@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 Lynch, {Ronald M.}",
note = "Funding Information: This work was funded by the Juvenile Diabetes Research Foundation. We also recognize the assistance of the Arizona Board of Regents, NIH Interdisciplinary Training in Cardiovascular Research Grant T32-HL-007249 (N. J. Hart), and NIH Systems and Integrative Training Grant 5T32-GM-0084 (N. J. Hart). Funding Information: Fig. 1. Combinatorial expression of glucagon-like peptide-1 receptor (GLP1R) and ATP-binding cassette subfamily C member 8 (ABCC8) was relatively specific to the pancreas and β-cells. RNA sequencing from the Human Protein Atlas (49; A), Genotype-Tissue Expression (GTEx; B), and Functional Annotation of Mammalian Genomes 5 (FANTOM5; 28; C) data sets showed that the combinatorial expression of GLP1R and ABCC8 was relatively specific to pancreatic tissue. However, the GLP1R and ABCC8 expression combination was also present in the brain and heart. Single-cell RNA sequencing by Segerstolpe et al. (42) showed that combinatorial expression of GLP1R and ABCC8 was restricted to β-cells (D) within the pancreas (D–H). RPKM, reads per kiolbase of transcript per million mapped reads; TPM, transcripts per million. The GTEx Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health and by the National Cancer Institute, National Human Genome Research Institute, National Heart, Lung, and Blood Institute, National Institute on Drug Abuse, National Institute of Mental Health, and National Institute of Neurological Disorders and Stroke. [Data used for tissue analysis (A–C) were accessed via the Human Protein Atlas (version 18; www.proteinatlas.org/ENSG00000112164-GLP1R/tissue and www.proteinatlas.org/ENSG00000006071-ABCC8/tissue), with permission under the Creative Commons Attribution-ShareAlike 3.0 International License.] Publisher Copyright: {\textcopyright} 2019 the American Physiological Society.",
year = "2019",
month = jan,
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",
}