Insulinotropic Actions of the Frog Skin Host-Defense Peptide Alyteserin-2a: A Structure-Activity Study

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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 Ca2+ 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.
LanguageEnglish
Pages196-204
JournalChemical Biology and Drug Design
Volume82
Issue number2
DOIs
Publication statusPublished - 6 Jun 2013

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Anura
Insulin
Skin
Peptides
Lysine
Glucose
L-Lactate Dehydrogenase
Tryptophan
Insulin Resistance
Obesity
Fats
Body Weight
Cell Membrane
Membranes

Cite this

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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 Ca2+ 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.",
author = "OO Ojo and Yasser Abdel-Wahab and Peter Flatt and JM Conlon",
year = "2013",
month = "6",
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doi = "10.1111/cbdd.12151",
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T1 - Insulinotropic Actions of the Frog Skin Host-Defense Peptide Alyteserin-2a: A Structure-Activity Study

AU - Ojo, OO

AU - Abdel-Wahab, Yasser

AU - Flatt, Peter

AU - Conlon, JM

PY - 2013/6/6

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N2 - 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 Ca2+ 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.

AB - 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 Ca2+ 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.

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