ROLE OF ADIPOCYTES IN INSULIN RESISTANCE AND CARDIOVASULAR DISEASE

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，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超重/肥胖个体中观察到的胰岛素介导的葡萄糖摄取（IMGU）变异性的原因。2. 通过针对脂肪组织的干预，肥胖个体的胰岛素抵抗（IR）亚组会表现出脂肪细胞分化/终末功能的异常，这些异常与胰岛素致敏相关，但这些变化不会在胰岛素敏感的对照组中看到，他们在同样的干预下胰岛素敏感性没有变化。目标：IR存在于25-50%的美国成年人中，可使糖尿病的风险增加24倍，心血管疾病（CVD）的风险增加4倍。导致IR高发病率的一个主要因素是美国成年人中日益增加的肥胖。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，并不是所有的肥胖者都有胰岛素敏感性，也不是所有的瘦人都有胰岛素敏感性。实验设计：第一次访问（筛选）将根据患者的年龄、身高、体重和病史确定患者是否符合研究条件。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血细胞比容（以检查贫血）。第二次检查是胰岛素敏感性测试。该测试将决定患者是否有资格参加本研究。在这个时候，血脂水平以及肝肾功能将被测量。那些IR或胰岛素敏感（IS）的人将有资格参加这项研究。该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小时的用餐记录将在另一天完成。经过一夜禁食（12-14小时）后，将在一只手臂上放置静脉导管以便抽血。在抽取空腹样本后，患者将接受标准化的早餐和四小时后的午餐。每小时抽血一次，持续8小时，检测胰岛素、葡萄糖、游离脂肪酸（FFA）和脂蛋白等与IR相关的指标。在进行膳食分析的同时，还要进行血脂的单独血液检查。该测试将在研究结束时重复进行。对于那些符合条件的人，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厘米，切除约1-2克浅表皮下脂肪组织。对于那些符合条件的人，将在研究之前和结束时对腹部进行单幅横断面CT扫描，以量化干预前后皮下（SC）与内脏脂肪分布。肱动脉血管舒张试验可以在研究之前和之后进行，如果在研究时我们有设备的话。这是一种非侵入性检查，使用超声探头对肱动脉进行成像。一旦所有基线研究完成，研究参与者将被随机分配接受减肥计划或开始使用吡格列酮。如果开始使用吡格列酮，开始剂量为每天30毫克，持续一个月，然后在研究的剩余时间（2个月以上）增加到每天45毫克。一旦干预开始，参与者将每两周到GCRC检查一次，持续三个月，如果需要的话，可以更频繁地测量他们的体重和血压，并由Reaven博士的一位同事检查。如果他们在减肥干预中，他们还会与研究营养师会面。每月进行一次肝功能（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. 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.