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

胰岛素增敏剂对 GE 受试者葡萄糖和脂肪代谢的影响

• 批准号: 7377676
• 负责人: Neda Rasouli
• 金额: $ 0.6万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7377676
• 关键词: EFFECTS; INSULIN; SENSITIZERS; GLUCOSE; FAT

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

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。2型糖尿病的进展是一种进化，是糖毒性和脂肪毒性作用减少胰岛素分泌和胰岛素作用的恶性循环的结果。在本研究中，我们将重点关注有妊娠糖尿病（GDM）病史的肥胖受试者，他们有发展为糖尿病的风险。我们将研究胰岛素分泌、胰岛素作用、肝脏葡萄糖生成和肌肉脂质代谢对两种不同作用模式的胰岛素增敏剂的反应。我们提出噻唑烷二酮可以通过逆转脂肪毒性来改善细胞功能，这反映在减少肌肉脂质积累上。我们的假设和具体目的如下：1)在有妊娠DM病史且有发生糖尿病风险的受试者中，噻唑烷二酮类药物而非双胍类药物能改善细胞功能。通过测量IGT患者对葡萄糖和非葡萄糖分泌剂的急性胰岛素反应的变化来评估细胞功能，并将其与吡格列酮和二甲双胍治疗的反应进行比较。2)在有妊娠DM病史的受试者中，噻唑烷二酮类药物（而非双胍类药物）可减少非脂肪组织（包括肌肉、胰腺、肝脏和心肌）的脂肪积累。肌肉脂肪含量将被评估为脂肪毒性和非脂肪组织中脂肪过度积累的替代措施。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。本研究探讨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益处。如果一种药物被证明在治疗病人方面比另一种药物有优势，那么最终会节省成本，要么选择更便宜的药物，要么使用延迟疾病进展的药物，改善病人的治疗。此外，本研究将提供机制信息，有助于指导糖尿病预防药物的选择。这将是一项试点研究，涉及20名在过去3年内患有妊娠糖尿病的受试者。体重指数在28 - 38之间，年龄大于18岁的受试者将使用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。肝葡萄糖生成、胰岛素分泌和敏感性将在二甲双胍或罗格列酮治疗后进行测量。这两种胰岛素增敏剂对身体组成的影响将通过DXA评估，对皮下和内脏脂肪分布的影响将通过腹部CT扫描评估。肌肉脂肪含量将通过大腿CT扫描和肌肉活检标本中细胞内甘油三酯的显微测量来评估不同治疗的反应。治疗后将进行肌肉和脂肪活检。这些标本也将被保存起来以供我们将来的研究。我们的长期目标是收集初步数据以扩大研究。考虑到一年内完成研究的可行性，我们无法在这段时间内探索吡格列酮或二甲双胍对脂肪和肌肉中基因表达的调节。本实验将为我们提供一个机会，通过对特定基因的微阵列或RT-PCR来研究人类脂肪组织和肌肉中基因表达的改变模式。我们将能够确定脂肪和肌肉中基因表达改变的模式是吡格列酮治疗所特有的，还是在二甲双胍治疗的受试者中也会发现。这项研究可能会导致识别新的基因参与脂肪组织肌肉对胰岛素的反应