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          Institute: MPI für molekulare Biomedizin     Collection: Jahrbuch 2016 (publ. 2015, arch)     Display Documents

ID: 717256.0, MPI für molekulare Biomedizin / Jahrbuch 2016 (publ. 2015, arch)
S6K1 controls pancreatic beta cell size independently of intrauterine growth restriction
Authors:Um, S. H.; Sticker-Jantscheff, M.; Chau, G. C.; Vintersten, K.; Mueller, M.; Gangloff, Y. G.; Adams, R. H.; Spetz, J. F.; Elghazi, L.; Pfluger, P. T.; Pende, M.; Bernal-Mizrachi, E.; Tauler, A.; Tschop, M. H.; Thomas, G.; Kozma, S. C.
Date of Publication (YYYY-MM-DD):2015-07-01
Title of Journal:J Clin Invest
Issue / Number:7
Start Page:2736
End Page:2747
Review Status:Internal review
Audience:Not Specified
Abstract / Description:Type 2 diabetes mellitus (T2DM) is a worldwide heath problem that is characterized by insulin resistance and the eventual loss of beta cell function. As recent studies have shown that loss of ribosomal protein (RP) S6 kinase 1 (S6K1) increases systemic insulin sensitivity, S6K1 inhibitors are being pursued as potential agents for improving insulin resistance. Here we found that S6K1 deficiency in mice also leads to decreased beta cell growth, intrauterine growth restriction (IUGR), and impaired placental development. IUGR is a common complication of human pregnancy that limits the supply of oxygen and nutrients to the developing fetus, leading to diminished embryonic beta cell growth and the onset of T2DM later in life. However, restoration of placental development and the rescue of IUGR by tetraploid embryo complementation did not restore beta cell size or insulin levels in S6K1-/- embryos, suggesting that loss of S6K1 leads to an intrinsic beta cell lesion. Consistent with this hypothesis, reexpression of S6K1 in beta cells of S6K1-/- mice restored embryonic beta cell size, insulin levels, glucose tolerance, and RPS6 phosphorylation, without rescuing IUGR. Together, these data suggest that a nutrient-mediated reduction in intrinsic beta cell S6K1 signaling, rather than IUGR, during fetal development may underlie reduced beta cell growth and eventual development of T2DM later in life.
Free Keywords:Animals; Cell Size; Diabetes Mellitus, Type 2/enzymology/etiology/pathology; Female; Fetal Growth Retardation/*enzymology/*pathology; Genetic Complementation Test; Humans; Insulin/metabolism; Insulin Resistance; Insulin-Secreting Cells/*enzymology/*pathology; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Placentation/genetics/physiology; Pregnancy; Pregnancy in Diabetics/enzymology/pathology; Ribosomal Protein S6 Kinases, 90-kDa/deficiency/genetics/*physiology; Tetraploidy
External Publication Status:published
Document Type:Article
Communicated by:Keuker
Affiliations:MPI für molekulare Biomedizin
Identifiers:ISSN:1558-8238 (Electronic) 0021-9738 (Linking) %R 10.1... [ID No:1]
URL: [ID No:2]
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