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Lookup NU author(s): Dr Laura Hampson, Professor Loranne Agius
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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- α 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-α (a negative modulator) in activating glycogen synthase and also by synergistic inactivation of phosphorylase-α by glucokinase activation and the indole carboxamide. Inactivation of phosphorylase-α by the indole carboxamide was counteracted by 5-amino-imidazole-4-carboxamide 1-β-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-α enables improved potency and efficacy in controlling hepatic glucose metabolism. © 2005 by the American Diabetes Association.
Author(s): Hampson LJ, Agius L
Publication type: Article
Publication status: Published
Journal: Diabetes
Year: 2005
Volume: 54
Issue: 3
Pages: 617-623
Print publication date: 01/03/2005
ISSN (print): 0012-1797
ISSN (electronic): 1939-327X
Publisher: American Diabetes Association
URL: http://dx.doi.org/10.2337/diabetes.54.3.617
DOI: 10.2337/diabetes.54.3.617
PubMed id: 15734835
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