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

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13 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
Externally publishedYes

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

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