Sung Hee Um1,2, Melanie Sticker-Jantscheff3, Gia Cac Chau2, Kristina Vintersten4, Matthias Mueller5, Yann-Gael Gangloff6, Ralf H. Adams7, Jean-Francois Spetz8, Lynda Elghazi9, Paul T. Pfluger10, Mario Pende11, Ernesto Bernal-Mizrachi9, Albert Tauler12, Matthias H. Tschop10, George Thomas1,13,14, and Sara C. Kozma1,14
1Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio, USA. 2Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea. 3Department of Molecular Pathology, Institute of Pathology, University Hospital Basel, Basel, Switzerland. 4Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. 5Novartis Pharma AG, Basel, Switzerland. 6Laboratoire de Biologie Moleculaire de la Cellule, CNRS UMR5239, Lyon, France. 7Max-Planck-Institute for Molecular Biomedicine, University of Munster, Munster, Germany. 8Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland. 9Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA. 10Helmholtz Zentrum Munchen, German Research Center for Environmental Health (GmbH), Institute for Diabetes and Obesity, Garching, Germany. 11INSERM, U1151, Universite Paris Descartes, Paris, France. 12Department of Biochemistry and Molecular Biology, Faculty of Farmacy, University of Barcelona, Barcelona, Spain. 13Department of Physiological Sciences II, Faculty of Medicine, University of Barcelona, Barcelona, Spain. 14Laboratory of Cancer Metabolism, Institut d’Investigacio Biomedica de Bellvitge (IDIBELL), Barcelona, Spain.
Address correspondence to: Sara C. Kozma Or Sung Hee Um
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.