S6K1 controls pancreatic β cell size independently of intrauterine growth restriction

Sung Hee Um, Melanie Sticker-Jantscheff, Gia Cac Chau, Kristina Vintersten, Matthias Mueller, Yann Gael Gangloff, Ralf H. Adams, Jean Francois Spetz, Lynda Elghazi, Paul T. Pfluger, Mario Pende, Ernesto Bernal-Mizrachi, Albert Tauler, Matthias H. Tschöp, George Thomas, Sara C. Kozma

Research output: Contribution to journalArticle

15 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2736-2747
Number of pages12
JournalJournal of Clinical Investigation
Volume125
Issue number7
DOIs
StatePublished - Jul 1 2015

ASJC Scopus subject areas

  • Medicine(all)

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    Um, S. H., Sticker-Jantscheff, M., Chau, G. C., Vintersten, K., Mueller, M., Gangloff, Y. G., Adams, R. H., Spetz, J. F., Elghazi, L., Pfluger, P. T., Pende, M., Bernal-Mizrachi, E., Tauler, A., Tschöp, M. H., Thomas, G., & Kozma, S. C. (2015). S6K1 controls pancreatic β cell size independently of intrauterine growth restriction. Journal of Clinical Investigation, 125(7), 2736-2747. https://doi.org/10.1172/JCI77030