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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.* ; Tschöp, M.H. ; Thomas, G.* ; Kozma, S.C.*

S6K1 controls pancreatic β cell size independently of intrauterine growth restriction.

J. Clin. Invest. 125, 2736-2747 (2015)
DOI PMC
Open Access Gold möglich sobald Verlagsversion bei der ZB eingereicht worden ist.
Type 2 diabetes mellitus (T2DM) is a worldwide heath problem that is characterized by insulin resistance and the eventual loss of β 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 β 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 β 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 β cell size or insulin levels in S6K1-/- embryos, suggesting that loss of S6K1 leads to an intrinsic β cell lesion. Consistent with this hypothesis, reexpression of S6K1 in β cells of S6K1-/- mice restored embryonic β cell size, insulin levels, glucose tolerance, and RPS6 phosphorylation, without rescuing IUGR. Together, these data suggest that a nutrient-mediated reduction in intrinsic β cell S6K1 signaling, rather than IUGR, during fetal development may underlie reduced β cell growth and eventual development of T2DM later in life.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Human Trophoblast Cells; Ribosomal-protein S6; Insulin-resistance; Mammalian Target; Serine Phosphorylation; Glucose; Rapamycin; Kinase; Mtor; Mass
ISSN (print) / ISBN 0021-9738
e-ISSN 1558-8238
Zeitschrift Journal of Clinical Investigation
Quellenangaben Band: 125, Heft: 7, Seiten: 2736-2747 Artikelnummer: , Supplement: ,
Verlag American Society of Clinical Investigation
Verlagsort Ann Arbor
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Obesity (IDO)