1. Friedrich Miescher Institute, CH-4058 Basel, Switzerland
2. Institute of Pharmacology and Toxicology , CH-1005 Lausanne, Switzerland
3. Department of Cell Biology, University Medical Center and Research Institute of Biomembranes, 3584CX Utrecht, The Netherlands
4. INSERM E 99-11, Biologie et physiologie de la Nutrition et Signalisation, Faculty of Medicine, 06107 Nice, France

Correspondence to: George Thomas¹ Correspondence and requests for materials should be addressed to G.T. (e-mail: Email: gthomas@fmi.ch).

Abstract

Insulin controls glucose homeostasis by regulating glucose use in peripheral tissues, and its own production and secretion in pancreatic cells^{1, 2, 3}. These responses are largely mediated downstream of the insulin receptor substrates, IRS-1 and IRS-2 (refs 4,5,6,7,8), through distinct signalling pathways. Although a number of effectors of these pathways have been identified, their roles in mediating glucose homeostasis are poorly defined⁹. Here we show that mice deficient for S6 kinase 1, an effector of the phosphatidylinositide-3-OH kinase signalling pathway⁹, are hypoinsulinaemic and glucose intolerant. Whereas insulin resistance is not observed in isolated muscle, such mice exhibit a sharp reduction in glucose-induced insulin secretion and in pancreatic insulin content. This is not due to a lesion in glucose sensing or insulin production, but to a reduction in pancreatic endocrine mass, which is accounted for by a selective decrease in -cell size. The observed phenotype closely parallels those of preclinical type 2 diabetes mellitus, in which malnutrition-induced hypoinsulinaemia predisposes individuals to glucose intolerance^{10, 11, 12}.