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Angew Chem Int Ed Engl. 2015 Dec 14;54(51):15565-9. doi: 10.1002/anie.201506384. Epub 2015 Nov 2.

Optical Control of Insulin Secretion Using an Incretin Switch.

Author information

1
LMU Munich, Department of Chemistry and Centre for Integrated Protein Science (CIPSM), Butenandtstrasse 5-13, 81377 Munich (Germany).
2
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).
3
Imperial College London, Section of Investigative Medicine, Division of Diabetes, Endocrinology and Metabolism, Hammersmith Hospital, Du Cane Road, London W12 0NN (UK).
4
LMU Munich, Department of Chemistry and Centre for Integrated Protein Science (CIPSM), Butenandtstrasse 5-13, 81377 Munich (Germany). anja.hoffmann-roeder@cup.lmu.de.
5
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.
6
LMU Munich, Department of Chemistry and Centre for Integrated Protein Science (CIPSM), Butenandtstrasse 5-13, 81377 Munich (Germany). dirk.trauner@cup.lmu.de.

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.

KEYWORDS:

beta cells; insulin; liraglutide; photopharmacology; type 2 diabetes

PMID:
26585495
PMCID:
PMC4736448
DOI:
10.1002/anie.201506384
[Indexed for MEDLINE]
Free PMC Article

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