@article{f2db171cc53d424ba819210fb6ed2c58,
title = "Optical control of insulin release using a photoswitchable sulfonylurea",
abstract = "Sulfonylureas are widely prescribed for the treatment of type 2 diabetes mellitus (T2DM). Through their actions on ATP-sensitive potassium (KATP) channels, sulfonylureas boost insulin release from the pancreatic beta cell mass to restore glucose homeostasis. A limitation of these compounds is the elevated risk of developing hypoglycemia and cardiovascular disease, both potentially fatal complications. Here, we describe the design and development of a photoswitchable sulfonylurea, JB253, which reversibly and repeatedly blocks KATP channel activity following exposure to violet-blue light. Using in situ imaging and hormone assays, we further show that JB253 bestows light sensitivity upon rodent and human pancreatic beta cell function. Thus, JB253 enables the optical control of insulin release and may offer a valuable research tool for the interrogation of KATP channel function in health and T2DM.",
author = "Johannes Broichhagen and Matthias Sch{\"o}nberger and Cork, {Simon C.} and Frank, {James A.} and Piero Marchetti and Marco Bugliani and Shapiro, {A. M.James} and Stefan Trapp and Rutter, {Guy A.} and Hodson, {David J.} and Dirk Trauner",
note = "Funding Information: J.B. was supported by a European Foundation for the Study of Diabetes (EFSD) Albert Renold Young Scientist Fellowship (94741) and Studienstiftung des deutschen Volkes PhD studentship. D.J.H. was supported by a Diabetes UK R.D. Lawrence Research Fellowship (12/0004431) and G.A.R. by Wellcome Trust Senior Investigator (WT098424AIA), MRC Programme (MR/J0003042/1), Diabetes UK Project Grant (11/0004210) and Royal Society Wolfson Research Merit Awards. S.T. was supported by a Diabetes UK Project Grant (12/0004529). D.T. was supported by an Advanced Grant from the European Research Council (268795). The work leading to this publication has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 155005 (IMIDIA), resources of which are composed of financial contribution from the European Union{\textquoteright}s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies{\textquoteright} in kind contribution (G.A.R. and P.M). We are grateful to Dr Peter Mayer from LMU Munich for X-Ray crystallography and Silke Duensing-Kropp, Dr Georg H{\"o}fner and Prof. Dr Klaus T. Wanner from LMU Munich for assistance with [3H]-glibenclamide studies. Lastly, we thank Mr. Ryan K. Mitchell, Miss Natalie R. Johnston and Miss Maria-Rita Paiva Pessoa from Imperial College London for technical assistance, Prof. Jin Zhang from the Johns Hopkins University for kindly providing us with the plasmid for Epac2-camps, and Drs Tatsuya Kin and Doug O{\textquoteright}Gorman from the Clinical Islet Isolation Laboratory in Edmonton for providing human islets. Publisher Copyright: {\textcopyright} 2014 Macmillan Publishers Limited. All rights reserved.",
year = "2014",
month = oct,
day = "14",
doi = "10.1038/ncomms6116",
language = "English (US)",
volume = "5",
journal = "Nature communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
}