Defective Glycogenesis Contributes Toward the Inability to Suppress Hepatic Glucose Production in Response to Hyperglycemia and Hyperinsulinemia in Zucker Diabetic Fatty Rats

OBJECTIVE: Examine whether normalizing net hepatic glycogenesis restores endogenous glucose production and hepatic glucose phosphorylation in response to diabetic levels of plasma glucose and insulin in Zucker diabetic fatty rats (ZDF). RESEARCH DESIGN AND METHODS: Hepatic glucose and intermediate fluxes (µmol ⋅ kg(−1) ⋅ min(−1)) were measured with and without a glycogen phosphorylase inhibitor (GPI) using [2-(3)H]glucose, [3-(3)H]glucose, and [U-(14)C]alanine in 20 h-fasted conscious ZDF and their lean littermates (ZCL) under clamp conditions designed to maintain diabetic levels of plasma glucose and insulin. RESULTS: With infusion of GPI into ZDF (ZDF-GPI+G), compared with vehicle infused ZDF (ZDF-V), high glycogen phosphorylase a activity was decreased and low synthase I activity was increased to that of ZCL. Low net glycogenesis from plasma glucose rose to 75% of ZCL levels (4 ± 1 in ZDF-V, 18 ± 1 in ZDF-GPI+G, and 24 ± 2 in ZCL) and phosphoenolpyruvate 260% (4 ± 2 in ZDF-V, 16 ± 1 in ZDF+GPI-G, and 6 ± 2 in ZCL). High endogenous glucose production was suppressed with GPI infusion but not to that of ZCL (46 ± 4 in ZDF-V, 18 ± 4 in ZDF-GPI+G, and −8 ± 3 in ZCL). This was accompanied by reduction of the higher glucose-6-phosphatase flux (75 ± 4 in ZDF-V, 41 ± 4 in ZDF-GPI+G, and 86 ± 12 in ZCL) and no change in low glucose phosphorylation or total gluconeogenesis. CONCLUSIONS: In the presence of hyperglycemic-hyperinsulinemia in ZDF, reduced glycogenic flux partially contributes to a lack of suppression of hepatic glucose production by failing to redirect glucose-6-phosphate flux from production of glucose to glycogen but is not responsible for a lower rate of glucose phosphorylation.