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oai:recercat.cat:2445/1772002025-12-05T09:21:09Zcom_2072_1057col_2072_478782col_2072_478799col_2072_478916col_2072_478917

00925njm 22002777a 4500 dc Um, Sung Hee author Sticker-Jantscheff, Melanie author Chau, Gia Cac author Vintersten, Kristina author Mueller, Matthias author Gangloff, Yann-Gael author Adams, Ralf H. author Spetz, Jean-François author Elghazi, Lynda author Pfluger, Paul T. author Pende, Mario author Bernal-Mizrachi, Ernesto author Tauler Girona, Albert author Tschöp, Matthias H. author Thomas, George author Kozma, Sara C. author 2021-05-11T14:32:50Z 2021-05-11T14:32:50Z 2015-07-01 2021-05-11T14:32:50Z 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. Retard del creixement intrauterí Insulina Enzimologia Fisiologia Proteïnes quinases Fetal growth retardation Insulin Enzymology Physiology Protein kinases S6K1 controls pancreatic β cell size independently of intrauterine growth restriction