S6K1 controls pancreatic β cell size independently of intrauterine growth restriction
Sung Hee Um, … , George Thomas, Sara C. Kozma
Sung Hee Um, … , George Thomas, Sara C. Kozma
Published June 15, 2015
Citation Information: J Clin Invest. 2015;125(7):2736-2747. https://doi.org/10.1172/JCI77030.
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Research Article Endocrinology

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

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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Figure 4

Tetraploid WT placenta rescues growth retardation but not β cell size in S6K1–/– embryos.

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Tetraploid WT placenta rescues growth retardation but not β cell size in...
(A–D) WT, S6K1–/–, and S6K1–/– TR placentas and embryos at E13.5: (A) pictures representative of sizes; (B) histology by H&E staining: S6K1–/– TR placenta reveals correct intermingling of maternal (open arrows) and embryonic blood vessels (filled arrows) in labyrinthine trophoblast (Lb); (C) Body weights (n = 3–9 per genotype). (D) Placenta weights (n = 3–9 per genotype). (E) Genotype of the tetraploid placenta and the ES cell–derived embryo from an S6K1–/– TR mouse by Southern blot analysis. The lanes were run on the same gel but were noncontiguous. (F and G) Pancreas sections from E16.5 WT and S6K1–/– TR embryos: (F) histology by H&E staining; (G) glucose transporter GLUT2 by immunofluorescence (IF) staining; and (H) insulin (red) and glucagon (green) by IF staining. (I) Diminished β cell size in S6K1–/– TR pancreata, calculated on 56 determinations from WT embryos and 43 from S6K1–/– TR embryos (n = 3 per genotype). (J) β cell number in embryonic pancreata (n = 3 for per genotype, 18 sections per genotype). (K) Reduced insulin content in E16.5 S6K1–/– TR embryos (n = 3, from independent experiments) compared with WT embryos (n = 6) developed in surrogate mother mice. Scale bars: 25 μm. In C–K, values are given as mean ± SEM. *P < 0.05; **P < 0.01 vs. WT, unpaired t test.