2007
DOI: 10.1038/sj.bjp.0707502
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An assessment of the in vivo efficacy of the glycogen phosphorylase inhibitor GPi688 in rat models of hyperglycaemia

Abstract: Background and purpose: Studies in cultured hepatocytes demonstrate glycogen synthase (GS) activation with glycogen phosphorylase (GP) inhibitors. The current study investigated whether these phenomena occurred in vivo using a novel GP inhibitor. Experimental approach: An allosteric GP inhibitor, GPi688, was evaluated against both glucagon-mediated hyperglycaemia and oral glucose challenge-mediated hyperglycaemia to determine the relative effects against GP and GS in vivo. Key results: In rat primary hepatocyt… Show more

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Cited by 10 publications
(6 citation statements)
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“…The increased muscle glucose uptake per se could be responsible for an increased glycogen synthesis, as muscle glycogen synthase is allosterically activated by glucose 6-phosphate 44 . Genetic or pharmacological interventions that increase glycogen synthesis relative to glycogenolysis can indeed promote glucose tolerance 45,46 , and the cellular physiology controlling the flux through these opposite pathways is being explored for new anti-diabetic drug targets.…”
Section: Discussionmentioning
confidence: 99%
“…The increased muscle glucose uptake per se could be responsible for an increased glycogen synthesis, as muscle glycogen synthase is allosterically activated by glucose 6-phosphate 44 . Genetic or pharmacological interventions that increase glycogen synthesis relative to glycogenolysis can indeed promote glucose tolerance 45,46 , and the cellular physiology controlling the flux through these opposite pathways is being explored for new anti-diabetic drug targets.…”
Section: Discussionmentioning
confidence: 99%
“…The balance between glycogen breakdown and synthesis is primarily a function of relative insulin and glucagon effects on hepatocytes, i.e., the relative cAMP signal, as well as the level of glycogen stores (443). Genetic or pharmacological interventions that increase glycogen synthesis relative to glycogenolysis promote glucose tolerance (210,319), and the cellular physiology controlling the flux through these pathways is being explored for drug targets. GCGR signaling also restrains glycolysis by modifying glycolytic enzymes, particularly fructose-2,6 bisphosphatase, regulating the flux between glucose-6-phosphate and fructose biphosphate, and inhibiting pyruvate kinase activity (195).…”
Section: B Glucagonmentioning
confidence: 99%
“…Hepatic triglyceride and glycogen concentrations were determined as described previously (Poucher et al ., ; Sörhede Winzell et al ., ).…”
Section: Methodsmentioning
confidence: 99%