Document Detail

Glycogen phosphorylase inhibition in type 2 diabetes therapy: a systematic evaluation of metabolic and functional effects in rat skeletal muscle.
MedLine Citation:
PMID:  16046314     Owner:  NLM     Status:  MEDLINE    
Inhibition of hepatic glycogen phosphorylase is a promising treatment strategy for attenuating hyperglycemia in type 2 diabetes. Crystallographic studies indicate, however, that selectivity between glycogen phosphorylase in skeletal muscle and liver is unlikely to be achieved. Furthermore, glycogen phosphorylase activity is critical for normal skeletal muscle function, and thus fatigue may represent a major development hurdle for this therapeutic strategy. We have carried out the first systematic evaluation of this important issue. The rat gastrocnemius-plantaris-soleus (GPS) muscle was isolated and perfused with a red cell suspension, containing 3 micromol/l glycogen phosphorylase inhibitor (GPi) or vehicle (control). After 60 min, the GPS muscle was snap-frozen (rest, n = 11 per group) or underwent 20 s of maximal contraction (n = 8, control; n = 9, GPi) or 10 min of submaximal contraction (n = 10 per group). GPi pretreatment reduced the activation of the glycogen phosphorylase a form by 16% at rest, 25% after 20 s, and 44% after 10 min of contraction compared with the corresponding control. AMP-mediated glycogen phosphorylase activation was impaired only at 10 min (by 21%). GPi transiently reduced muscle lactate production during contraction, but other than this, muscle energy metabolism and function remained unaffected at both contraction intensities. These data indicate that glycogen phosphorylase inhibition aimed at attenuating hyperglycaemia is unlikely to negatively impact muscle metabolic and functional capacity.
David J Baker; James A Timmons; Paul L Greenhaff
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Diabetes     Volume:  54     ISSN:  0012-1797     ISO Abbreviation:  Diabetes     Publication Date:  2005 Aug 
Date Detail:
Created Date:  2005-07-27     Completed Date:  2005-10-20     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0372763     Medline TA:  Diabetes     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2453-9     Citation Subset:  AIM; IM    
Centre for Integrated Systems Biology and Medicine, School of Biomedical Science, University of Nottingham, UK.
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MeSH Terms
Diabetes Mellitus, Type 2 / drug therapy*
Energy Metabolism
Enzyme Activation
Enzyme Inhibitors / adverse effects*,  therapeutic use
Glycogen Phosphorylase / antagonists & inhibitors*,  metabolism
Indoles / adverse effects*,  therapeutic use
Lactic Acid / biosynthesis
Liver / enzymology
Muscle Contraction / drug effects
Muscle, Skeletal / drug effects,  enzymology*,  physiopathology*
Phenylbutyrates / adverse effects*,  therapeutic use
Rats, Wistar
Reg. No./Substance:
0/3-(5-chloroindole-2-carbonyl)amino-2-hydroxy-4-phenylbutyric acid N-methyl-N-methoxyamide; 0/Enzyme Inhibitors; 0/Indoles; 0/Phenylbutyrates; 50-21-5/Lactic Acid; EC 2.4.1.-/Glycogen Phosphorylase

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