14-3-3-zeta mediates GLP-1 receptor agonist action to alter α cell proglucagon processing

  • Sci Adv. 2022 Jul 22;8(29):eabn3773. doi: 10.1126/sciadv.abn3773.
Marlena M Holter  1 ,  Daryl J Phuong  1 ,  Isaac Lee  1 ,  Mridusmita Saikia  1  2 ,  Lisa Weikert  1 ,  Samantha Fountain  1 ,  Elizabeth T Anderson  3 ,  Qin Fu  3 ,  Sheng Zhang  3 ,  Kyle W Sloop  4 ,  Bethany P Cummings  1  5
Affiliations
  • 1. Department of Biomedical Sciences, Cornell University, College of Veterinary Medicine, Ithaca, NY, USA.
  • 2. Nancy E. and Peter C. Meinig School of Biomedical Engineering, Ithaca, NY, USA.
  • 3. Proteomics and Metabolomics Facility, Institute of Biotechnology, Cornell University, Ithaca, NY, USA.
  • 4. Diabetes and Complications, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
  • 5. Department of Surgery, Center for Alimentary and Metabolic Sciences, School of Medicine, University of California, Davis, Sacramento, CA, USA.
PMID: 35867787 DOI: 10.1126/sciadv.abn3773
Abstract

Recent studies demonstrate that α cells contribute to glucose-stimulated Insulin secretion (GSIS). Glucagon-like peptide-1 receptor (GLP-1R) agonists potently potentiate GSIS, making these drugs useful for diabetes treatment. However, the role of α and β cell paracrine interactions in the effects of GLP-1R agonists is undefined. We previously found that increased β cell GLP-1R signaling activates α cell GLP-1 expression. Here, we characterized the bidirectional paracrine cross-talk by which α and β cells communicate to mediate the effects of the GLP-1R agonist, liraglutide. We find that the effect of liraglutide to enhance GSIS is blunted by α cell ablation in male mice. Furthermore, the effect of β cell GLP-1R signaling to activate α cell GLP-1 is mediated by a secreted protein factor that is regulated by the signaling protein, 14-3-3-zeta, in mouse and human islets. These data refine our understanding of GLP-1 pharmacology and identify 14-3-3-zeta as a potential target to enhance α cell GLP-1 production.

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