Control of glucokinase translocation in rat hepatocytes by sorbitol and the cytosolic redox state

Abstract

In rat hepatocytes cultured in 5 (A50 550,uM). These substrates also stimulate glucose conversion into glycogen with a similar relative potency, suggesting that conversion of glucose into glycogen is dependent on the binding and/or location of glucokinase within the hepatocyte. Ethanol and glycerol inhibited the effects of fructose, sorbitol and glucose on glucokinase translocation, whereas dihydroxyacetone had a small additive effect at sub-maximal substrate stimulation. The converse effects of glycerol and dihydroxyacetone suggest a role for the cytosolic NADH/NAD+ redox state in controlling glucokinase translocation. Titrations with three competitive inhibitors of glucokinase did not provide evidence for involvement of glucokinase flux in glucose-induced glucokinase translocation: N-acetylglucosamine inhibited glucose conversion into glycogen, but not glucose-induced glucokinase translocation; glucosamine partially suppressed glucoseinduced and fructose-induced glucokinase translocation, at concentrations that caused total inhibition of glucose conversion into glycogen; D-mannoheptulose increased glucokinase release and had an additive effect with glucose. 3,3'-Tetramethyleneglutaric acid (5 mM), an inhibitor of aldose reductase, inhibited glucokinase translocation induced by glucose, but not that by sorbitol or fructose, suggesting that glucose may induce glucokinase translocation by conversion into sorbitol. Sorbitol generated from glucose intrahepatically or extrahepatically in hyperglycaemic conditions may be a physiological regulator of hepatic glucokinase translocation.

Effects of Supplemental D-Psicose on Glucose Tolerance and Serum Adipocytokine Levels in Rats Fed a High-Fat Diet or a Low-Fat Diet

“…Bar (31) tagatose and D-psicose increase liver glycogen deposition and liver weight remain unknown. However, the following pathway is supported by the results of many studies (34)(35)(36). Three ketohexoses appear to stimulate the formation of glycogen from glucose.…”

“…In the liver, glucokinase catalyzes the phosphorylation of glucose to glucose-6-phosphate. In experiments with isolated hepatocytes, D-fructose and D-tagatose were found to stimulate the glucokinase reaction at a concentration of 0.1 mM (35,36). The authors ascribed this enzyme activation either to D-fructose-1-phosphate (or D-tagatose-1-phosphate) acting on a glucokinase-regulatory protein complex (37,38).…”

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

“…However, the glucose effect on GK translocation could not be explained solely by increased F-1-P, since more translocation of GK was observed with the same concentration of F-1-P in the presence of an elevated concentration of glucose than in the presence of fructose or sorbitol, at a low concentration of glucose (41). The effect of inhibition of aldose reductase in the polyol pathway in which glucose is converted to F-1-P on GK translocation is controversial (1,41). In our in vivo studies, furthermore, hepatic F-1-P contents (nmol/g liver) were not increased during a hyperglycemic clamp (17 Ϯ 3) compared with that under the basal condition (15 Ϯ 4) in normal rats and were not different between 10-wk-old ZDF rats and the lean littermates (unpublished data).…”

Stimulation of Hepatocyte Glucose Metabolism by Novel Small Molecule Glucokinase Activators

“…The only known physiological activators of GK in liver are precursors of fructose 1-phosphate (fructose and sorbitol), which causes dissociation of GK from GKRP (20,34). To test the efficacy of GKA1 and GKA2 at stimulating glucose metabolism in hepatocytes, we compared their effects with sorbitol, which is taken up by hepatocytes more rapidly than fructose and is thereby more effective at stimulating glucose metabolism (20,34). As expected, sorbitol caused a concentration-dependent increase in free GK, glucose phosphorylation, glycolysis, and glycogen synthesis (Fig.…”