title: Insulinotropic actions of the frog skin host-defense peptide alyteserin-2a: a structure-activity study.
abstract: Alyteserin-2a (ILGKLLSTAAGLLSNL.NH2 ) stimulated the rate of insulin release from BRIN-BD11 clonalβ cells at a concentration of 30 nm (p < 0.05) with a response of 296 ± 26% of basal release at 3 μm (p < 0.001). The insulinotropic actions of analogs containing substitutions by l-lysine, d-lysine, or l-tryptophan at sites that maintain amphipathicity were evaluated. The [G11K], [S7k], [S7k,G11k], and [G11k,N15K] analogs were the most potent stimulating insulin release at 0.01 nm (p < 0.05). The [S7K], [G11K], [S14K], [N15K], [G11k], and [S7K,G11K] analogs were the most effective producing an approximately twofold greater (p < 0.001) release of insulin at 3 μm compared with alyteserin-2a. The [T8W] and [A9W] analogs were less active than alyteserin-2a. No peptide-stimulated release of lactate dehydrogenase at concentrations up to 3 μm, indicating that the integrity of the plasma membrane had been preserved. Membrane depolarization and an increase in intracellular Ca(2+) concentration are involved in the mechanism of action of the peptides. Administration of [G11k]alyteserin-2a (75 nmol/kg body weight) to high-fat-fed mice with obesity and insulin resistance significantly (p < 0.01) enhanced insulin release and improved glucose tolerance during the 60-min period following an intraperitoneal glucose load.
authors.affiliation: School of Biomedical Sciences, University of Ulster, Cromore Road, Coleraine, BT52 1SA, UK.
authors.forename: Opeolu O
authors.initials: OO
authors.lastname: Ojo
authors.forename: Yasser H A
authors.initials: YH
authors.lastname: Abdel-Wahab
authors.forename: Peter R
authors.initials: PR
authors.lastname: Flatt
authors.forename: J Michael
authors.initials: JM
authors.lastname: Conlon
mesh_terms: D000595:Amino Acid Sequence; D029845:Amphibian Proteins / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D005951:Glucose Tolerance Test; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism; D011898:Ranidae
chemical_list: D029845:Amphibian Proteins; D023181:Antimicrobial Cationic Peptides; D007328:Insulin; C573618:alyteserin-2a peptide, Alytes obstetricans; D002118:Calcium
keywords: Type 2 diabetes; alyteserin-2a; insulin-releasing activity; structure-activity