| Disruption of the allosteric phosphorylase a regulation of the hepatic glycogen-targeted protein phosphatase 1 improves glucose tolerance in vivo. | |
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MedLine Citation:
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PMID: 19275933 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Type 2 diabetes is characterised by elevated blood glucose concentrations, which potentially could be normalised by stimulation of hepatic glycogen synthesis. Under glycogenolytic conditions, the interaction of hepatic glycogen-associated protein phosphatase-1 (PP1-G(L)) with glycogen phosphorylase a is believed to inhibit the dephosphorylation and activation of glycogen synthase (GS) by the PP1-G(L) complex, suppressing glycogen synthesis. Consequently, the interaction of G(L) with phosphorylase a has emerged as an attractive anti-diabetic target, pharmacological disruption of which could provide a novel mechanism to lower blood glucose levels by increasing hepatic glycogen synthesis. Here we report for the first time the in vivo consequences of disrupting the G(L)-phosphorylase a interaction, using a mouse model containing a Tyr284Phe substitution in the phosphorylase a-binding region of the G(L) protein. The resulting G(L)(Y284F/Y284F) mice display hepatic PP1-G(L) activity that is no longer sensitive to allosteric inhibition by phosphorylase a, resulting in increased GS activity under glycogenolytic conditions, demonstrating that regulation of G(L) by phosphorylase a operates in vivo. G(L)(Y284F/Y284F) and G(L)(Y284F/+) mice display improved glucose tolerance compared with G(L)(+/+) littermates, without significant accumulation of hepatic glycogen. The data provide the first in vivo evidence in support of targeting the G(L)-phosphorylase a interaction for treatment of hyperglycaemia. During prolonged fasting the G(L)(Y284F/Y284F) mice lose more body weight and display decreased blood glucose levels in comparison with their G(L)(+/+) littermates. These results suggest that, during periods of food deprivation, the phosphorylase a regulation of G(L) may prevent futile glucose-glycogen cycling, preserving energy and thus providing a selective biological advantage that may explain the observed conservation of the allosteric regulation of PP1-G(L) by phosphorylase a in mammals. |
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Authors:
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Ian R Kelsall; Doron Rosenzweig; Patricia T W Cohen |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-03-09 |
Journal Detail:
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Title: Cellular signalling Volume: 21 ISSN: 1873-3913 ISO Abbreviation: Cell. Signal. Publication Date: 2009 Jul |
Date Detail:
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Created Date: 2009-04-27 Completed Date: 2009-06-03 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8904683 Medline TA: Cell Signal Country: England |
Other Details:
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Languages: eng Pagination: 1123-34 Citation Subset: IM |
Affiliation:
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Medical Research Council Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee, Scotland, UK. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Allosteric Regulation Animals Body Weight Crosses, Genetic Fasting / blood Female Gene Targeting Glucose / metabolism* Glucose Tolerance Test Glycogen Phosphorylase, Liver Form / metabolism* Glycogen Synthase / metabolism Heterozygote Humans Liver / enzymology Liver Glycogen / metabolism* Male Mice Mice, Inbred C57BL Mutation / genetics Phosphorylation Protein Phosphatase 1 / metabolism* Rabbits Weight Loss |
| Grant Support | |
ID/Acronym/Agency:
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//Medical Research Council |
| Chemical | |
Reg. No./Substance:
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0/Liver Glycogen; 50-99-7/Glucose; EC 2.4.1.-/Glycogen Phosphorylase, Liver Form; EC 2.4.1.11/Glycogen Synthase; EC 3.1.3.16/Protein Phosphatase 1 |
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