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）：作为对口服葡萄糖负荷的反应，肝脏吸收并储存三分之一的摄入葡萄糖，这一过程被2型糖尿病改变。我们实验室的早期研究提供了关于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。肌糖原升高会降低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，我们将使用禁食18小时的清醒狗。在每项研究的前4小时内，所有动物将接受SRIF外周输注以禁用内分泌胰腺，并接受胰岛素和胰高血糖素的基础门静脉内替代。巧合的是，肝脏的葡萄糖负荷将加倍，并开始门静脉内输注盐水或果糖。果糖的给药速率经计算可使肝糖原分别增加40和80 mg/g。果糖输注后将进行2小时的对照期，在此期间，激素和底物（果糖除外）的基础替代将继续进行，使肝脏葡萄糖代谢恢复至基线水平。最后两个小时（即，实验期）的特征在于以4倍基础胰岛素的门静脉内输注，或以4 mg/kg/min的速率胰岛素输注加门静脉内葡萄糖输注。这样，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的能力的影响。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摄取葡萄糖及其在肝脏中的命运的影响。 公共卫生相关性：作为对进食的反应，肝脏会吸收大量的葡萄糖负荷，这是2型糖尿病患者受损的一个过程，导致该人群中的高血糖水平。正在开发用于治疗糖尿病的药物以增加肝脏对葡萄糖的摄取和储存，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。需要更多地了解肝糖原对肝脏葡萄糖代谢的影响，因为这些知识可以提高对以肝脏葡萄糖摄取受损为特征的疾病状态（如2型糖尿病）的理解。