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Diabetes 54:617-623, 2005
© 2005 by the American Diabetes Association, Inc.

Increased Potency and Efficacy of Combined Phosphorylase Inactivation and Glucokinase Activation in Control of Hepatocyte Glycogen Metabolism

Laura J. Hampson, and Loranne Agius

From the School of Clinical Medical Sciences–Diabetes, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, U.K

Glucokinase and phosphorylase both have a high control strength over hepatocyte glycogen metabolism and are potential therapeutic targets for type 2 diabetes. We tested whether combined phosphorylase inactivation and glucokinase activation is a more effective strategy for controlling hepatic glycogen metabolism than single-site targeting. Activation of glucokinase by enzyme overexpression combined with selective dephosphorylation of phosphorylase-a by an indole carboxamide that favors the T conformation of phosphorylase caused a greater stimulation of glycogen synthesis than the sum of either treatment alone. This result is explained by the complementary roles of elevated glucose-6-phosphate (G6P; a positive modulator) and depleted phosphorylase-a (a negative modulator) in activating glycogen synthase and also by synergistic inactivation of phosphorylase-a by glucokinase activation and the indole carboxamide. Inactivation of phosphorylase-a by the indole carboxamide was counteracted by 5-aminoimidazole-4-carboxamide 1-ß-D-ribofuranoside, which is metabolized to an AMP analog; this effect was reversed by G6P. Our findings provide further evidence for the inverse roles of G6P and AMP in regulating the activation state of hepatic phosphorylase. It is proposed that dual targeting of glucokinase and phosphorylase-a enables improved potency and efficacy in controlling hepatic glucose metabolism.

Address correspondence and reprint requests to Loranne Agius, School of Clinical Medical Sciences–Diabetes, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, NE2 4HH, U.K. E-mail: loranne.agius{at}ncl.ac.uk


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Diabetes Diabetes Care Clinical Diabetes Diabetes Spectrum
Copyright © 2005 by the American Diabetes Association.