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dc.contributor.authorTanabe, Katsuya
dc.contributor.authorLiu, Zhonghao
dc.contributor.authorPatel, Satish
dc.contributor.authorDoble, Bradley W
dc.contributor.authorCras-Méneur, Corentin
dc.contributor.authorMartinez, Sara C
dc.contributor.authorWelling, Cris M
dc.contributor.authorBernal-Mizrachi, Ernesto
dc.contributor.authorWoodgett, James R
dc.contributor.authorPermutt, M. Alan
dc.contributor.authorLi, Lin
dc.contributor.authorWhite, Morris Francis
dc.date.accessioned2011-10-20T03:04:21Z
dc.date.issued2008
dc.identifier.citationTanabe, Katsuya, Zhonghao Liu, Satish Patel, Bradley W. Doble, Lin Li, Corentin Cras-Méneur, Sara C. Martinez, et al. 2008. Genetic Deficiency of Glycogen Synthase Kinase-3β Corrects Diabetes in Mouse Models of Insulin Resistance. PLoS Biology 6(2): e37.en_US
dc.identifier.issn1544-9173en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:5266861
dc.description.abstractDespite treatment with agents that enhance β-cell function and insulin action, reduction in β-cell mass is relentless in patients with insulin resistance and type 2 diabetes mellitus. Insulin resistance is characterized by impaired signaling through the insulin/insulin receptor/insulin receptor substrate/PI-3K/Akt pathway, leading to elevation of negatively regulated substrates such as glycogen synthase kinase-3β (Gsk-3β). When elevated, this enzyme has antiproliferative and proapoptotic properties. In these studies, we designed experiments to determine the contribution of Gsk-3β to regulation of β-cell mass in two mouse models of insulin resistance. Mice lacking one allele of the insulin receptor (Ir+/−) exhibit insulin resistance and a doubling of β-cell mass. Crossing these mice with those having haploinsufficiency for Gsk-3β (Gsk-3β+/−) reduced insulin resistance by augmenting whole-body glucose disposal, and significantly reduced β-cell mass. In the second model, mice missing two alleles of the insulin receptor substrate 2 (Irs2−/−), like the Ir+/− mice, are insulin resistant, but develop profound β-cell loss, resulting in early diabetes. We found that islets from these mice had a 4-fold elevation of Gsk-3β activity associated with a marked reduction of β-cell proliferation and increased apoptosis. Irs2−/− mice crossed with Gsk-3β+/− mice preserved β-cell mass by reversing the negative effects on proliferation and apoptosis, preventing onset of diabetes. Previous studies had shown that islets of Irs2−/− mice had increased cyclin-dependent kinase inhibitor p27kip1 that was limiting for β-cell replication, and reduced Pdx1 levels associated with increased cell death. Preservation of β-cell mass in Gsk-3β+/−Irs2−/− mice was accompanied by suppressed p27kip1 levels and increased Pdx1 levels. To separate peripheral versus β-cell–specific effects of reduction of Gsk3β activity on preservation of β-cell mass, mice homozygous for a floxed Gsk-3β allele (Gsk-3F/F) were then crossed with rat insulin promoter-Cre (RIP-Cre) mice to produce β-cell–specific knockout of Gsk-3β (βGsk-3β−/−). Like Gsk-3β+/− mice, βGsk-3β−/− mice also prevented the diabetes of the Irs2−/− mice. The results of these studies now define a new, negatively regulated substrate of the insulin signaling pathway specifically within β-cells that when elevated, can impair replication and increase apoptosis, resulting in loss of β-cells and diabetes. These results thus form the rationale for developing agents to inhibit this enzyme in obese insulin-resistant individuals to preserve β-cells and prevent diabetes onset.en_US
dc.language.isoen_USen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.isversionofdoi:10.1371/journal.pbio.0060037en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2245985/pdf/en_US
dash.licenseLAA
dc.subjectdiabetesen_US
dc.subjectendocrinologyen_US
dc.titleGenetic Deficiency of Glycogen Synthase Kinase-3β Corrects Diabetes in Mouse Models of Insulin Resistanceen_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalPLoS Biologyen_US
dash.depositing.authorWhite, Morris Francis
dc.date.available2011-10-20T03:04:21Z
dash.affiliation.otherHMS^Pediatrics-Children's Hospitalen_US
dc.identifier.doi10.1371/journal.pbio.0060037*
dash.authorsorderedfalse
dash.contributor.affiliatedLi, Lin
dash.contributor.affiliatedWhite, Morris


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