Enteroendocrine cell function in diabetes and obesity. (360G-Wellcome-088357_Z_09_Z)

This program will address some of the fundamental unanswered questions about L-cell biology. L-cells produce hormones affecting glucose homeostasis and appetite, and are the target of current drug development programs for type 2 diabetes. The prediction is that stimulating GLP-1 release from L-cells will provide oral therapies that could be used alongside recently-licensed DPPIV inhibitors. Understanding L-cell physiology is critical to the success of this type of approach, but has been hindered by difficulties in identifying and culturing intestinal endocrine cells. We made transgenic mice with fluorescently labelled L-cells, and developed methodologies to characterise the cells by expression analysis, electrophysiology and imaging, providing a first opportunity to study primary L-cells at a single cell level. This technology will be used to probe the physiology of the L-cell using a range of electrophysiological and optical recording techniques, and to address key questions and hypot heses about L-cell function, such as that electrogenic transporters act as sensors of the luminal constituents, that L-cells from different gut regions are not identical and that the cells exhibit plasticity in number/function in an altered metabolic environment. In parallel, we will develop new technologies to study L-cells from humans, and downstream targets of GLP-1 in the intestine.