Optical control of insulin release using a photoswitchable sulfonylurea

Johannes Broichhagen, Matthias Schönberger, Simon C. Cork, James A. Frank, Piero Marchetti, Marco Bugliani, A. M. James Shapiro, Stefan Trapp, Guy A. Rutter, David J. Hodson () and Dirk Trauner ()
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Johannes Broichhagen: Ludwig-Maximilians-Universität München, and Munich Center for Integrated Protein Science, Butenandtstrasse 5-13, 81377 München, Germany
Matthias Schönberger: Ludwig-Maximilians-Universität München, and Munich Center for Integrated Protein Science, Butenandtstrasse 5-13, 81377 München, Germany
Simon C. Cork: Physiology and Pharmacology, University College London
James A. Frank: Ludwig-Maximilians-Universität München, and Munich Center for Integrated Protein Science, Butenandtstrasse 5-13, 81377 München, Germany
Piero Marchetti: Islet Cell Laboratory, University of Pisa
Marco Bugliani: Islet Cell Laboratory, University of Pisa
A. M. James Shapiro: Clinical Islet Laboratory and Clinical Islet transplant program, University of Alberta
Stefan Trapp: Physiology and Pharmacology, University College London
Guy A. Rutter: Section of Cell Biology, Imperial College London, Imperial Centre for Translational and Experimental Medicine, Hammersmith Hospital, Du Cane Road
David J. Hodson: Section of Cell Biology, Imperial College London, Imperial Centre for Translational and Experimental Medicine, Hammersmith Hospital, Du Cane Road
Dirk Trauner: Ludwig-Maximilians-Universität München, and Munich Center for Integrated Protein Science, Butenandtstrasse 5-13, 81377 München, Germany

Nature Communications, 2014, vol. 5, issue 1, 1-11

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms6116

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