Effect of hepatic glycogen level on hepatic glucose uptake and disposition

肝糖原水平对肝葡萄糖摄取和处置的影响

• 批准号: 7408366
• 负责人: Jason Winnick
• 金额: $ 4.68万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7408366
• 关键词: Animals; Blood Glucose; Canis familiaris; Conscious; Diabetes Mellitus; Disease; Elevation; Fasting; Fructose; Glucagon; Glucose; Glycogen; Hepatic; Hormones; Hour; Infusion procedures; Insulin; Islets of Langerhans; Knowledge; Lead; Liver; Liver Glycogen; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Oral; Peripheral; Pharmaceutical Preparations; Population; Process; Public Health; Rate; Saline; Signal Transduction; Time; feeding; glucose metabolism; glucose uptake; improved; response; uptake

DESCRIPTION (provided by applicant): In response to an oral glucose load, the liver takes up and stores one-third of ingested glucose, a process that is altered by type 2 diabetes mellitus. Earlier studies from our lab have provided information concerning factors that regulate hepatic glucose uptake, including glucose load to the liver, insulin level, and portal glucose delivery. Elevation of muscle glycogen reduces glucose uptake and glycogen synthesis, however the effect of hepatic glycogen level on hepatic glucose uptake and disposition is not known. To investigate this topic, we will use the 18 hour fasted conscious dog. During the first four hours of each study, all animals will receive peripheral infusion of SRIF to disable the endocrine pancreas, and basal intraportal replacement of insulin and glucagon. Coincidently, glucose load to the liver will be doubled, and an intraportal infusion of saline or fructose will be started. Fructose will be given at rates calculated to increase hepatic glycogen by 40 and 80 mg/g, respectively. The fructose infusion will be followed by a two hour control period, during which basal replacement of hormones and substrates (except fructose) will continue, allowing hepatic glucose metabolism to return to baseline. The final two hours (i.e., the experimental period) will be characterized by either the intraportal infusion of insulin at four times basal, or insulin infusion plus intraportal infusion of glucose at a rate of 4 mg/kg/min. In this way we will be able to examine the effect of hepatic glycogen loading on the ability of insulin to alter net hepatic glucose uptake and hepatic glucose disposition. We will also be able to determine the impact of hepatic glycogen loading on the impact of the portal glucose signal on hepatic uptake of glucose and its fate in the liver. PUBLIC HEALTH RELEVANCE: In response to feeding, the liver takes up a significant amount of the glucose load, a process that is impaired in people with type 2 diabetes mellitus, contributing to the high blood glucose levels seen in this population. Medications for the treatment of diabetes mellitus are being developed to increase uptake and storage of glucose by the liver, but the effect of increasing liver glycogen levels is not known, and may limit the utility of such approaches. More needs to be known about the impact of hepatic glycogen on glucose metabolism by the liver, as such knowledge could lead to an improved understanding of disease states that are characterized by impaired hepatic glucose uptake, such as type 2 diabetes mellitus.

描述（由申请人提供）：响应口服葡萄糖负荷，肝脏吸收并储存三分之一的摄入葡萄糖，这一过程因 2 型糖尿病而改变。我们实验室的早期研究提供了有关调节肝脏葡萄糖摄取的因素的信息，包括肝脏的葡萄糖负荷、胰岛素水平和门静脉葡萄糖输送。肌糖原升高会减少葡萄糖摄取和糖原合成，但肝糖原水平对肝脏葡萄糖摄取和处置的影响尚不清楚。为了研究这个主题，我们将使用 18 小时禁食、神志清醒的狗。在每项研究的前四个小时内，所有动物将接受外周输注 SRIF 以禁用内分泌胰腺，并接受基础门脉内胰岛素和胰高血糖素替代。巧合的是，肝脏的葡萄糖负荷将加倍，并且将开始门静脉内输注盐水或果糖。果糖的施用量经计算可分别增加肝糖原 40 和 80 mg/g。果糖输注后将有一个两小时的控制期，在此期间将继续激素和底物（果糖除外）的基础替代，使肝脏葡萄糖代谢恢复到基线。最后两小时（即实验期）的特点是按基础四倍的门静脉内输注胰岛素，或以 4 mg/kg/min 的速率输注胰岛素加门静脉内输注葡萄糖。通过这种方式，我们将能够检查肝糖原负荷对胰岛素改变肝葡萄糖净摄取和肝葡萄糖处置能力的影响。我们还将能够确定肝糖原负荷对门静脉葡萄糖信号对肝脏对葡萄糖的摄取及其在肝脏中的命运的影响的影响。 公共健康相关性：在进食时，肝脏会吸收大量的葡萄糖负荷，这一过程在 2 型糖尿病患者中会受到损害，从而导致该人群出现高血糖水平。正在开发治疗糖尿病的药物以增加肝脏对葡萄糖的吸收和储存，但增加肝糖原水平的效果尚不清楚，并且可能限制此类方法的实用性。我们需要更多地了解肝糖原对肝脏葡萄糖代谢的影响，因为这些知识可以帮助我们更好地了解以肝葡萄糖摄取受损为特征的疾病状态，例如 2 型糖尿病。