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 journalArticle

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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

Keywords

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

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