WHAT ARE THE UNIQUE BENEFITS OF PIOGLITAZONE COMPARED TO WEIGHT LOSS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 假设： 1.在超重/肥胖人群中观察到的胰岛素介导的葡萄糖摄取(IMGU)的变化与卡路里过量/肥胖状态下脂肪细胞分化的缺陷有关。 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，这种异常与针对脂肪组织的胰岛素敏化相关，但在胰岛素敏感型对照组中不会看到这些变化，他们在相同的干预措施下胰岛素敏感性没有变化。 IR存在于25%-50%的美国成年人中，它会使患糖尿病的风险增加24倍，使心血管疾病(CVD)的风险增加4倍。胰岛素抵抗患病率高的一个主要原因是美国成年人中肥胖的增加。虽然体重与胰岛素抵抗呈正相关，但肥胖症与胰岛素抵抗之间的生理机制尚不清楚。例如，并不是所有肥胖的人都是胰岛素抵抗，也不是所有的瘦人都对胰岛素敏感(IS)。 实验设计： 第一次就诊(筛查)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。参与者将测量身高、体重、血压和心率，并进行实验室测试以检查血糖水平和红细胞压积(以检查贫血)。 第二次检查将是胰岛素敏感性测试。这项测试将决定患者是否有资格参与这项研究。此时将测量血脂水平以及肝肾功能。那些是IR或IS的人将有资格参加这项研究。这项测试将在研究结束时对符合条件的参与者重复进行。 对于那些符合条件的人，8小时的用餐概况将在另一天完成。在隔夜禁食(12-14小时)后，将静脉导管放置在一只手臂上进行抽血。在抽取禁食样本后，患者将得到一份标准早餐，四个小时后的午餐。胰岛素、葡萄糖、游离脂肪酸(FFA)和脂蛋白等与IR相关的指标将每小时抽血一次，持续8小时。在进餐时，将对血脂进行单独的血液测试。这项测试将在研究结束时重复进行。 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，用手术刀在脐周切开1厘米长的切口，切除约1-2g的皮下浅脂肪组织。 对于符合条件的患者，将在研究前和研究结束时进行脐部水平的腹部单一图像横断面CT扫描，以量化干预前后皮下(SC)和内脏脂肪的分布。 如果我们在研究期间有可用的设备，可以在研究之前和之后进行臂动脉扩张试验。这是一种使用超声探头对臂动脉成像的非侵入性测试。 一旦所有基线研究完成，研究参与者将被随机接受减肥计划或开始服用吡格列酮。如果开始服用吡格列酮，开始剂量将是每天30毫克，持续一个月，然后在研究的剩余时间(再过两个月)，剂量将增加到每天45毫克。一旦开始干预，参与者将在三个月内每两周来GCRC一次，如果需要，也可以更频繁地来GCRC测量他们的体重和血压，并由Reaven博士的一名同事检查。如果他们正在进行减肥干预，他们还将与研究营养师会面。实验室检测肝功能(ALT)将每月进行一次。

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.