Hepatic Adaptations to Increased Glucose Availability

描述(由申请人提供)：胰岛素作用或代谢途径中的组织特异性缺陷被认为是维持葡萄糖稳态所必需的，但并不总是产生预期的结果。例如，完全移除肌肉中的GLUT4或胰岛素受体不会表现出显著的表型，除非受到衰老或高脂肪喂养的挑战。尽管肌肉葡萄糖摄取明显受损，但未能表现出明显的高血糖，这表明其他组织可以弥补这一缺陷。胰腺通过增加胰岛素分泌来进行补偿，脂肪组织通过增加葡萄糖摄取和脂肪沉积或分泌一种改变其他组织中葡萄糖代谢的因子来进行补偿。很少或根本没有研究涉及肝脏的作用。在体内测量的检测肝脏代谢变化的主要变量是示踪剂确定的葡萄糖周转率和胰岛素在正常血糖高胰岛素钳夹期间抑制肝脏葡萄糖产生的能力。有趣的是，在大多数情况下，很难发现肝脏胰岛素作用的潜在缺陷，除非存在糖尿病和相关的高血糖。我们的数据表明，肝脏具有独特的能力，通过增强其吸收葡萄糖的能力来适应葡萄糖可获得性的持续增加。此外，虽然肝脏最初将葡萄糖存储为糖原，但随着高糖暴露时间的增加，很大一部分葡萄糖以乳酸的形式释放出来，随后被外周组织清除。正血糖高胰岛素钳夹虽然能有效检测外周葡萄糖摄取的变化，但不能用于区分外周和肝脏葡萄糖摄取的变化。为了直接评估肝脏葡萄糖摄取，需要动静脉差异技术，虽然这种技术在大型动物模型中很容易获得，但不能移植到清醒的小鼠身上。因此，在小鼠模型中，很少有工作研究肝脏葡萄糖摄取是如何调节的，以及肝脏如何适应外周胰岛素作用和葡萄糖处置的损害。 范德比尔特的小鼠代谢表型中心(MMPC)已经开发出手术方法，这将使我们第一次能够研究清醒小鼠肝脏的适应性反应。我们将结合新的示踪剂方法和长期置管的清醒小鼠模型来量化肝脏的适应性反应，然后在胰岛素抵抗的小鼠模型中测试这种适应性反应。

DESCRIPTION (provided by applicant): Tissue specific defects in insulin action or in metabolic pathways thought to be essential to maintaining glucose homeostasis do not always produce the expected outcome. For example, complete removal of either GLUT4 or insulin receptor in muscle does not exhibit a significant phenotype unless challenged by aging or high fat feeding. The failure to manifest marked hyperglycemia despite significant impairments in muscle glucose uptake suggests that other tissues compensate for the defect. The pancreas compensates by increasing insulin secretion and adipose tissue compensates by enhancing glucose uptake and lipid deposition or secreting a factors that modifies glucose metabolism in other tissues. Little or no work has addressed the role of the liver. The primary variables measured in vivo to detect changes in hepatic metabolism especially in mice are tracer determined glucose turnover and the ability of insulin to inhibit hepatic glucose production during a euglycemic hyperinsulinemic clamp. Interestingly in most cases it has been difficult to detect underlying defects in hepatic insulin action except when diabetes and the associated hyperglycemia are present. Our data indicate that the liver has the unique ability to adapt to a sustained increase in glucose availability by enhancing its capacity to take up glucose. Moreover, while the liver initially stores the glucose as glycogen, as the duration of high glucose exposure increases a large fraction of the glucose is released as lactate which is subsequently removed by peripheral tissues. The euglycemic hyperinsulinemic clamp, while effective in detecting alterations in peripheral glucose uptake, cannot be used to discriminate between changes in peripheral and liver glucose uptake. To directly assess liver glucose uptake requires arterio-venous difference techniques that, while readily available in large animal models, cannot be implanted in conscious mice. Consequently very little work in mouse models has examined how liver glucose uptake is regulated and how the liver adapts to impairments in peripheral insulin action and glucose disposal. The Mouse Metabolic Phenotyping Center (MMPC) here at Vanderbilt has developed surgical approaches that will allow us for the first time to study the adaptive response of the liver in a conscious mouse. We will combine novel tracer methodology with a chronically catheterized conscious mouse model to quantify the adaptive response of the liver and then test this adaptive response in mouse models of insulin resistance.