Glucagon-like peptides-1 from phylogenetically ancient fish show potent anti-diabetic activities by acting as dual GLP1R and GCGR agonists.


SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, Northern Ireland, BT52 1SA, UK. Electronic address: [Email]


Glucagon-like peptides-1 (GLP-1)from phylogenetically ancient fish (lamprey, dogfish, ratfish, paddlefish and bowfin) and from a teleost, the rainbow trout produced concentration-dependent stimulations of insulin release from clonal β-cells and isolated mouse islets. Lamprey and paddlefish GLP-1 were the most potent and effective. Incubation of BRIN-BD11 cells with GLP-1 receptor (GLP1R) antagonist, exendin-4 (9-39) attenuated insulinotropic activity of all peptides whereas glucagon receptor (GCGR) antagonist [des-His1,Pro4,Glu9] glucagon amide significantly decreased the activities of lamprey and paddlefish GLP-1 only. The GIP receptor antagonist GIP (6-30) Cex-K40 [Pal] attenuated the activity of bowfin GLP-1. All peptides (1 μM) produced significant increases in cAMP concentration in CHL cells transfected with GLP1R but only lamprey and paddlefish GLP-1 stimulated cAMP production in HEK293 cells transfected with GCGR. Intraperitoneal administration of lamprey and paddlefish GLP-1 (25 nmol/kg body weight) in mice produced significant decreases in blood glucose and increased insulin concentrations comparable to the effects of human GLP-1. Lamprey and paddlefish GLP-1 display potent insulinotropic activity in vitro and glucose-lowering activity in vivo that is mediated through GLP1R and GCGR so that these peptides may constitute templates for design of new antidiabetic drugs.