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

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 beta-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-Ala(2)]palmitoyl-lamprey GLP-1 and [D-Ser(2)]palmitoyl-paddlefish glucagon over 21 days improves glucose tolerance and insulin sensitivity. This was associated with beta-cell proliferation, protection of beta-cells against apoptosis, decreased pancreatic glucagon content, improved lipid profile, reduced food intake and selective alteration in the expression of genes involved in beta-cell stimulus-secretion coupling. In insulin-deficient Glu(CreERT2);ROSA26-eYFP transgenic mice, the peptides promoted an increase in beta-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.

Automated summary

Peptides derived from ancient fish, such as lamprey GLP-1 and paddlefish glucagon, act as naturally occurring dual agonists at GLP1R and GCPR receptors, showing potential in improving glucose tolerance, insulin sensitivity, and beta-cell proliferation. Studies suggest that these fish-derived peptides have therapeutic potential for obesity-related T2DM.