S6K1 controls pancreatic β cell size independently of intrauterine growth restriction

Type 2 diabetes mellitus (T2DM) is a worldwide heath problem that is characterized by insulin resistance and the eventual loss of beta 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 beta 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 beta 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 beta cell size or insulin levels in S6K1(-/-) embryos, suggesting that loss of S6K1 leads to an intrinsic beta cell lesion. Consistent with this hypothesis, reexpression of S6K1 in beta cells of S6K1(-/-) mice restored embryonic beta cell size, insulin levels, glucose tolerance, and RP56 phosphorylation, without rescuing IUGR. Together, these data suggest that a nutrient-mediated reduction in intrinsic beta cell S6K1 signaling, rather than IUGR, during fetal development may underlie reduced beta cell growth and eventual development of T2DM later in life.