"Glucose sensing cells constantly monitor glucose absorption from food and variations in blood glycemic levels. They control the secretion of GLP-1, insulin and glucagon, and the activity of the autonomic nervous system. These hormonal and nervous signals coordinate glucose utilization by liver, fat and muscle, and endogenous glucose production as well as feeding and energy expenditure. Type 2 diabetes, a disease that afflicts an increasing proportion of the world population, is characterized by insufficient insulin production by pancreatic beta-cells, abnormal secretion of GLP-1 and glucagon, and is often associated with imbalance between feeding and energy expenditure. Type 2 diabetes can thus be considered a disease of glucose sensing. Here, I propose a research program using cell biological, genetic, genomic and physiology techniques to investigate three aspects of this integrated glucose sensing network:1. The identification of novel molecular pathways activated by GLP-1 and that control adult beta-cell proliferation, glucose competence and apoptosis in order to maintain sufficient insulin secretion capacity.2. The identification and molecular characterization of brain glucose sensors, which share functional similarities with pancreatic beta-cells, and which control glucose homeostasis and pancreatic islet mass and function.3. The discovery by unbiased genetic-genomic analysis of loci, genes, and gene networks involved in central hypoglycemia detection and the secretion of glucagon, a process whose deregulation is a major limitation in insulin treatment of both type 1 and type 2 diabetes.Together these investigations will bring new knowledge on the integrated control of glucose homeostasis that may lead to novel strategies to control diabetes."