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dc.contributor.authorYaluri N
dc.contributor.authorModi S
dc.contributor.authorKokkola T
dc.date.accessioned2017-02-03T08:59:24Z
dc.date.available2017-02-03T08:59:24Z
dc.date.issued2016-11-11
dc.identifier10.1016/j.bbrc.2016.10.026fi_FI
dc.identifier.issn0006-291X
dc.identifier.urihttps://erepo.uef.fi/handle/123456789/248
dc.descriptionArticle
dc.description.abstractSimvastatin is a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor widely used for the treatment of hypercholesterolemia. Recent data indicates that simvastatin increases the risk of new-onset diabetes by impairing both insulin secretion and insulin sensitivity. However, systematic evaluation of mechanistic pathways is lacking. We aimed to explore the effects of simvastatin on glucose uptake and underlying mechanisms using L6 skeletal muscle myotubes. We performed our experiments at basal and insulin-stimulated conditions, at normal (5.5 mM) and high (16.7 mM) glucose. We showed that simvastatin inhibited glucose uptake at all conditions. We also found out that pravastatin, another widely used statin with different physicochemical properties, did not inhibit glucose uptake. The effect of simvastatin was reversed with geranylgeranyl pyrophosphate but not with farnesyl pyrophosphate, implying that reduced protein geranylgeranylation has a role in simvastatin-induced insulin resistance. Simvastatin also decreased phosphorylation of insulin receptor (IR), insulin receptor substrate 1 (IRS-1), AKT and glycogen synthase kinase 3β (GSK-3β), and downregulated GLUT4. In conclusion, our data indicate that simvastatin decreased both basal and insulin-stimulated glucose uptake through inhibiting the critical steps in IR/IRS-1/AKT signaling cascade, and by hindering GLUT4 function and normal regulation of glycogen synthesis, contributing to insulin resistance.fi_FI
dc.language.isoengfi_FI
dc.publisherElsevier BVfi_FI
dc.relation.ispartofseriesBIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
dc.relation.urihttp://dx.doi.org/10.1016/j.bbrc.2016.10.026fi_FI
dc.rightsCC BY-NC-ND https://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectSimvastatinfi_FI
dc.subjectGlucose uptakefi_FI
dc.subjectGlucose transporter 4fi_FI
dc.subjectIR-Dependent IRS-1/PI3K/Akt pathwayfi_FI
dc.subjectL6 myotubesfi_FI
dc.titleSimvastatin induces insulin resistance in L6 skeletal muscle myotubes by suppressing insulin signaling, GLUT4 expression and GSK-3ß phosphorylationfi_FI
dc.typehttp://purl.org/eprint/type/JournalArticle
dc.description.versionFinal Draftfi_FI
dc.contributor.departmentSchool of Medicine / Clinical Medicine
uef.solecris.id43689451
eprint.statushttp://purl.org/eprint/status/PeerReviewedfi_FI
dc.type.publicationinfo:eu-repo/semantics/article
dc.rights.accessrights© Elsevier Inc.
uef.citationinfo.issue2
uef.citationinfo.pages194-200
dc.relation.doi10.1016/j.bbrc.2016.10.026
dc.description.reviewstatushttp://purl.org/eprint/status/PeerReviewed
dc.format.pagerange194-200
dc.relation.issn0006-291X
dc.relation.issue2
dc.relation.volume480
dc.rights.accesslevelopenAccess


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