Molecular Basis of Insulin Resistance

胰岛素抵抗的分子基础

• 批准号: 7463147
• 负责人: MAUREEN J CHARRON
• 金额: $ 24.9万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7463147
• 关键词: Address; Adult; Adverse effects; Age; Animal Model; Blood Pressure; Blood Vessels; Body Weight; Body Weight decreased; Carbon; Cardiovascular Diseases; Consumption; Data; Developed Countries; Developing Countries; Development; Diabetes Mellitus; Diet; Dietary Intervention; Disease; Disruption; Dyslipidemias; Environment; Environmental Risk Factor; 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; Patient currently pregnant; Peripheral; Peroxisome Proliferator-Activated Receptors; Plague; Play; Predisposition; Pregnancy; Process; Public Health; Regulation; Risk; Risk Factors; Rodent; Role; Severities; Signal Transduction; Skeletal Muscle; Societies; Supplementation; Testing; Tissues; Weaning; Weight Gain; Woman; base; blood glucose regulation; cohort; day; disease transmission; fetal; glucose tolerance; glucose uptake; glucose-6-phosphatase; human study; impaired glucose tolerance; in utero; insight; insulin sensitivity; ketogenic diet; male; mouse model; novel; prevent; programs; response; vascular endothelial dysfunction

DESCRIPTION (provided by applicant): 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 PPAR1 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 PPAR1 may play a pivotal role in mediating these effects. The contribution of environmental 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. PUBLIC HEALTH RELEVANCE: 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.

描述（由申请人提供）：2型糖尿病（T2DM）和代谢综合征的发病率已达到流行病的比例。人类和啮齿动物研究为这些病理的遗传易感性提供了强有力的支持。GLUT 4小鼠模型（G4）代表了“处于风险中”个体的一个实例，因为雄性G4小鼠随着年龄的增长出现胰岛素抵抗、高血压和T2DM。尽管存在遗传易感性，但很明显，其他因素在疾病传播和发病率中起着重要作用。研究表明，生命早期“计划”中营养物质的改变增加了成年后对代谢疾病和高血压的易感性。然而，这些研究提供了有限的洞察这些过程背后的表观遗传机制。妊娠期间食用西式高脂肪（HF）饮食也与成人的血管功能障碍、血脂异常和高血糖症有关。肝脏底物利用和胰岛素敏感性的调节对于维持全身葡萄糖稳态至关重要，因为它整合了来自肠道、外周组织和中枢神经系统的信号。这一过程在TD2M和代谢综合征等疾病中被破坏。宫内（IU）环境改变的几种模型显示肝脏葡萄糖和脂质利用（包括PPAR1和G6 β）基因的病理改变，通常与T2DM相关。该建议的中心假设是，妊娠期和哺乳期食用高脂肪（HF）致糖尿病饮食会使后代对代谢综合征和T2DM的易感性增加。我们认为代谢综合征的易感性增加是由调节肝脏葡萄糖和脂质利用的基因甲基化改变介导的。我们预测通过添加一个碳供体的饮食干预将阻止这些表观遗传修饰。强有力的初步数据表明，PPAR1可能在介导这些效应中发挥关键作用。将测量环境因素（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和代谢综合征发生率相关的肝脏基因表达和甲基化改变的贡献。这些代谢紊乱的早期生命编程的分子机制将被揭示。建议进行其他研究，以测试高脂肪IU后代对改变体重和代谢的饮食的反应，包括成年期的高脂肪致糖尿病饮食或减肥生酮饮食。这些研究的结果可能为制定孕妇和哺乳期妇女的饮食指南提供新的信息，这些指南可能会保护后代免受这些代谢疾病的易感性增强。公共卫生关系：2型糖尿病（T2DM）和代谢综合征是工业化国家和发展中国家的现代社会瘟疫。研究表明，在生命早期的“计划”中，营养物质的改变增加了对代谢疾病的易感性。然而，这些研究提供了有限的洞察这些过程的潜在表观遗传机制。该提案旨在使用正常小鼠和具有发生代谢性疾病遗传“风险”的小鼠来定义代谢综合征和T2DM编程的分子基础。这些研究的结果可能会产生新的信息，为孕妇和哺乳期妇女制定指导方针，保护后代免受这些代谢性疾病的易感性增强。