TY - JOUR
T1 - Optical Control of Insulin Secretion Using an Incretin Switch
AU - Broichhagen, Johannes
AU - Podewin, Tom
AU - Meyer-Berg, Helena
AU - Von Ohlen, Yorrick
AU - Johnston, Natalie R.
AU - Jones, Ben J.
AU - Bloom, Stephen R.
AU - Rutter, Guy A.
AU - Hoffmann-Röder, Anja
AU - Hodson, David J.
AU - Trauner, Dirk
N1 - Funding Information:
J.B. was supported by an EFSD Albert Renold Young Scientist Fellowship and a Studienstiftung des deutschen Volkes PhD studentship. T.P., H.M.B and N.R.J. were supported by Center for Integrated Protein Science Munich (CIPSM), Bavarian Grant for Studies andaDiabetes UK RW and JM Collins Studentship, respectively. G.A.R. was supported by Wellcome Trust Senior Investigator (WT098424AIA), MRC Programme (MR/J0003042/1), Diabetes UK Project Grant (11/0004210) and Royal Society Wolfson Research Merit Awards. B.J.J. was funded by an MRC Clinical Research Training Fellowship. S.R.B. is funded by grants from the MRC, BBSRC, IHR, an Integrative Mammalian Biology (MB) Capacity Building Award, an FP7-HEALTH-2009-241592 EuroCHIP grant and is supported by the NIHR Imperial Biomedical Research Centre Funding Scheme. A.H.R. was supported by CIPSM and SFB 749. D.J.H. was supported by Diabetes UK R.D. Lawrence (12/0004431) and EFSD/Novo Nordisk Rising Star Fellowships, as well as an MRC project grant (MR/N00275X/1). D.J.H. and G.A.R. were supported by Imperial Confidence in Concept (ICiC) Grants. D.T. was supported by an Advanced Grant from the European Research Council (268795). We are grateful to Dr. David Stephenson and Claudia Dubler for assistance with NMR spectroscopy.
Publisher Copyright:
© 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
PY - 2015/12/14
Y1 - 2015/12/14
N2 - 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. Incretins in the spotlight: An azobenzene photoswitch was placed between the alpha helices of the incretin mimetic liraglutide to yield isomer-biased optical control over glucagon-like peptide-1 receptor (GLP-1R) signaling, pancreatic beta cell function, and insulin release.
AB - 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. Incretins in the spotlight: An azobenzene photoswitch was placed between the alpha helices of the incretin mimetic liraglutide to yield isomer-biased optical control over glucagon-like peptide-1 receptor (GLP-1R) signaling, pancreatic beta cell function, and insulin release.
KW - beta cells
KW - insulin
KW - liraglutide
KW - photopharmacology
KW - type 2 diabetes
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U2 - 10.1002/anie.201506384
DO - 10.1002/anie.201506384
M3 - Article
C2 - 26585495
AN - SCOPUS:84955181360
VL - 54
SP - 15565
EP - 15569
JO - Angewandte Chemie - International Edition
JF - Angewandte Chemie - International Edition
SN - 1433-7851
IS - 51
ER -