Increased potency and efficacy of combined phosphorylase inactivation and glucokinase activation in control of hepatocyte glycogen metabolism.
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-beta-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.
Hampson
Laura J
LJ
School of Clinical Medical Sciences-Diabetes, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, NE2 4HH, U.K.
Agius
Loranne
L
D000249:Adenosine Monophosphate; D000577:Amides / Q000494:pharmacology*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression; D005941:Glucokinase / Q000378:metabolism*; D006006:Glycogen Synthase / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D008112:Liver Glycogen / Q000378:metabolism*; D008297:Male; D010762:Phosphorylase a / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012265:Ribonucleotides / Q000494:pharmacology
D000577:Amides; C110844:CP 91149; D007211:Indoles; D008112:Liver Glycogen; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D000249:Adenosine Monophosphate; D010762:Phosphorylase a; D006006:Glycogen Synthase; D005941:Glucokinase; C031143:AICA ribonucleotide