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 6

Pancreatic β cell–specific expression of S6K1 improves glucose tolerance.

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Pancreatic β cell–specific expression of S6K1 improves glucose tolerance...
(A) RIP-S6K1 transgene expression in islet extracts by Western blot analysis detecting Myc-tag and S6K1 protein. (B) Body weight was measured in 8-month-old male mice (n = 6–12 per genotype). (C–H) Male mice were analyzed at 3–6 months of age for (C) percent of fat-mass and (D) lean mass. They were normalized by body weight and determined by NMR analysis (n = 5–9 mice of per genotype); (E) increased oxygen consumption in S6K1 transgenic mice measured either during the day or night as indicated (n = 4–9 mice per genotype). (F) Plasma insulin concentrations in mice fasted for 6 hours (n = 6–10 mice of per genotype; experiments were performed twice). (G) Blood glucose concentrations before and after i.p. injection of 2 g d-glucose per kg body weight in mice fasted overnight (n = 5–9 mice per genotype). (H) Insulin tolerance test after 3 hours fasting: plasma glucose concentration before and after intraperitoneal injection of insulin (0.75 U per kg body weight; n = 5–9 mice per genotype). Values in B–H are given as mean ± SEM. *P < 0.05 vs. other genotypes, **P < 0.01 vs. other genotypes, ANOVA.