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.
authors.affiliation: Department of Chemistry, Ludwig-Maximilians-Universität München, and Munich Center for Integrated Protein Science, Butenandtstrasse 5-13, 81377 München, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Broichhagen
authors.affiliation: Department of Chemistry, Ludwig-Maximilians-Universität München, and Munich Center for Integrated Protein Science, Butenandtstrasse 5-13, 81377 München, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schönberger
authors.affiliation: Division of Biosciences, Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, UK.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Cork
authors.affiliation: Department of Chemistry, Ludwig-Maximilians-Universität München, and Munich Center for Integrated Protein Science, Butenandtstrasse 5-13, 81377 München, Germany.
authors.forename: James A
authors.initials: JA
authors.lastname: Frank
authors.affiliation: Department of Clinical and Experimental Medicine, Islet Cell Laboratory, University of Pisa, 56126 Pisa, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Marchetti
authors.affiliation: Department of Clinical and Experimental Medicine, Islet Cell Laboratory, University of Pisa, 56126 Pisa, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Bugliani
authors.affiliation: Clinical Islet Laboratory and Clinical Islet transplant program, University of Alberta, Edmonton, Alberta T6G 2C8, Canada.
authors.forename: A M James
authors.initials: AM
authors.lastname: Shapiro
authors.affiliation: Division of Biosciences, Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, UK.
authors.forename: Stefan
authors.initials: S
authors.lastname: Trapp
authors.affiliation: Section of Cell Biology, Department of Medicine, Imperial College London, Imperial Centre for Translational and Experimental Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rutter
authors.affiliation: Section of Cell Biology, Department of Medicine, Imperial College London, Imperial Centre for Translational and Experimental Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Hodson
authors.affiliation: Department of Chemistry, Ludwig-Maximilians-Universität München, and Munich Center for Integrated Protein Science, Butenandtstrasse 5-13, 81377 München, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Trauner
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects / Q000528:radiation effects; D002460:Cell Line; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D054086:KATP Channels / Q000378:metabolism; D008027:Light; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013453:Sulfonylurea Compounds / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D054086:KATP Channels; D013453:Sulfonylurea Compounds