Linked Life Data

19289105

Source:http://linkedlifedata.com/resource/pubmed/id/19289105

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2009-4-15
pubmed:abstractText
Silencing of PIKfyve, the sole enzyme for PtdIns(3,5)P(2) biosynthesis that controls proper endosome dynamics, inhibits retroviral replication. A novel PIKfyve-specific inhibitor YM201636 disrupts retroviral budding at 800 nM, suggesting its potential use as an antiretroviral therapeutic. Because PIKfyve is also required for optimal insulin activation of GLUT4 surface translocation and glucose influx, we tested the outcome of YM201636 application on insulin responsiveness in 3T3L1 adipocytes. YM201636 almost completely inhibited basal and insulin-activated 2-deoxyglucose uptake at doses as low as 160 nM, with IC(50)=54+/-4 nM for the net insulin response. Insulin-induced GLUT4 translocation was partially inhibited at substantially higher doses, comparable to those required for inhibition of insulin-induced phosphorylation of Akt/PKB. In addition to PIKfyve, YM201636 also completely inhibited insulin-dependent activation of class IA PI 3-kinase. We suggest that apart from PIKfyve, there are at least two additional targets for YM201636 in the context of insulin signaling to GLUT4 and glucose uptake: the insulin-activated class IA PI 3-kinase and a here-unidentified high-affinity target responsible for the greater inhibition of glucose entry vs. GLUT4 translocation. The profound inhibition of the net insulin effect on glucose influx at YM201636 doses markedly lower than those required for efficient retroviral budding disruption warns of severe perturbations in glucose homeostasis associated with potential YM201636 use in antiretroviral therapy.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/6-amino-N-(3-(4-(4-morpholinyl)pyrid..., http://linkedlifedata.com/resource/pubmed/chemical/Aminopyridines, http://linkedlifedata.com/resource/pubmed/chemical/Antiviral Agents, http://linkedlifedata.com/resource/pubmed/chemical/Glucose, http://linkedlifedata.com/resource/pubmed/chemical/Glucose Transporter Type 4, http://linkedlifedata.com/resource/pubmed/chemical/Heterocyclic Compounds, 3-Ring, http://linkedlifedata.com/resource/pubmed/chemical/Insulin, http://linkedlifedata.com/resource/pubmed/chemical/Insulin Antagonists, http://linkedlifedata.com/resource/pubmed/chemical/Phosphatidylinositol 3-Kinases, http://linkedlifedata.com/resource/pubmed/chemical/Phosphatidylinositol Phosphates, http://linkedlifedata.com/resource/pubmed/chemical/Pikfyve protein, mouse, http://linkedlifedata.com/resource/pubmed/chemical/phosphatidylinositol 3,5-diphosphate
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
1090-2104
pubmed:author
pubmed:issnType
Electronic
pubmed:day
8
pubmed:volume
382
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
566-70
pubmed:dateRevised
2011-11-17
pubmed:meshHeading
pubmed:year
2009
pubmed:articleTitle
YM201636, an inhibitor of retroviral budding and PIKfyve-catalyzed PtdIns(3,5)P2 synthesis, halts glucose entry by insulin in adipocytes.
pubmed:affiliation
Department of Physiology, Wayne State University School of Medicine, 540 E. Canfield, Detroit, MI 48201, United States.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural