Molecular Basis of Insulin Resistance

描述(申请人提供)：2型糖尿病(T2 DM)和代谢综合征的发病率已达到流行水平。人类和啮齿动物的研究为这些疾病的遗传易感性提供了强有力的支持。GLUT4小鼠模型(G4)代表了一个“高危”个体的例子，因为雄性G4小鼠随着年龄的增长会出现胰岛素抵抗、高血压和T2 DM。尽管有遗传易感性，但很明显，其他因素在疾病传播和发病中发挥着重要作用。研究表明，早期生活中营养物质的变化增加了成年后代谢性疾病和高血压的易感性。然而，这些研究对这些过程背后的表观遗传机制提供的洞察力有限。怀孕期间食用西式高脂肪(HF)饮食也与成人的血管功能障碍、血脂异常和高血糖有关。肝脏底物利用和胰岛素敏感性的调节是维持全身葡萄糖稳态的关键，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和新陈代谢综合征等疾病中被打乱。一些具有宫内环境改变的模型显示出经常与T2 DM相关的肝脏葡萄糖和脂肪利用基因(包括PPAR1和G6Pase)的病理改变。这一建议的中心假设是，在怀孕和哺乳期间食用高脂肪(HF)糖尿病饮食会增加代谢综合征和T2 DM的易感性。我们认为，代谢综合征易感性的增加是由调节肝脏中葡萄糖和脂肪利用的基因的甲基化改变所介导的。我们预测，通过增加一个碳供体进行饮食干预将防止这些表观遗传修饰。强有力的初步数据表明，PPAR1可能在调节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(外周葡萄糖摄取半合子病变，G4)对与T2 DM和代谢综合征的发病率相关的肝脏基因表达和甲基化变化的影响。这些代谢紊乱的早期生命编程的分子机制将被揭示。建议进行更多的研究，以测试高脂肪IU子代在成年后对改变体重和新陈代谢的饮食的反应，包括高脂肪糖尿病饮食或减肥生酮饮食。这些研究的结果可能会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性疾病的增强易感性。公共卫生相关性：在工业化国家和发展中国家，2型糖尿病(T2 DM)和新陈代谢综合症都是当今社会的瘟疫。研究表明，早期生活中营养物质的变化会增加代谢性疾病的易感性。然而，这些研究对这些过程背后的潜在表观遗传机制提供的洞察力有限。这项建议试图确定代谢综合征和T2 DM的基础，使用正常小鼠和那些在遗传上“有风险”发展代谢性疾病的小鼠。这些研究的结果可能会为制定孕妇和哺乳期妇女指南提供新的信息，这些指南可能会保护后代免受这些代谢性疾病的增强易感性。

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.