title: Esculentin-2CHa-Related Peptides Modulate Islet Cell Function and Improve Glucose Tolerance in Mice with Diet-Induced Obesity and Insulin Resistance.
abstract: The frog skin host-defense peptide esculentin-2CHa (GFSSIFRGVA10KFASKGLGK D20LAKLGVDLVA30CKISKQC) displays antimicrobial, antitumor, and immunomodulatory properties. This study investigated the antidiabetic actions of the peptide and selected analogues. Esculentin-2CHa stimulated insulin secretion from rat BRIN-BD11 clonal pancreatic β-cells at concentrations greater than 0.3 nM without cytotoxicity by a mechanism involving membrane depolarization and increase of intracellular Ca2+. Insulinotropic activity was attenuated by activation of KATP channels, inhibition of voltage-dependent Ca2+ channels and chelation of extracellular Ca2+. The [L21K], [L24K], [D20K, D27K] and [C31S,C37S] analogues were more potent but less effective than esculentin-2CHa whereas the [L28K] and [C31K] analogues were both more potent and produced a significantly (P < 0.001) greater maximum response. Acute administration of [L28K]esculentin-2CHa (75 nmol/kg body weight) to high fat fed mice with obesity and insulin resistance enhanced glucose tolerance and insulin secretion. Twice-daily administration of this dose of [L28K]esculentin-2CHa for 28 days had no significant effect on body weight, food intake, indirect calorimetry or body composition. However, mice exhibited decreased non-fasting plasma glucose (P < 0.05), increased non-fasting plasma insulin (P < 0.05) as well as improved glucose tolerance and insulin secretion (P < 0.01) following both oral and intraperitoneal glucose loads. Impaired responses of isolated islets from high fat fed mice to established insulin secretagogues were restored by [L28K]esculentin-2CHa treatment. Peptide treatment was accompanied by significantly lower plasma and pancreatic glucagon levels and normalization of α-cell mass. Circulating triglyceride concentrations were decreased but plasma cholesterol and LDL concentrations were not significantly affected. The data encourage further investigation of the potential of esculentin-2CHa related peptides for treatment of patients with type 2 diabetes.
authors.affiliation: SAAD Centre for Pharmacy & Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, BT52 1SA, United Kingdom; School of Sport, Health and Bioscience, University of East London, Stratford, E15 4LZ, United Kingdom.
authors.forename: Opeolu O
authors.initials: OO
authors.lastname: Ojo
authors.affiliation: SAAD Centre for Pharmacy & Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, BT52 1SA, United Kingdom.
authors.forename: Dinesh K
authors.initials: DK
authors.lastname: Srinivasan
authors.affiliation: SAAD Centre for Pharmacy & Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, BT52 1SA, United Kingdom.
authors.forename: Bosede O
authors.initials: BO
authors.lastname: Owolabi
authors.affiliation: SAAD Centre for Pharmacy & Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, BT52 1SA, United Kingdom.
authors.forename: Srividya
authors.initials: S
authors.lastname: Vasu
authors.affiliation: SAAD Centre for Pharmacy & Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, BT52 1SA, United Kingdom.
authors.forename: J Michael
authors.initials: JM
authors.lastname: Conlon
authors.affiliation: SAAD Centre for Pharmacy & Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, BT52 1SA, United Kingdom.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Flatt
authors.affiliation: SAAD Centre for Pharmacy & Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, BT52 1SA, United Kingdom.
authors.forename: Yasser H A
authors.initials: YH
authors.lastname: Abdel-Wahab
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology* / Q000627:therapeutic use; D001786:Blood Glucose / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D009765:Obesity / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*
chemical_list: D023181:Antimicrobial Cationic Peptides; D001786:Blood Glucose; C582446:esculentin-2CHa, Lithobates chiricahuensis