Molecular Basis of Insulin Resistance

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程度。人类和啮齿动物研究为这些病理的遗传倾向提供了强有力的支持。 GLUT4 小鼠模型 (G4) 代表了“高危”个体的一个例子，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 T2DM。尽管存在遗传倾向，但显然其他因素在疾病传播和发病中也发挥着重要作用。研究表明，生命早期“计划”期间营养物质的改变会增加成年后患代谢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的了解有限。怀孕期间摄入西式高脂肪 (HF) 饮食也与成人血管功能障碍、血脂异常和高血糖有关。肝底物利用率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、周围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。几种宫内 (IU) 环境改变的模型显示出通常与 T2DM 相关的肝葡萄糖和脂质利用基因（包括 PPAR1 和 G6Pase）的病理改变。该提案的核心假设是，怀孕和哺乳期间摄入高脂肪 (HF) 糖尿病饮食会增加后代对代谢综合征和 T2DM 的易感性。我们认为，代谢综合征发生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的。我们预测通过添加一种碳供体进行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（外周葡萄糖摄取中的半合子病变，G4）对与 T2DM 和代谢综合征发病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背后的分子机制将被揭示。还提出了其他研究来测试高脂肪 IU 后代在成年期间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，从而保护后代免受这些代谢疾病的易感性增加。公共卫生相关性：2 型糖尿病 (T2DM) 和代谢综合征是工业化国家和发展中国家社会的现代瘟疫。研究表明，生命早期“计划”期间营养物质的改变会增加对代谢疾病的易感性。然而，这些研究对这些过程潜在的表观遗传机制的了解有限。该提案旨在利用正常小鼠和遗传上“有患代谢性疾病风险”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南，从而保护后代免受这些代谢疾病的易感性增加。

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.