tailieunhanh - Báo cáo khoa học: The role of glucose 6-phosphate in mediating the effects of glucokinase overexpression on hepatic glucose metabolism

Pharmacological activation or overexpression of glucokinase in hepatocytes stimulates glucose phosphorylation, glycolysis and glycogen synthesis. We used an inhibitor of glucose 6-phosphate (Glc6P) hydrolysis, namely the chlorogenic derivative, 1-[2-(4-chloro-phenyl)-cyclopropylmethoxy]-3, 4-di-hydroxy-5-(3-imidazo[4,5-b]pyridin-1-yl-3-phenyl-acryloyloxy)-cyclohexane- | iFEBS Journal The role of glucose 6-phosphate in mediating the effects of glucokinase overexpression on hepatic glucose metabolism Linda Harndahl1 Dieter Schmoll2 Andreas W. Herling2 and Loranne Agius1 1 Schoolof ClinicalMedicalSciences-Diabetes The University of Newcastle upon Tyne Medical School Newcastle upon Tyne UK 2 Aventis Pharma Deutschland GmbH TD Metabolism Frankfurt Germany Keywords glucokinase activators glucokinase glucose 6-phosphate glycogen liver Correspondence L. Agius Schoolof Clinical Medical Sciences-Diabetes The Medical School University of Newcastle upon Tyne Newcastle upon Tyne NE2 4HH UK Fax 44 191 2220723 Tel 44 191 2227033 E-mail Received 25 August 2005 revised 15 October 2005 accepted 18 November 2005 doi Pharmacological activation or overexpression of glucokinase in hepatocytes stimulates glucose phosphorylation glycolysis and glycogen synthesis. We used an inhibitor of glucose 6-phosphate Glc6P hydrolysis namely the chlorogenic derivative 1- 2- 4-chloro-phenyl -cyclopropylmethoxy -3 4-di-hydroxy-5- 3-imidazo 4 5-b pyridin-1-yl-3-phenyl-acryloyloxy -cyclohexane-carboxylic acid also known as S4048 to determine the contribution of Glc6P concentration as distinct from glucokinase protein or activity to the control of glycolysis and glycogen synthesis by glucokinase overexpression. The validity of S4048 for testing the role of Glc6P was supported by its lack of effect on glucokinase binding and its nuclear cytoplasmic distribution. The stimulation of glycolysis by glucokinase overexpression correlated strongly with glucose phosphorylation whereas glycogen synthesis correlated strongly with Glc6P concentration. Metabolic control analysis was used to determine the sensitivity of glycogenic flux to glucokinase or Glc6P at varying glucose concentrations 5-20 mm . The concentration control coefficient of glucokinase on Glc6P was relatively independent of glucose concentration .