Mueller, Matthias (2015) S6K1 controls pancreatic β cell size independently of intrauterine growth restriction. Journal of Clinical Investigation., 125 (7). pp. 2736-2747. ISSN 0021-9738

Abstract

Type 2 diabetes mellitus (T2DM) is a major worldwide medical problem, characterized by insulin-resistance and the eventual loss of -cell function. Given that loss of ribosomal protein (RP) S6 kinase1 (S6K1) increases systemic insulin sensitivity, S6K1 inhibitors are being pursued as potential sensitizers for the treatment of insulin-resistance. However, we show here that loss of S6K1 also leads to impaired -cell growth, intrauterine growth restriction (IUGR) and impaired placental development. IUGR, is a common human-pregnancy complication that limits the supply of oxygen and nutrients from the placenta to the developing fetus, leading to diminished embryonic -cell growth and the onset of T2DM later in life. Unexpectedly, restoration of placental development and IUGR by tetraploid embryo complementation did not restore -cell size and insulin levels in S6K1-/- embryos, suggesting that loss of S6K1 leads to an intrinsic -cell lesion. Consistent with this hypothesis, re-expression of S6K1 in -cells of S6K1-/- mice restored embryonic -cell size, insulin levels, glucose tolerance and RPS6 phosphorylation, without rescuing IUGR. Thus, a nutrient-mediated reduction in S6K1 signaling during fetal development may be the cause of reduced -cell growth and impaired insulin secretion later in life, rather than IUGR.

Item Type:	Article
Date Deposited:	27 Apr 2016 23:45
Last Modified:	27 Apr 2016 23:45
URI:	https://oak.novartis.com/id/eprint/26328