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 July 1, 2015; First 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 1

Diminished pancreatic β cell size and number in S6K1–/– embryos.

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Diminished pancreatic β cell size and number in S6K1–/– embryos. (A–D) P...
(A–D) Pancreas sections from WT or S6K1–/– embryos at E16.5: (A) histology, by H&E staining; (B) GLUT2 glucose transporter, by immunofluorescence (IF) staining; (C) cleaved caspase-3 (red), insulin (green) by IF staining and DAPI (blue) staining; and (D) insulin (red) and glucagon (green), by IF staining. (E) β cell number in embryonic pancreata (n = 3 per genotype). (F) β cell size in embryonic pancreata from 45–52 determinations in WT embryos and 29–44 determinations in S6K1–/– embryos (n = 3 per genotype; β cell surface: WT, 95.60 ± 2.69 μm2; S6K1–/–, 69.54 ± 1.5 μm2). (G) Reduced insulin content, normalized for body weight, in embryonic pancreata (n = 6–9 per genotype). Scale bars: 25 μm. In E–G, values are given as mean ± SEM. *P < 0.05, **P < 0.01 vs. WT, unpaired t test.