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
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 125 Issue 7 Pg. 2736-47 (Jul 01 2015) ISSN: 1558-8238 [Electronic] United States
• PMID: 26075820 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Insulin
• Ribosomal Protein S6 Kinases, 90-kDa
• Rps6ka1 protein, mouse

Topics

• Animals
• Cell Size
• Diabetes Mellitus, Type 2 (enzymology, etiology, pathology)
• Female
• Fetal Growth Retardation (enzymology, pathology)
• Genetic Complementation Test
• Humans
• Insulin (metabolism)
• Insulin Resistance
• Insulin-Secreting Cells (enzymology, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Placentation (genetics, physiology)
• Pregnancy
• Pregnancy in Diabetics (enzymology, pathology)
• Ribosomal Protein S6 Kinases, 90-kDa (deficiency, genetics, physiology)
• Tetraploidy