Effect of hepatic glycogen level on hepatic glucose uptake and disposition

描述(申请人提供)：对口服葡萄糖负荷的反应，肝脏吸收并存储摄入葡萄糖的三分之一，这一过程会因2型糖尿病而改变。我们实验室的早期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。为了研究这个话题，我们将使用禁食18小时的清醒狗。在每项研究的前四个小时内，所有动物都将接受SRIF外周输注以禁用内分泌胰腺，以及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增加一倍，门静脉内将开始输注生理盐水或果糖。果糖将按计算速度分别增加肝糖原40 mg/g和80 mg/g。果糖输注后将有两个小时的控制期，在此期间将继续进行激素和底物(果糖除外)的基础更换，使肝脏葡萄糖代谢恢复到基线水平。最后两个小时(即实验期)的特点是门脉内以基础胰岛素的4倍输注，或胰岛素输注+门脉内葡萄糖输注，速度为4毫克/公斤/分钟。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脏葡萄糖净摄取和肝脏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葡萄糖摄取的影响及其在肝脏中的去向的影响。 公共卫生相关性：作为对喂养的反应，肝脏承担了相当大的葡萄糖负荷，这一过程在2型糖尿病患者中受到损害，导致了这一人群中出现的高血糖水平。治疗糖尿病的药物正在开发中，以增加肝脏对葡萄糖的吸收和储存，但提高肝糖原水平的效果尚不清楚，可能会限制此类方法的应用。需要更多地了解肝糖原对肝脏葡萄糖代谢的影响，因为这种知识可能有助于更好地了解以肝脏葡萄糖摄取受损为特征的疾病状态，如2型糖尿病。

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.