素抵抗（IR）亚组将表现出脂肪细胞分化/终末功能的异常，其通过靶向脂肪组织的干预与胰岛素增敏相关，但这些变化在胰岛素敏感性对照中不会观察到，这些对照在相同干预下胰岛素敏感性没有变化。 IR存在于25-50%的美国成年人中，使糖尿病的风险增加24倍，心血管疾病（CVD）的风险增加4倍。IR高患病率的一个主要原因是美国成年人中肥胖症的增加。虽然体重与IR呈正相关，但肥胖与IR之间的生理机制尚不清楚。例如，并非所有肥胖个体都是IR，也并非所有瘦个体都是胰岛素敏感的（IS）。 实验设计： 首次访视（筛选）将根据年龄、身高、体重和病史确定患者是否有资格参加研究。参与者将有身高，体重测量和血压和心率采取和实验室测试，以检查血糖水平和红细胞压积（检查贫血）。 第二次访视将是胰岛素敏感性试验。该测试将确定患者是否有资格参与本研究。此时，将测量脂质水平以及肝脏和肾脏功能。IR或IS患者将有资格参加研究。研究结束时，将对合格受试者重复进行该试验。 对于那些符合条件的人，将在另一天完成8小时的膳食档案。禁食过夜（12-14小时）后，将在一只手臂上放置静脉导管进行抽血。在抽取空腹样本后，患者将接受标准化早餐，四小时后午餐。胰岛素、葡萄糖、游离脂肪酸（FFA）和脂蛋白等与IR相关的血液将每小时抽血一次，持续8小时。在进餐时将进行单独的血脂检查。研究结束时将重复该试验。 对于符合条件的患者，将在研究开始和结束时进行脂肪细胞活检。局部麻醉诱导后，用手术刀在脐周区域切开1 cm切口，切除约1-2 g浅表皮下脂肪组织。 对于符合条件的受试者，将在研究之前和研究结束时进行腹部脐部水平的单一图片、横断面CT扫描，以量化干预前后皮下（SC）与内脏脂肪分布。 如果在本研究进行时设备可用，则可在研究前后进行肱动脉血管舒张试验。这是一种使用超声探头对肱动脉进行成像的无创检查。 一旦完成所有基线研究，研究受试者将随机接受减肥计划或开始接受吡格列酮治疗。如果开始接受吡格列酮治疗，起始剂量将为每日30 mg，持续1个月，然后在研究的剩余时间内（再持续2个月），剂量将增加至每日45 mg。一旦开始干预，受试者将每两周一次，持续3个月，或根据需要更频繁地前往GCRC，测量体重和血压，并由Reaven博士的一位同事进行检查。如果他们在减肥干预，他们也将与研究营养师会面。将每月进行一次测量肝功能（ALT）的实验室检查。

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. 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 (IS). 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 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.