| Glycogen phosphorylase inhibition in type 2 diabetes therapy: a systematic evaluation of metabolic and functional effects in rat skeletal muscle. | |
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MedLine Citation:
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PMID: 16046314 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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David J Baker; James A Timmons; Paul L Greenhaff |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Diabetes Volume: 54 ISSN: 0012-1797 ISO Abbreviation: Diabetes Publication Date: 2005 Aug |
Date Detail:
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Created Date: 2005-07-27 Completed Date: 2005-10-20 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 0372763 Medline TA: Diabetes Country: United States |
Other Details:
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Languages: eng Pagination: 2453-9 Citation Subset: AIM; IM |
Affiliation:
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Centre for Integrated Systems Biology and Medicine, School of Biomedical Science, University of Nottingham, UK. dbaker@kin.ucalgary.ca |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals 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 Male Muscle Contraction / drug effects Muscle, Skeletal / drug effects, enzymology*, physiopathology* Phenylbutyrates / adverse effects*, therapeutic use Rats Rats, Wistar |
| Chemical | |
Reg. No./Substance:
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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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