EXCESS GLUCOSE PRODUCTION: GLYCOGEN OR TCA-CYCLE GLUCONEOGENESIS?

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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.