Metabolic heterogeneity underlying hypertriglyceridemia in insulin resistance

项目摘要/摘要 胰岛素抵抗(IR)是2型糖尿病和血脂异常发展的核心；然而，没有 胰岛素抵抗患者的单一表型。这种表型的异质性在临床实践中表现为 代谢性疾病的不同表现和对降糖和甘油三酯的不同反应 降落剂(如贝特酸盐和鱼油)。一种精确的医学方法，其中对 利用疾病的异质性来针对单个患者的病理情况进行治疗，需要 了解这种疾病的异质性。值得注意的是，在同样肥胖的患者中，一些人在全球范围内使用胰岛素 抵抗，其他人对胰岛素敏感，一些人表现出组织特异性IR。因此，驱动机制 任何特定患者的甘油三酯产量增加可能取决于患者的组织特异性模式 胰岛素抵抗，骨骼肌胰岛素抵抗以新生脂肪生成为主， 以及在脂肪胰岛素抵抗的背景下占主导地位的预制脂肪酸的酯化。 这项建议的总体目标是建立一个机械知识库，以识别和优化治疗 对于IR的离散子群。为了实现这一目标，瓦特纳博士的目标是：1)阐明支持 肝脏胰岛素抵抗啮齿动物模型的肝脏新生脂肪生成(DNL)；2)量化离散的 脂肪和肌肉胰岛素抵抗促进肝脏甘油三酯生成的途径；以及3)评估 人类脂肪和肌肉胰岛素抵抗的差异如何影响潜在的机制 肝脏甘油三酯合成。 为了实现这些目标，对啮齿动物和人类的研究将是至关重要的。表现出不同的啮齿动物模型 胰岛素抵抗的特定组织模式将被使用，包括高脂饮食喂养的小鼠，胰岛素受体T1160A 突变小鼠，Tbc1d4p.Arg684Ter突变小鼠，MKR小鼠(骨骼肌特异性胰岛素抵抗和 IGF1)和脂肪Pde3b基因敲除小鼠。具有不同组织特异性胰岛素模式的受试者 将对抗性进行研究。将使用稳定的同位素示踪技术来评估从头开始的贡献 预制脂肪酸的脂肪生成和酯化为甘油三酯的合成。标准和尖端 分子生物学工具，包括染色质免疫沉淀、定量聚合酶链式反应、RNA-Seq和 免疫印迹将被用来描述在肝脏调节中起关键作用的分子通路。 甘油三酯生产。在这项提议中感兴趣的关键主题是临床异质性 胰岛素抵抗背景下的高甘油三酯血症：使用药物干预的研究(SGLT2 抑制、抑制脂肪分解)和运动干预将直接解决这一临床问题 异质性。

Project Summary/Abstract Insulin resistance (IR) is central to the development of type 2 diabetes and dyslipidemia; however, there is no single phenotype of the insulin resistant patient. This phenotypic heterogeneity is reflected in clinical practice as variable manifestations of metabolic disease and variable response to both glucose lowering and triglyceride lowering agents (such as fibrates and fish oil). A precision medicine approach, wherein an understanding of the heterogeneity of disease is leveraged to target therapies to an individual patient’s pathology, requires an understanding of this heterogeneity of disease. Notably, among equally obese patients, some are globally insulin resistant, others insulin sensitive, and some demonstrate tissue specific IR. Thus, the mechanisms driving increased triglyceride production an any particular patient may depend on the patient’s pattern of tissue specific insulin resistance, with de novo lipogenesis predominating in the setting of skeletal muscle insulin resistance, and esterification of preformed fatty acids predominating in the setting of adipose insulin resistance. The overarching aim of this proposal is to build a mechanistic knowledge base to identify and optimize therapy for discrete subgroups of IR. To achieve this goal, Dr. Vatner aims to: 1) elucidate the pathways that support hepatic de novo lipogenesis (DNL) in rodent models of hepatic insulin resistance; 2) quantify the discrete pathways by which adipose and muscle insulin resistance promote hepatic triglyceride production; and 3) assess how differences in adipose and muscle insulin resistance in humans impact on the mechanisms underlying hepatic triglyceride synthesis. To achieve these goals, studies in both rodents and humans will be critical. Rodent models that exhibit different tissue specific patterns of insulin resistance will be used, including high fat diet fed mice, insulin receptor T1160A mutant mice, Tbc1d4p.Arg684Ter mutant mice, Mkr mice (mice with skeletal muscle specific resistance to insulin and IGF1), and adipose Pde3b knockout mice. Human subjects with different patterns of tissue specific insulin resistance will be studied. Stable isotope tracer techniques will be used to assess contributions of de novo lipogenesis and esterification of preformed fatty acids to triglyceride synthesis. Standard and cutting-edge molecular biology tools, including chromatin immunoprecipitation, quantitative PCR, RNA-Seq, and immunoblotting, will be used to delineate the molecular pathways playing key roles in the regulation of hepatic triglyceride production. The key subject of interest in this proposal is the clinical heterogeneity of hypertriglyceridemia in the setting of insulin resistance; studies using pharmacologic interventions (SGLT2 inhibition, inhibition of adipose lipolysis) and exercise interventions will directly address this clinical heterogeneity.