Abstracts from The 8th International Workshop on Lessons from Animal Diabetes

s of the 8th International Workshop on Lessons from Animal Diabetes Joint with The 15th Japan Association of Animal Diabetes Research TOKYO, JAPAN, JULY 24–26, 2001 Pancreatic Stem Cells and Islet Cell Differentiation PALLE SERUP, JAN JENSEN, JACOB HALD and OLE D. MADSEN Department of Developmental Biology, Hagedorn Research Institute, Gentofte, Denmark During the embryonic growth mechanisms that are not fully clear ensures that exoand endocrine cells are formed in the correct proportion. The embryonic endocrine progenitor cells are a subset of the developing Pdx1 pancreatic epithelial cells marked by the expression of Neurogenin3 (Ngn3). Ngn3 encodes a basic-Helix-Loop-Helix (bHLH) transcription factor (NGN3) that is required for the expression of NeuroD (as well as other transcription factor genes); moreover, ectopic Ngn3 expression can induce differentiation of embryonic pancreatic epithelium into α-cells at the expense of other pancreatic cell types. Notch signaling appears to control the activity of NGN3 and acts as a switch that determines the choice of the progenitor cells; the choice being to either remain as dividing precursor cells or to differentiate into endocrine cells. NGN3 is thought to activate transcription of the Notch ligand Dll–1. Once Dll–1 expression is induced in a differentiating cell it interacts with Notch, expressed on neighbouring cells. Notch activates a number of genes among which is the negatively acting bHLH gene Hes-1. This pathway (termed lateral inhibition) thus inhibits NGN3 activity and consequently endocrine differentiation and Dll–1 expression in the receiving cells. Lateral inhibition assures that only a few precursor cells differentiate and that a large fraction of the endocrine precursor cells in the pancreas are maintained in a dividing state until late stages of pancreatic development. In mice deficient for Notch pathway components, the precursor cells differentiate prematurely into endocrine cells. (Supported by NIH DK-55284) Molecular Pathogenesis of Type 2 Diabetes in Knockout Mice Models TAKASHI KADOWAKI, M.D., Ph.D. Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo Type 2 diabetes is a complex disease caused by interactions of multiple genes and environmental factors such as high-fat diet and sedentary life-style. Since type 2 diabetes is characterized by insulin resistance and relative insulin deficiency, we have tried to dissect molecular pathogenesis of type 2 diabetes by generating several knockout mice models with a lack of each key molecules of signalling pathways of either insulin action or insulin Int. Jnl. Experimental Diab. Res., Vol. 2, pp. 251–297 Copyright © 2001 Taylor & Francis, Inc. 1560-4284/01 $12.00 + .00