title: Optical Control of Insulin Secretion Using an Incretin Switch.
abstract: Incretin mimetics are set to become a mainstay of type 2 diabetes treatment. By acting on the pancreas and brain, they potentiate insulin secretion and induce weight loss to preserve normoglycemia. Despite this, incretin therapy has been associated with off-target effects, including nausea and gastrointestinal disturbance. A novel photoswitchable incretin mimetic based upon the specific glucagon-like peptide-1 receptor (GLP-1R) agonist liraglutide was designed, synthesized, and tested. This peptidic compound, termed LirAzo, possesses an azobenzene photoresponsive element, affording isomer-biased GLP-1R signaling as a result of differential activation of second messenger pathways in response to light. While the trans isomer primarily engages calcium influx, the cis isomer favors cAMP generation. LirAzo thus allows optical control of insulin secretion and cell survival.
authors.affiliation: LMU Munich, Department of Chemistry and Centre for Integrated Protein Science (CIPSM), Butenandtstrasse 5-13, 81377 Munich (Germany).
authors.forename: Johannes
authors.initials: J
authors.lastname: Broichhagen
authors.affiliation: LMU Munich, Department of Chemistry and Centre for Integrated Protein Science (CIPSM), Butenandtstrasse 5-13, 81377 Munich (Germany).
authors.forename: Tom
authors.initials: T
authors.lastname: Podewin
authors.affiliation: LMU Munich, Department of Chemistry and Centre for Integrated Protein Science (CIPSM), Butenandtstrasse 5-13, 81377 Munich (Germany).
authors.forename: Helena
authors.initials: H
authors.lastname: Meyer-Berg
authors.affiliation: Imperial College London, Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN (UK).
authors.forename: Yorrick
authors.initials: Y
authors.lastname: von Ohlen
authors.affiliation: Imperial College London, Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN (UK).
authors.forename: Natalie R
authors.initials: NR
authors.lastname: Johnston
authors.affiliation: Imperial College London, Section of Investigative Medicine, Division of Diabetes, Endocrinology and Metabolism, Hammersmith Hospital, Du Cane Road, London W12 0NN (UK).
authors.forename: Ben J
authors.initials: BJ
authors.lastname: Jones
authors.affiliation: Imperial College London, Section of Investigative Medicine, Division of Diabetes, Endocrinology and Metabolism, Hammersmith Hospital, Du Cane Road, London W12 0NN (UK).
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Bloom
authors.affiliation: Imperial College London, Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN (UK).
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rutter
authors.affiliation: LMU Munich, Department of Chemistry and Centre for Integrated Protein Science (CIPSM), Butenandtstrasse 5-13, 81377 Munich (Germany). anja.hoffmann-roeder@cup.lmu.de.
authors.forename: Anja
authors.initials: A
authors.lastname: Hoffmann-Röder
authors.affiliation: Imperial College London, Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN (UK). d.hodson@imperial.ac.uk.
authors.forename: David J
authors.initials: DJ
authors.lastname: Hodson
authors.affiliation: LMU Munich, Department of Chemistry and Centre for Integrated Protein Science (CIPSM), Butenandtstrasse 5-13, 81377 Munich (Germany). dirk.trauner@cup.lmu.de.
authors.forename: Dirk
authors.initials: D
authors.lastname: Trauner
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D002461:Cell Line, Transformed; D006224:Cricetinae; D003412:Cricetulus; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism; D054795:Incretins / Q000737:chemistry*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D000069450:Liraglutide / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D015398:Signal Transduction; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
chemical_list: D000067757:Glucagon-Like Peptide-1 Receptor; D054795:Incretins; D007328:Insulin; D000069450:Liraglutide; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
keywords: beta cells; insulin; liraglutide; photopharmacology; type 2 diabetes