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

Abstract

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
Volume316
Issue number1
DOIs
StatePublished - Jan 1 2019

Fingerprint

Sulfonylurea Receptors
Glyburide
Second Messenger Systems
Glucagon-Like Peptide 1
Insulin
Ligands
Glucose
Cell Surface Receptors
Glucagon-Like Peptide-1 Receptor
Islets of Langerhans
Pancreas

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

Cite this

@article{e255baa9ce804c24b7c4543640788458,
title = "Multivalent activation of GLP-1 and sulfonylurea receptors modulates β-cell second-messenger signaling and insulin secretion",
abstract = "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.",
keywords = "Cell targeting, Diabetes, GLP-1, GPCR signaling, Incretin, Multivalent, Sulfonylurea, β-cell",
author = "Hart, {Nathaniel J.} and Craig Weber and Papas, {Klearchos K} and Limesand, {Sean W} and Josef Vagner and Ron Lynch",
year = "2019",
month = "1",
day = "1",
doi = "10.1152/ajpcell.00209.2018",
language = "English (US)",
volume = "316",
pages = "C48--C56",
journal = "American Journal of Physiology",
issn = "0363-6143",
publisher = "American Physiological Society",
number = "1",

}

TY - JOUR

T1 - Multivalent activation of GLP-1 and sulfonylurea receptors modulates β-cell second-messenger signaling and insulin secretion

AU - Hart, Nathaniel J.

AU - Weber, Craig

AU - Papas, Klearchos K

AU - Limesand, Sean W

AU - Vagner, Josef

AU - Lynch, Ron

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

KW - Cell targeting

KW - Diabetes

KW - GLP-1

KW - GPCR signaling

KW - Incretin

KW - Multivalent

KW - Sulfonylurea

KW - β-cell

UR - http://www.scopus.com/inward/record.url?scp=85060232240&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85060232240&partnerID=8YFLogxK

U2 - 10.1152/ajpcell.00209.2018

DO - 10.1152/ajpcell.00209.2018

M3 - Article

C2 - 30404557

AN - SCOPUS:85060232240

VL - 316

SP - C48-C56

JO - American Journal of Physiology

JF - American Journal of Physiology

SN - 0363-6143

IS - 1

ER -