Hypoinsulinaemia, glucose intolerance and diminished beta-cell size in S6K1-deficient mice

Insulin controls glucose homeostasis by regulating glucose use in periphera l tissues, and its own production and secretion in pancreatic beta cells(1- 3). These responses are largely mediated downstream of the insulin receptor substrates, IRS-1 and IRS-2 (refs 4-8), through distinct signalling pathwa ys. Although a number of effectors of these pathways have been identified, their roles in mediating glucose homeostasis are poorly defined(9). Here we show that mice deficient for S6 kinase 1, an effector of the phosphatidyli nositide-3-OH kinase signalling pathway(9), are hypoinsulinaemic and glucos e 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 s ensing or insulin production, but to a reduction in pancreatic endocrine ma ss, which is accounted for by a selective decrease in beta -cell size. The observed phenotype closely parallels those of preclinical type 2 diabetes m ellitus, in which malnutrition-induced hypoinsulinaemia predisposes individ uals to glucose intolerance(10-12).