A Defect in Glucose-Induced Dissociation of Glucokinase from the Regulatory Protein in Zucker Diabetic Fatty Rats in the Early Stage of Diabetes Running head: Impaired GK translocation and type 2 diabetes

Effect of stimulation of glucokinase (GK) export from the nucleus by small amounts of sorbitol on hepatic glucose flux in response to elevated plasma glucose was examined in 6-h fasted Zucker diabetic fatty rats at 10 weeks of age. Under basal conditions, plasma glucose, insulin and glucagon were ~8 mM, 2000 pmol/l, and 60 ng/l, respectively. Endogenous glucose production (EGP) was 44 ± 4 μmol⋅kg-1⋅min-1. When plasma glucose was raised to ~17 mM, GK was still predominantly localized with its inhibitory protein in the nucleus. EGP was not suppressed. When sorbitol was infused at 5.6 and 16.7 μmol⋅kg-1⋅min-1, along with the increase in plasma glucose, GK was exported to the cytoplasm. EGP (23 ±19 and 12 ± 5 μmol⋅kg-1⋅min-1) was suppressed without a decrease in glucose 6-phosphatase flux (145 ± 23 and 126 ± 16 vs 122 ± 10 μmol·kg-1·min-1 without sorbitol) but with an increase in glucose phosphorylation, as indicated by increases in glucose recycling (122 ± 17 and 114 ± 19 vs 71 ± 11 μmol⋅kg1⋅min-1), glucose-6-phosphate content (254 ± 32 and 260 ± 35 vs. 188 ± 20 nmol⋅g liver-1), fractional contribution of plasma glucose to uridine 5'-diphosphate-glucose flux (43 ± 8 and 42 ± 8 vs 27 ± 6%) and glycogen synthesis from plasma glucose (20 ± 4 and 22 ± 5 vs. 9 ± 4 μmol glucose⋅g liver-1). The decreased glucose effectiveness to suppress EGP and stimulate HGU may result from failure of the sugar to activate GK by stimulating the translocation of the enzyme.