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

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 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.

• Authors: J Michael Conlon, Finbarr P M O'Harte, Peter R Flatt
• Journal: Peptides (Peptides) Vol. 147 Pg. 170706 (01 2022) ISSN: 1873-5169 [Electronic] United States
• PMID: 34861327 (Publication Type: Journal Article, Review)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Anti-Obesity Agents
• Fish Proteins
• GLP1R protein, human
• Glucagon-Like Peptide-1 Receptor
• Hypoglycemic Agents
• Incretins
• Proglucagon
• Glucagon-Like Peptide 1
• Glucose

Topics

• Animals
• Anti-Obesity Agents (pharmacology)
• Diabetes Mellitus, Type 2 (drug therapy, etiology)
• Eating (drug effects)
• Fish Proteins (pharmacology)
• Glucagon-Like Peptide 1 (agonists)
• Glucagon-Like Peptide-1 Receptor (agonists)
• Glucose (metabolism)
• Humans
• Hypoglycemic Agents (pharmacology)
• Incretins (agonists, pharmacology)
• Insulin Resistance
• Obesity (complications, drug therapy)
• Proglucagon (chemistry)