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Increased potency and efficacy of combined phosphorylase inactivation and glucokinase activation in control of hepatocyte glycogen metabolism

Lookup NU author(s): Dr Laura Hampson, Professor Loranne Agius

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Abstract

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.


Publication metadata

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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