Multivalent activation of GLP-1 and sulfonylurea receptors modulates β-cell second-messenger signaling and insulin secretion

Nathaniel J. Hart, Craig Weber, Klearchos K Papas, Sean W Limesand, Josef Vagner, Ron Lynch

Research output: Contribution to journalArticle


Linking two pharmacophores that bind different cell surface receptors into a single molecule can enhance cell-targeting specificity to cells that express the complementary receptor pair. In this report, we developed and tested a synthetic multivalent ligand consisting of glucagon-like peptide-1 (GLP-1) linked to glibenclamide (Glb) (GLP-1/Glb) for signaling efficacy in β-cells. Expression of receptors for these ligands, as a combination, is relatively specific to the β-cell in the pancreas. The multivalent GLP-1/Glb increased both intracellular cAMP and Ca2+, although Ca2+ responses were significantly depressed compared with the monomeric Glb. Moreover, GLP-1/Glb increased glucose-stimulated insulin secretion in a dose-dependent manner. However, unlike the combined monomers, GLP-1/Glb did not augment insulin secretion at nonstimulatory glucose concentrations in INS 832/13 β-cells or human islets of Langerhans. These data suggest that linking two binding elements, such as GLP-1 and Glb, into a single bivalent ligand can provide a unique functional agent targeted to β-cells.

Original languageEnglish (US)
Pages (from-to)C48-C56
JournalAmerican Journal of Physiology - Cell Physiology
Issue number1
Publication statusPublished - Jan 1 2019



  • Cell targeting
  • Diabetes
  • GLP-1
  • GPCR signaling
  • Incretin
  • Multivalent
  • Sulfonylurea
  • β-cell

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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