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Insulinotropic Actions of the Frog Skin Host‐Defense Peptide Alyteserin‐2a: A Structure–Activity Study
Author(s) -
Ojo Opeolu O.,
AbdelWahab Yasser H. A.,
Flatt Peter R.,
Conlon J. Michael
Publication year - 2013
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12151
Subject(s) - insulin , medicine , peptide , chemistry , tryptophan , endocrinology , basal (medicine) , lysine , intracellular , depolarization , extracellular , biochemistry , biology , amino acid
Alyteserin‐2a ( ILGKLLSTAAGLLSNL . NH 2 ) stimulated the rate of insulin release from BRIN‐BD 11 clonalβ cells at a concentration of 30 n m (p < 0.05) with a response of 296 ± 26% of basal release at 3 μ m (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 [ G 11 K ], [ S 7k], [ S 7k, G 11k], and [ G 11k, N 15K] analogs were the most potent stimulating insulin release at 0.01 n m (p < 0.05). The [ S 7 K ], [ G 11 K ], [ S 14 K ], [ N 15 K ], [ G 11k], and [ S 7 K , G 11 K ] analogs were the most effective producing an approximately twofold greater (p < 0.001) release of insulin at 3 μ m compared with alyteserin‐2a. The [ T 8 W ] and [ A 9 W ] analogs were less active than alyteserin‐2a. No peptide‐stimulated release of lactate dehydrogenase at concentrations up to 3 μ m , 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 [ G 11k]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.