title: S6K1 controls pancreatic β cell size independently of intrauterine growth restriction.
abstract: 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.
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Um
authors.forename: Melanie
authors.initials: M
authors.lastname: Sticker-Jantscheff
authors.forename: Gia Cac
authors.initials: GC
authors.lastname: Chau
authors.forename: Kristina
authors.initials: K
authors.lastname: Vintersten
authors.forename: Matthias
authors.initials: M
authors.lastname: Mueller
authors.forename: Yann-Gael
authors.initials: YG
authors.lastname: Gangloff
authors.forename: Ralf H
authors.initials: RH
authors.lastname: Adams
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Spetz
authors.forename: Lynda
authors.initials: L
authors.lastname: Elghazi
authors.forename: Paul T
authors.initials: PT
authors.lastname: Pfluger
authors.forename: Mario
authors.initials: M
authors.lastname: Pende
authors.forename: Ernesto
authors.initials: E
authors.lastname: Bernal-Mizrachi
authors.forename: Albert
authors.initials: A
authors.lastname: Tauler
authors.forename: Matthias H
authors.initials: MH
authors.lastname: Tschöp
authors.forename: George
authors.initials: G
authors.lastname: Thomas
authors.forename: Sara C
authors.initials: SC
authors.lastname: Kozma
mesh_terms: D000818:Animals; D048429:Cell Size; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000209:etiology / Q000473:pathology; D005260:Female; D005317:Fetal Growth Retardation / Q000201:enzymology* / Q000473:pathology*; D005816:Genetic Complementation Test; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000201:enzymology* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010929:Placentation / Q000235:genetics / Q000502:physiology; D011247:Pregnancy; D011254:Pregnancy in Diabetics / Q000201:enzymology / Q000473:pathology; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D057891:Tetraploidy
chemical_list: D007328:Insulin; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse