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S6K1 controls pancreatic β cell size independently of intrauterine growth restriction
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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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UM, Sung hee, STICKER-JANTSCHEFF, Melanie, CHAU, Gia cac, VINTERSTEN, Kristina, MUELLER, Matthias, GANGLOFF, Yann-gael, ADAMS, Ralf h., SPETZ, Jean-françois, ELGHAZI, Lynda, PFLUGER, Paul t., PENDE, Mario, BERNAL-MIZRACHI, Ernesto, TAULER GIRONA, Albert, TSCHÖP, Matthias h., THOMAS, George, KOZMA, Sara c.. S6K1 controls pancreatic β cell size independently of intrauterine growth restriction. _Journal of Clinical Investigation_. 2015. Vol. 125, núm. 7, pàgs. 2736-2747. [consulta: 20 de gener de 2026]. ISSN: 0021-9738. [Disponible a: https://hdl.handle.net/2445/177200]