Hepatic Adaptations to Increased Glucose Availability

描述（由申请方提供）：胰岛素作用或代谢途径中的组织特异性缺陷被认为对维持葡萄糖稳态至关重要，但并不总是产生预期结果。例如，完全去除肌肉中的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，但未表现出明显的高血糖，这表明其他组织弥补了这一缺陷。胰腺通过增加胰岛素分泌进行补偿，脂肪组织通过增强葡萄糖摄取和脂质沉积或分泌改变其他组织中葡萄糖代谢的因子进行补偿。很少或没有工作已经解决了肝脏的作用。在体内测量以检测肝脏代谢变化（尤其是小鼠）的主要变量是示踪剂确定的葡萄糖转换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，除非存在糖尿病和相关的高血糖症，否则很难检测到肝脏胰岛素作用的潜在缺陷。我们的数据表明，肝脏具有通过增强其摄取葡萄糖的能力来适应葡萄糖可用性持续增加的独特能力。此外，虽然肝脏最初将葡萄糖储存为糖原，但随着高葡萄糖暴露的持续时间增加，大部分葡萄糖以乳酸盐的形式释放，乳酸盐随后被外周组织除去。正常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，虽然在大型动物模型中很容易获得，但不能植入清醒小鼠。因此，在小鼠模型中很少有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理的损伤。 范德比尔特的小鼠代谢表型中心（MMPC）已经开发出了外科手术方法，这将使我们能够首次研究清醒小鼠肝脏的适应性反应。我们将结合联合收割机新的示踪方法与长期导管清醒小鼠模型，以量化肝脏的适应性反应，然后在胰岛素抵抗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.