Metabolic heterogeneity underlying hypertriglyceridemia in insulin resistance

项目总结/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， 胰岛素抵抗患者的单一表型。这种表型异质性反映在临床实践中， 代谢性疾病的不同表现以及对降糖和甘油三酯的不同反应 降低剂（如贝特类和鱼油）。一种精确的医学方法，其中对 利用疾病的异质性来针对个体患者的病理进行靶向治疗， 了解疾病的这种异质性。值得注意的是，在同样肥胖的患者中，有些人是全球胰岛素 胰岛素抵抗，其他胰岛素敏感，一些表现出组织特异性IR。 任何特定患者的增加的甘油三酯产生可取决于患者的组织特异性甘油三酯的模式。 胰岛素抵抗，在骨骼肌胰岛素抵抗的情况下以新生脂肪生成为主， 以及在脂肪胰岛素抵抗的情况下占主导地位的预先形成的脂肪酸的酯化。 这个建议的首要目标是建立一个机械的知识库，以确定和优化治疗 为了实现这一目标，Vatner博士的目标是：1）阐明支持IR的途径， 在肝胰岛素抵抗的啮齿动物模型中的肝从头脂肪生成（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产生的途径;和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 肝甘油三酯合成。 为了实现这些目标，啮齿动物和人类的研究将是至关重要的。啮齿动物模型表现出不同的 将使用胰岛素抵抗的组织特异性模式，包括高脂肪饮食喂养的小鼠，胰岛素受体T1160 A Arg 684 Ter突变小鼠、Mkr小鼠（具有骨骼肌特异性胰岛素抵抗和 IGF 1）和脂肪Pde 3b敲除小鼠。具有不同组织特异性胰岛素模式的人类受试者 将研究阻力。稳定同位素示踪技术将用于评估从头开始的贡献。 脂肪生成和将预先形成的脂肪酸酯化为甘油三酯合成。标准和尖端 分子生物学工具，包括染色质免疫沉淀，定量PCR，RNA-Seq， 免疫印迹，将被用来描绘在肝脏调节中起关键作用的分子途径， 甘油三酯的产生。本提案中感兴趣的关键主题是 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（SGLT 2 抑制、脂肪分解的抑制）和运动干预将直接解决这种临床问题。 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.