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Molecular Basis of Insulin Resistance

胰岛素抵抗的分子基础

基本信息

批准号：
7991947
负责人：
MAUREEN J CHARRON
金额：
$ 6.88万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-12-03 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7991947
关键词：
Address Adult Adverse effects Age Animal Model Blood Pressure Blood Vessels Body Weight Body Weight decreased Carbon Cardiovascular Diseases Consumption Data Developing Countries Development Diet Dietary Intervention Disease Dyslipidemias Environment Epidemic Epigenetic Process Exposure to Fat-Restricted Diet Fatty acid glycerol esters Fetal Growth Retardation Follow-Up Studies Functional disorder GLUT4 gene Gene Expression Genes Genetic Genetic Predisposition to Disease Glucose Guidelines Health Hepatic Homeostasis Human Hyperglycemia Hypertension Incidence Individual Insulin Insulin Resistance Lactation Lesion Life Link Lipids Liver Low Birth Weight Infant Maintenance Malnutrition Measures Mediating Metabolic Metabolic Diseases Metabolic syndrome Metabolism Methylation Modeling Modification Molecular Mothers Mus Neuraxis Non-Insulin-Dependent Diabetes Mellitus Nutrient Obesity Organ Pathologic Pathology Peripheral Peroxisome Proliferator-Activated Receptors Plague Play Predisposition Pregnancy Process Regulation Risk Risk Factors Rodent Role Severities Signal Transduction Skeletal Muscle Societies Supplementation Testing Tissues Weaning Weight Gain Woman base blood glucose regulation cohort disease transmission fetal glucose tolerance glucose uptake glucose-6-phosphatase impaired glucose tolerance in utero insight insulin sensitivity ketogenic diet male mouse model novel offspring pregnant prevent programs response vascular endothelial dysfunction

项目摘要

The incidence of Type 2 diabetes mellitus (T2DM) and the Metabolic Syndrome has reached epidemic proportions. Human and rodent studies provide strong support for a genetic predisposition to these pathologies. The GLUT4+/- mouse model (G4+/-) represents an example of an `At Risk' individual as male G4+/- mice develop insulin resistance, hypertension and T2DM with age. Despite genetic predisposition, it is clear that other factors play an important role in disease transmission and incidence. Studies have shown that alterations in nutrients during early life `program' increased susceptibility to metabolic disease and hypertension in adult life. However, these studies provide limited insight into the epigenetic mechanisms underlying these processes. Consumption of a western style, high fat (HF) diet during pregnancy has also been linked to vascular dysfunction, dyslipidemia and hyperglycemia in adults. Modulation of hepatic substrate utilization and insulin sensitivity is crucial for maintenance of whole body glucose homeostasis as it integrates signals from the gut, peripheral tissue and central nervous system. This process is disrupted in diseases such as TD2M and the Metabolic Syndrome. Several models with alterations in the intrauterine (IU) milieu display pathologic alterations in genes of hepatic glucose and lipid utilization (including PPAR? and G6Pase) often associated with T2DM. The central hypothesis of this proposal is that consumption of a high fat (HF) diabetogenic diet during pregnancy and lactation `programs' offspring for increased susceptibility to Metabolic Syndrome and T2DM. We propose that increased susceptibility to the development of Metabolic Syndrome is mediated by altered methylation of genes that regulate glucose and lipid utilization in liver. We predict dietary intervention by adding one carbon donors will prevent these epigenetic modifications. Strong preliminary data suggests PPAR? may play a pivotal role in mediating these effects. The contribution of enviromental factors (IU diet) and offspring genetics (hemizygous lesion in peripheral glucose uptake, G4+/-) to alterations in hepatic gene expression and methylation related to the incidence of T2DM and Metabolic Syndrome will be measured. Molecular mechanisms underlying the early life programming of these metabolic derangements will be revealed. Additional studies are proposed to test the response of high fat IU offspring to diets that alter body weight and metabolism including a high fat diabetogenic diet or a weight loss ketogenic diet during their adult life. Results of these studies may yield new information for setting dietary guidelines for pregnant and lactating women that may protect offspring from enhanced susceptibility to these metabolic diseases. Type 2 diabetes mellitus (T2DM) and the Metabolic Syndrome are modern day plagues of societies in industrialized and developing nations alike. Studies have shown that alterations in nutrients during early life `program' increased susceptibility to metabolic disease. However, these studies provide limited insight into the potential epigenetic mechanisms underlying these processes. This proposal seeks to define the molecular basis underlying the programming of Metabolic Syndrome and T2DM using normal mice and ones genetically `at risk' for developing metabolic diseases. Results of these studies may yield new information for setting guidelines for pregnant and lactating women that may protect offspring from enhanced susceptibility to these metabolic diseases.

2 型糖尿病 (T2DM) 和代谢综合征的发病率已达到流行趋势比例。人类和啮齿动物研究为这些疾病的遗传倾向提供了强有力的支持病理学。 GLUT4+/- 小鼠模型 (G4+/-) 代表“处于危险中”的男性个体的一个例子 G4+/- 小鼠随着年龄的增长会出现胰岛素抵抗、高血压和 T2DM。尽管有遗传倾向，但明确其他因素在疾病传播和发病中发挥着重要作用。研究表明生命早期“计划”期间营养物质的改变增加了对代谢疾病的易感性成人生活中的高血压。然而，这些研究对表观遗传机制的了解有限。这些过程的基础。怀孕期间食用西式高脂肪 (HF) 饮食也会导致与成人血管功能障碍、血脂异常和高血糖有关。肝底物的调节利用率和胰岛素敏感性对于维持全身葡萄糖稳态至关重要，因为它整合来自肠道、周围组织和中枢神经系统的信号。这个过程在疾病中被破坏，例如如 TD2M 和代谢综合症。几种具有宫内 (IU) 环境显示变化的模型肝脏葡萄糖和脂质利用基因（包括 PPAR? 和 G6Pase）经常发生病理改变与 T2DM 相关。该提案的中心假设是摄入高脂肪（HF）怀孕和哺乳期间的糖尿病饮食会增加后代对代谢的易感性综合征和 T2DM。我们认为，代谢综合症的易感性增加是由调节肝脏中葡萄糖和脂质利用的基因甲基化改变介导。我们预测饮食通过添加一个碳供体进行干预将阻止这些表观遗传修饰。强有力的初步数据建议PPAR？可能在调节这些影响中发挥关键作用。环境因素的贡献（IU 饮食）和后代遗传学（外周葡萄糖摄取的半合子病变，G4+/-）对与 T2DM 和代谢综合征发病相关的肝脏基因表达和甲基化将测量。这些代谢紊乱的早期生命编程背后的分子机制将被揭露。建议进行更多研究来测试高脂肪 IU 后代对改变身体的饮食的反应体重和新陈代谢，包括成年期间的高脂肪糖尿病饮食或减肥生酮饮食生活。这些研究的结果可能会为制定孕妇和哺乳期饮食指南提供新信息女性可能会保护后代免受这些代谢疾病的易感性增加。 2 型糖尿病 (T2DM) 和代谢综合征是现代社会的瘟疫工业化国家和发展中国家都一样。研究表明，生命早期营养物质的变化 “程序”增加了对代谢疾病的易感性。然而，这些研究对这一问题的了解有限这些过程背后的潜在表观遗传机制。该提案旨在定义分子使用正常小鼠和遗传小鼠进行代谢综合征和 T2DM 编程的基础处于患代谢疾病的“风险”中。这些研究的结果可能会为设置提供新的信息针对孕妇和哺乳期妇女的指南，可保护后代免受这些疾病的易感性增加代谢性疾病。