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

Abstract

Shin J-S, Torres TP, Catlin RL, Donahue EP, Shiota M. A defect in glucose-induced dissociation of glucokinase from the regulatory protein in Zucker diabetic fatty rats in the early stage of diabetes. Am J Physiol Regul Integr Comp Physiol 292: R1381-R1390, 2007. First published January 4, 2007; doi:10.1152/ajpregu.00260.2006.-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 ϳ8 mM, 2,000 pmol/l, and 60 ng/l, respectively. Endogenous glucose production (EGP) was 44 Ϯ 4 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 . When plasma glucose was raised to ϳ17 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 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 , along with the increase in plasma glucose, GK was exported to the cytoplasm. EGP (23 Ϯ 19 and 12 Ϯ 5 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ) was suppressed without a decrease in glucose 6-phosphatase flux (145 Ϯ 23 and 126 Ϯ 16 vs. 122 Ϯ 10 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 without sorbitol) but increased in glucose phosphorylation as indicated by increases in glucose recycling (122 Ϯ 17 and 114 Ϯ 19 vs. 71 Ϯ 11 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ), glucose-6-phosphate content (254 Ϯ 32 and 260 Ϯ 35 vs. 188 Ϯ 20 nmol/g liver), fractional contribution of plasma glucose to uridine 5Ј-diphosphateglucose flux (43 Ϯ 8 and 42 Ϯ 8 vs. 27 Ϯ 6%), and glycogen synthesis from plasma glucose (20 Ϯ 4 and 22 Ϯ 5 vs. 9 Ϯ 4 mol 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 EXCESSIVE POSTPRANDIAL HYPERGLYCEMIA is a prominent and early defect in subjects with type 2 diabetes, which is the result, at least in part, from an inadequate suppression of net hepatic glucose production (NHGP) (15,34,36) and an insufficient increase in hepatic glucose uptake (HGU) (6,7,21). Glucoseinduced suppression of NHGP was associated with increased hepatic glucose phosphorylation (47) and was abolished by inhibiting hepatic glucokinase (GK) activity in normal rats (5). This suggests that increased hepatic GK flux mediates glucose's effect not only to increase HGU, but also to decrease NHGP by the opposition of glucose 6-phosphatase flux. Basu et al. (6,7) showed that in type 2 diabetic patients, lower splanchnic glucose uptake in the face of hyperglycemic hyperinsulinemia was associated with a blunted increase in glucose phosphorylation. This implies impaired activity of GK in the liver of these patients.Studies using mouse models showed a large impact of altered hepatic GK expression in regulating postabsorptive blood glucose levels and hyperglycemia-induced HGU (35). However, decreased hepatic GK activity is not always present in patients (8,...

Correlation of rare coding variants in the gene encoding human glucokinase regulatory protein with phenotypic, cellular, and kinetic outcomes

“…The reduction in glycemic control is likely attributable to a decrease in the Gkrpbound Gck nuclear pool that is normally mobilized in response to a glucose challenge. This loss of nuclear stabilization and/or glucose-dependent translocation has been shown to be associated with impaired glucose tolerance in rodent models (24,60). Phenotype comparisons and results of genotyping for the severe LOF subgroup were consistent with these findings.…”

Nutritional regulation of glucokinase: a cross-species story

“…A recent study also suggests that the impaired inhibition of hepatic glucose production and increased glucose uptake in the liver of hyperglycaemic Zucker rats could be due to a failure of GK to be released from the GK-GKRP complex (107) . The relationship between human GK and insulin was first evident from the study of hepatic activity in diabetic patients, in which GK can be depressed 50 % when compared with a healthy volunteer (63) .…”

Targeting Hepatic Glucokinase in Type 2 Diabetes

“…1). It could be speculated that decreased "glucose effectiveness" in type 2 diabetes in humans may involve decreased glucokinase expression or impaired regulation by GKRP, as occurs in animal models of insulin resistance (11,12), in addition to other metabolic defects.…”