Our laboratory studies insulin secretion and structure-mechanism relations underlying the ATP-inhibited potassium (KATP) channel response to physiologically important ligands, ATP, ADP, and anti-diabetic sulfonylureas. In pancreatic beta cells, the KATP channel brings insulin secretion under the control of blood glucose levels. Our major goal is to establish the molecular mechanisms underlying how ATP binding to the KATP channel signaling changes in glucose metabolism, in turn, signals commensurate changes in insulin granule exocytosis. Normally, the fraction of time the KATP channel spends in the inhibited state determines insulin secretory rates. When this regulation goes awry, serious complications at the whole-organism level lead to diabetes and other diseases. Recently, we have demonstrated how ATP binding to the Kir6.2 subunit of the KATP channel electrostatically couples to the transmembrane domain to cause gate closure. One of the positions of the KATP channel required for this signaling is mutated in the conserved position of the human KATP channel in permanent neonatal diabetes (PNDM). We have also combined confocal fluorescence microscopy and a novel molecular strategy to visualize insulin secretion in live cells. The Ins-C-GFP reporter has exploded our ability to look inside live insulin-secreting cells to study glucose-stimulated insulin granule transport and exocytosis. Using this approach we have localized KATP channels to insulin secretory granules. We are currently investigating the role of granule KATP channels in insulin secretion. Finally, we are using the Ins-C-GFP reporter together with the mouse body wall window technique for unprecedented live-cell imaging of Ins-C-GFP labeled human islets in diabetic NODscid mice to characterize parameters associated with successful transplantation. Trainees in our laboratory have the opportunity to combine the techniques of molecular genetics and confocal live-cell fluorescence imaging, with transgenic techniques to integrate understanding at the molecular, whole cell, organ, and organism level.