EFFECTS OF INSULIN SENSITIZERS ON GLUCOSE AND FAT METABOLISM IN SUBJECTS WITH GE

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。发展为2型糖尿病是一种进化，是糖毒性和脂毒性共同作用于减少胰岛素分泌和胰岛素作用的恶性循环的结果。在这项研究中，我们将重点关注有妊娠期糖尿病(GDM)病史的肥胖者，他们有患糖尿病的风险。我们将检测两种不同作用模式的胰岛素增敏剂对胰岛素分泌、胰岛素作用、肝脏葡萄糖生成和肌肉脂肪代谢的影响。我们认为，噻唑烷二酮类化合物可以通过逆转脂肪毒性来改善细胞功能，这一点反映在肌肉脂肪堆积减少。我们的假设和具体目的如下：1)在有妊娠期糖尿病病史且有糖尿病风险的受试者中，噻唑烷二酮类药物能改善细胞功能，但不能改善细胞功能。将通过测量IGT受试者对葡萄糖和非葡萄糖促分泌剂的急性胰岛素反应的变化来评估细胞功能，并将其与吡格列酮治疗的反应进行比较。2)在有妊娠期糖尿病病史的受试者中，噻唑烷二酮类化合物，而不是双胍类化合物，可以减少脂肪在非脂肪组织中的积聚，包括肌肉、胰腺、肝脏和心肌。肌肉脂肪含量将作为脂肪毒性和脂肪在非脂肪组织中过度蓄积的替代指标。从肌肉活检标本中，我们将测量吡格列酮与二甲双胍治疗前后心肌细胞内甘油三酯的含量。这项研究考察了两种广泛使用的胰岛素增敏药物吡格列酮和二甲双胍的作用机制和潜在的益处。如果一种药物被证明在治疗患者方面比另一种具有优势，那么最终将会节省成本，要么选择价格较低的药物，要么使用可以延缓疾病进展并改善患者护理的药物。此外，这项研究将提供机制信息，有助于指导糖尿病预防药物的选择。这将是一项试验性研究，涉及20名在过去3年中患有妊娠期糖尿病的受试者。体重指数在28到38之间，年龄超过18岁/o的受试者将接受二甲双胍或吡格列酮治疗10周。排除标准将是使用药物或护理的禁忌症。将测量肝脏葡萄糖产生、胰岛素分泌和对二甲双胍或罗格列酮治疗的敏感性。这两种胰岛素增敏剂对身体成分的影响将通过DXA进行评估，对皮下和内脏脂肪分布的影响将通过腹部CT扫描进行评估。肌肉脂肪含量将通过大腿CT扫描和肌肉活检标本中肌细胞内甘油三酯的显微镜测量来评估不同治疗方法的反应。肌肉和脂肪活组织检查都将在治疗后进行。标本也将被储存起来，以供我们未来的研究。我们的长期目标是收集初步数据以扩大研究范围。考虑到一年内完成这项研究的可行性，我们无法在此期间探讨吡格列酮或二甲双胍对脂肪和肌肉中基因表达的调控。本实验将为我们利用基因芯片或RT-PCR技术研究人类脂肪组织和肌肉中基因表达的变化模式提供一个机会。我们将能够确定脂肪和肌肉中基因表达变化的模式是否为吡格列酮治疗所特有，或者也将在二甲双胍治疗的受试者中发现。这项研究可能导致识别与脂肪组织肌肉对胰岛素反应有关的新基因。

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. The progression to type 2 diabetes represents an evolution, resulting from a vicious cycle where both glucotoxicity and lipotoxicity act to reduce insulin secretion and insulin action. In this study, we will focus on obese subjects with history of gestational diabetes (GDM) who are at risk of developing diabetes. We will examine insulin secretion, insulin action, hepatic glucose production, and muscle lipid metabolism in response to two insulin sensitizers with two different modes of action. We propose that thiazolidinediones will improve cell function by reversing lipotoxicity as reflected by reduced muscle lipid accumulation. Our hypotheses and specific aims are the followings: 1) In subjects with history of gestational DM who are at risk of developing diabetes, thiazolidinediones, but not biguanides, improve ¿ cell function. ¿ cell function will be evaluated by measuring changes in acute insulin response to glucose and non-glucose secretagogues in subjects with IGT and it will be compared in response to treatment with pioglitazone versus metformin. 2) In subjects with history of gestational DM, thiazolidinediones, but not biguanides, decrease the accumulation of fat in non-adipose tissues including muscle, pancreas, liver and myocardium. The muscle fat content will be evaluated as the surrogate measure for lipotoxicity and overaccumulation of fat in non-adipose tissue. From the muscle biopsy specimens, we will measure the amount of intramyocellular triglyceride before and after treatment with pioglitazone versus metformin. This study examines the mechanisms of effects and the potential benefits of two widely used insulin sensitizing drugs, pioglitazone and metformin. If one drug were shown to have an advantage over the other in the care of patients, then there would eventually be a cost saving, either by choosing the less expensive drug, or by using the drug that delays the progression of the disease, and improves the care of the patient. In addition, this study will provide mechanistic information that will help guide the choice of drug for prevention of diabetes. This will be a pilot study involving 20 subjects who had gestational diabetes in the previous 3 years. Subjects with body mass index range between 28 and 38, and age older than 18 y/o will be treated with either metformin or pioglitazone for ten weeks. Exclusion criteria will be a contraindication to the use of either medication or nursing. Hepatic glucose production, insulin secretion and sensitivity will be measured in response to either metformin or rosiglitazone treatment. Effects of these two insulin sensitizers on body composition will be assessed using DXA and on distribution of subcutaneous and visceral fat will be evaluated by CT scan of abdomen. Muscle fat content will be evaluated in response to different treatments using CT scanning of thigh and microscopic measurement of intramyocellular triglyceride from muscle biopsy specimens. Both muscle and fat biopsies will be performed in response to treatment. The specimens will be also stored for our future studies. Our long-term goal is to gather preliminary data to expand the study. Considering the feasibility of completing the study within one year, we would not be able to explore the modulation of the gene expression in fat and muscle by pioglitazone or metformin during this time. This experiment will give us an opportunity to study the pattern of altered gene expression in human adipose tissue and muscle by using microarray or RT-PCR for specific genes. We will be able to determine whether the pattern of altered gene expression in the fat and muscle is specific to pioglitazone therapy or will also be found in the subjects treated with metformin. This study may result in the identification of novel genes involved in the adipose tissue muscle response to insulin