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

During the embryonic growth mechanisms that are not fully clear ensures that exo-and endocrine cells are formed in the correct proportion. The embryonic endocrine progenitor cells are a subset of the developing Pdxl pancre-atic 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 c-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. Type 2 diabetes is a complex disease caused by interactions of multiple genes and environmental factors such as high-fat diet and sedentary lifestyle. 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 251