Acute inhibition of hepatic glucose-6-phosphatase does not affect gluconeogenesis but directs gluconeogenic flux toward glycogen in fasted rats - A pharmacological study with the chlorogenic acid derivative S4048

Effects of acute inhibition of glucose-6-phosphatase activity by the chloro genic acid derivative S4048 on hepatic carbohydrate fluxes were examined in isolated rat hepatocytes and in vivo in rats. Fluxes were calculated using tracer dilution techniques and mass isotopomer distribution analysis in pl asma glucose and urinary paracetamol-glucuronide after infusion of [U-C-13] glucose, [2-C-13]glycerol, [1-H-2]galactose, and paracetamol, In hepatocyte s, glucose-g-phosphate (Glc-6-P) content, net glycogen synthesis, and lacta te production from glucose and dihydroxyacetone increased strongly in the p resence of S4048 (10 muM) In livers of S4048-treated rats (0.5 mg kg(-1) mi n(-1); 8 h) Glc-6-P content increased strongly (+440%), and massive glycoge n accumulation (+1260%) was observed in periportal areas. Total glucose pro duction was diminished by 50%, The gluconeogenic flux to Glc-6-P was unaffe cted (i,e, 33.3 +/- 2.0 versus 33.2 +/- 2.9 mu mol kg(-1) min(-1) in contro l and S4048-treated rats, respectively). Newly synthesized Glc-6-P was redi stributed from glucose production (62 +/- 1 Dersus 38 +/- 1%; p < 0.001) to glycogen synthesis (35 +/- 5% versus 65 +/- 5%; p < 0.005) by S4048, This was associated with a strong inhibition (-82%) of the flux through glucokin ase and an increase (+83%) of the flux through glycogen synthase, while the flux through glycogen phosphorylase remained unaffected. In livers from S4 048-treated rats, mRNA levels of genes encoding Glc-6-P hydrolase (similar to4-fold), Glc-6-P translocase (similar to4-fold), glycogen synthase (simil ar to7-fold) and L-type pyruvate kinase (similar to4-fold) were increased, whereas glucokinase expression was almost abolished. In accordance with una ltered gluconeogenic flux, expression of the gene encoding phosphoenolpyruv ate carboxykinase was unaffected in the S4048-treated rats. Thus, acute inh ibition of glucose-6-phosphatase activity by S4048 elicited 1) a repartitio ning of newly synthesized Glc-6-P from glucose production into glycogen syn thesis without affecting the gluconeogenic flux to Glc-6-P and 2) a cellula r response aimed at maintaining cellular Glc-6-P homeostasis.