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Am J Physiol Regul Integr Comp Physiol 292: R1381-R1390, 2007. First published January 4, 2007; doi:10.1152/ajpregu.00260.2006
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APPETITE, OBESITY, DIGESTION, AND METABOLISM

A defect in glucose-induced dissociation of glucokinase from the regulatory protein in Zucker diabetic fatty rats in the early stage of diabetes

Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee

Submitted 15 April 2006 ; accepted in final form 31 December 2006

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 wk of age. Under basal conditions, plasma glucose, insulin, and glucagon were 8 mM, 2,000 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 increased in glucose phosphorylation as indicated by increases in glucose recycling (122 ± 17 and 114 ± 19 vs. 71 ± 11 µmol·kg^–1·min^–1), glucose-6-phosphate content (254 ± 32 and 260 ± 35 vs. 188 ± 20 nmol/g liver), 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). The decreased glucose effectiveness to suppress EGP and stimulate hepatic glucose uptake may result from failure of the sugar to activate GK by stimulating the translocation of the enzyme.

obese-type 2 diabetes; glucokinase regulatory protein

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