Optical Control of Insulin Secretion Using an Incretin Switch

Johannes Broichhagen, Tom Podewin, Helena Meyer-Berg, Yorrick Von Ohlen, Natalie R. Johnston, Ben J. Jones, Stephen R. Bloom, Guy A. Rutter, Anja Hoffmann-Röder, David J. Hodson, Dirk Trauner

Research output: Contribution to journalArticle

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. 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.

Original languageEnglish (US)
Pages (from-to)15565-15569
Number of pages5
JournalAngewandte Chemie - International Edition
Volume54
Issue number51
DOIs
StatePublished - Dec 14 2015

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Keywords

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

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)

Cite this

Broichhagen, J., Podewin, T., Meyer-Berg, H., Von Ohlen, Y., Johnston, N. R., Jones, B. J., Bloom, S. R., Rutter, G. A., Hoffmann-Röder, A., Hodson, D. J., & Trauner, D. (2015). Optical Control of Insulin Secretion Using an Incretin Switch. Angewandte Chemie - International Edition, 54(51), 15565-15569. https://doi.org/10.1002/anie.201506384