Um, Sung HeeSticker-Jantscheff, MelanieChau, Gia CacVintersten, KristinaMueller, MatthiasGangloff, Yann-GaelAdams, Ralf H.Spetz, Jean-FrançoisElghazi, LyndaPfluger, Paul T.Pende, MarioBernal-Mizrachi, ErnestoTauler Girona, AlbertTschöp, Matthias H.Thomas, GeorgeKozma, Sara C.2021-05-112021-05-112015-07-010021-9738https://hdl.handle.net/2445/177200Type 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.12 p.application/pdfeng(c) American Society for Clinical Investigation, 2015Retard del creixement intrauteríInsulinaEnzimologiaFisiologiaProteïnes quinasesFetal growth retardationInsulinEnzymologyPhysiologyProtein kinasesinfo:eu-repo/semantics/article6567832021-05-11info:eu-repo/semantics/openAccess26075820