Effect of hepatic glycogen level on hepatic glucose uptake and disposition

描述（由申请人提供）：作为对口服葡萄糖负荷的反应，肝脏吸收并储存摄入葡萄糖的三分之一，这一过程被2型糖尿病改变。我们实验室早期的研究已经提供了有关调节肝脏葡萄糖摄取的因素的信息，包括肝脏葡萄糖负荷、胰岛素水平和门静脉葡萄糖输送。肌糖原升高可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。为了研究这个话题，我们将使用18小时禁食有意识的狗。在每项研究的前四小时，所有动物将接受外周输注SRIF以使内分泌胰腺失效，并接受基础门静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增加一倍，并开始静脉输注生理盐水或果糖。果糖的剂量将分别使肝糖原增加40和80毫克/克。果糖输注后是两个小时的控制期，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到基线。最后两小时（即实验期）的特点是静脉注射胰岛素，速度是基础注射的四倍，或者静脉注射胰岛素加静脉注射葡萄糖，速度为4mg /kg/min。通过这种方式，我们将能够检查肝糖原负荷对胰岛素改变净肝糖摄取和肝糖处置能力的影响。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摄取葡萄糖及其在肝脏中的命运的影响。

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.