A long-acting, dual-agonist analogue of lamprey GLP-1 shows potent insulinotropic, β-cell protective, and anorexic activities and improves glucose homeostasis in high fat-fed mice

Galyna Graham, Andrew Mc Closkey, Yasser Abdel-Wahab, JM Conlon, PR Flatt

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)
32 Downloads (Pure)

Abstract

Peptidase-resistant analogues of GLP-1 peptides from sea lamprey and paddlefish ([D-Ala 2]palmitoyl-lamprey GLP-1 and [D-Ala 2]palmitoyl-paddlefish GLP-1) produced significant (P ≤ 0.05) and concentration-dependent increases in insulin release from BRIN-BD11 clonal β-cells and from isolated mouse islets. Both analogues retained the ability of the native peptides to activate both the GLP-1 receptor (GLP1R) and the glucagon receptor (GCGR). [D-Ala 2]palmitoyl-lamprey GLP-1 significantly (P < 0.001) stimulated proliferation of BRIN-BD11 cells and protected against cytokine-induced apoptosis. Administration of the lamprey analogue (25 nmol/kg body weight) to lean mice up to 4 h before a glucose load improved glucose tolerance and increased plasma insulin concentrations. Twice daily administration of the lamprey GLP-1 analogue to high fat-fed mice for 21 days decreased body weight, food intake, and circulating glucose and insulin concentrations. The analogue significantly improved glucose tolerance and insulin sensitivity with beneficial effects on islet β-cell area and insulin secretory responsiveness. Islet gene expression of Glp1r, Gcgr and Gipr significantly increased. The lamprey GLP-1 analogue shows therapeutic promise for treatment of patients with obesity-related Type 2 diabetes.

Original languageEnglish
Article number110584
JournalMolecular and Cellular Endocrinology
Volume499
Early online date17 Sep 2019
DOIs
Publication statusPublished - 1 Jan 2020

Bibliographical note

Funding Information:
The authors wish to thank Bernard Thorens (University of Lausanne, Switzerland) for GLP-1 receptor-transfected CHL cells, Cecilia Unson (The Rockefeller University, USA) for glucagon receptor-transfected HEK293?cells, and Jaqueline Naylor (MedImmune, Cambridge, UK) for CRISPR/Cas9-engineered INS-1?cells lacking GLP-1 or GIP receptors. pSpCas9(BB)-2A-GFP (PX458) was a gift from Feng Zhang (Broad Institute, MIT) and pU6-(BbsI)_CBh-Cas9-T2A-mCherry was a gift from Ralf Kuehn (Broad Institute, MIT). Funding for this study was provided by the Northern Ireland Department of Education and Learning (DEL), and Ulster University Strategic Funding.

Funding Information:
The authors wish to thank Bernard Thorens ( University of Lausanne , Switzerland) for GLP-1 receptor-transfected CHL cells, Cecilia Unson (The Rockefeller University , USA) for glucagon receptor-transfected HEK293 cells, and Jaqueline Naylor ( MedImmune , Cambridge, UK) for CRISPR/Cas9-engineered INS-1 cells lacking GLP-1 or GIP receptors. pSpCas9(BB)-2A-GFP (PX458) was a gift from Feng Zhang ( Broad Institute , MIT ) and pU6-( Bbs I)_CBh-Cas9-T2A-mCherry was a gift from Ralf Kuehn ( Broad Institute , MIT ). Funding for this study was provided by the Northern Ireland Department of Education and Learning (DEL) , and Ulster University Strategic Funding.

Publisher Copyright:
© 2019 Elsevier B.V.

Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.

Keywords

  • Dual agonist
  • Insulinotropic
  • Lamprey GLP-1
  • Obesity
  • Paddlefish GLP-1
  • Type 2 diabetes

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