Dual-agonist incretin peptides from fish with potential for obesity-related Type 2 diabetes therapy – a review

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Abstract

The long-acting glucagon-like peptide-1 receptor (GLP1R) agonist, semaglutide and the unimolecular glucose-dependent insulinotropic polypeptide receptor (GIPR)/GLP1R dual-agonist, tirzepatide have been successfully introduced as therapeutic options for patients with Type-2 diabetes (T2DM) and obesity. Proglucagon-derived peptides from phylogenetically ancient fish act as naturally occurring dual agonists at the GLP1R and the glucagon receptor (GCGR) with lamprey GLP-1 and paddlefish glucagon being the most potent and effective in stimulating insulin release from BRIN-BD11 clonal β-cells. These peptides were also the most effective in lowering blood glucose and elevating plasma insulin concentrations when administered intraperitoneally to overnight-fasted mice together with a glucose load. Zebrafish GIP acts as a dual agonist at the GIPR and GLP1R receptors. Studies with the high fat-fed mouse, an animal model with obesity, impaired glucose-tolerance and insulin-resistance, have shown that twice-daily administration of the long-acting analogs
[D-Ala2]palmitoyl-lamprey GLP-1 and [D-Ser2]palmitoyl-paddlefish glucagon over 21 days improves glucose tolerance and insulin sensitivity. This was associated with β-cell proliferation, protection of β-cells against apoptosis, decreased pancreatic glucagon content, improved the lipid profile, reduced food intake and selective alteration in the expression of genes involved in β-cell stimulus-secretion coupling. In insulin-deficient GluCreERT2;ROSA26-eYFP transgenic mice, the peptides promoted an increase in β-cell mass with positive effects on transdifferentiation of glucagon-producing to insulin-producing cells. Naturally occurring fish dual agonist peptides, particularly lamprey GLP-1 and paddlefish glucagon, provide templates for development into therapeutic agents for obesity-related T2DM.
Original languageEnglish
Article number170706
Number of pages10
JournalPeptides
Volume147
Early online date30 Nov 2021
DOIs
Publication statusPublished - 1 Jan 2022

Keywords

  • Lamprey GLP-1
  • paddlefish glucagon
  • dogfish glucagon
  • dual agonist
  • type 2 diabetes
  • obesity

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