Linked Life Data

19275933

Source:http://linkedlifedata.com/resource/pubmed/id/19275933

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
7
pubmed:dateCreated
2009-4-27
pubmed:abstractText
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.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
1873-3913
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
21
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1123-34
pubmed:meshHeading
pubmed-meshheading:19275933-Allosteric Regulation, pubmed-meshheading:19275933-Animals, pubmed-meshheading:19275933-Body Weight, pubmed-meshheading:19275933-Crosses, Genetic, pubmed-meshheading:19275933-Fasting, pubmed-meshheading:19275933-Female, pubmed-meshheading:19275933-Gene Targeting, pubmed-meshheading:19275933-Glucose, pubmed-meshheading:19275933-Glucose Tolerance Test, pubmed-meshheading:19275933-Glycogen Phosphorylase, Liver Form, pubmed-meshheading:19275933-Glycogen Synthase, pubmed-meshheading:19275933-Heterozygote, pubmed-meshheading:19275933-Humans, pubmed-meshheading:19275933-Liver, pubmed-meshheading:19275933-Liver Glycogen, pubmed-meshheading:19275933-Male, pubmed-meshheading:19275933-Mice, pubmed-meshheading:19275933-Mice, Inbred C57BL, pubmed-meshheading:19275933-Mutation, pubmed-meshheading:19275933-Phosphorylation, pubmed-meshheading:19275933-Protein Phosphatase 1, pubmed-meshheading:19275933-Rabbits, pubmed-meshheading:19275933-Weight Loss
pubmed:year
2009
pubmed:articleTitle
Disruption of the allosteric phosphorylase a regulation of the hepatic glycogen-targeted protein phosphatase 1 improves glucose tolerance in vivo.
pubmed:affiliation
Medical Research Council Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee, Scotland, UK.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't