EXCESS GLUCOSE PRODUCTION: GLYCOGEN OR TCA-CYCLE GLUCONEOGENESIS?

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。雄性Zucker糖尿病脂肪（fa/fa）大鼠是2型糖尿病（T2DM）相关肥胖的无功能瘦素受体转基因啮齿动物模型。早期对fa/fa大鼠葡萄糖代谢的研究主要集中在空腹条件下对肝糖原消耗的抵抗。空腹fa/fa大鼠的大量肝糖原储存可能是空腹高血糖的重要原因，因为葡萄糖生成（GP）和相对糖原分解/糖异生受到肝糖原储存的影响。葡萄糖过度产生在T2DM的空腹高血糖中起主要作用，但糖原分解和糖异生的相对作用仍然存在争议。葡萄糖过量产生的另一个因素可能是过量血浆游离脂肪酸驱动的过量TCA循环通量。本研究的目的是：(i)比较fa/fa大鼠糖尿病前期和糖尿病显性阶段的综合GP模式，（ii）评估肝糖原在空腹意识fa/fa大鼠高血糖中的作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A male Zucker diabetic fatty (fa/fa) rat is a genetically modified rodent model with nonfunctional leptin receptors for type 2 diabetes mellitus (T2DM) associated obesity. Early studies of glucose metabolism in fa/fa rats have focused on resistance to liver glycogen depletion in fasted condition. Substantial liver glycogen store in fasted fa/fa rats could be a significant contribution for fasted hyperglycemia because glucose production (GP) and relative glycogenolysis/gluconeogenesis are under the influence of liver glycogen storage. Glucose over-production has a major role in fasted hyperglycemia of T2DM, but the relative roles of glycogenolysis and gluconeogenesis remained controversial. Another factor in over-production of glucose may be excess TCA cycle flux driven by excess plasma FFA. The objectives of this study are (i) to compare comprehensive GP patterns of prediabetic and overt diabetic stages of fa/fa rats, and (ii) to evaluate the role of hepatic glycogen in hyperglycemia of fasted conscious fa/fa rats.