title: Actions of PGLa-AM1 and its [A14K] and [A20K] analogues and their therapeutic potential as anti-diabetic agents.
abstract: PGLa-AM1 (GMASKAGSVL10GKVAKVALKA20AL.NH2) was first identified in skin secretions of the frog Xenopus amieti (Pipidae) on the basis of its antimicrobial properties. PGLa-AM1 and its [A14K] and [A20K] analogues produced a concentration-dependent stimulation of insulin release from BRIN-BD11 rat clonal β-cells without cytotoxicity at concentrations up to 3 μM. In contrast, the [A3K] analogue was cytotoxic at concentrations ≥ 30 nM. The potency and maximum rate of insulin release produced by the [A14K] and [A20K] peptides were significantly greater than produced by PGLa-AM1. [A14K]PGLa-AM1 also stimulated insulin release from mouse islets at concentrations ≥ 1 nM and from the 1.1B4 human-derived pancreatic β-cell line at concentrations > 30 pM. PGLa-AM1 (1 μM) produced membrane depolarization in BRIN-BD11 cells with a small, but significant (P < 0.05), increase in intracellular Ca2+concentrations but the peptide had no direct effect on KATPchannels. The [A14K] analogue (1 μM) produced a significant increase in cAMP concentration in BRIN-BD11 cells and down-regulation of the protein kinase A pathway by overnight incubation with forskolin completely abolished the insulin-releasing effects of the peptide. [A14K]PGLa-AM1 (1 μM) protected against cytokine-induced apoptosis (p < 0.001) in BRIN-BD11 cells and augmented (p < 0.001) proliferation of the cells to a similar extent as GLP-1. Intraperitoneal administration of the [A14K] and [A20K] analogues (75 nmol/kg body weight) to both lean mice and high fat-fed mice with insulin resistance improved glucose tolerance with a concomitant increase in insulin secretion. The data provide further support for the assertion that host defense peptides from frogs belonging to the Pipidae family show potential for development into agents for the treatment of patients with Type 2 diabetes.
authors.affiliation: SAAD Centre for Pharmacy & Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, BT52 1SA, UK.
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, UK.
authors.forename: Vishal
authors.initials: V
authors.lastname: Musale
authors.affiliation: SAAD Centre for Pharmacy & Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, BT52 1SA, UK.
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, UK.
authors.forename: R Charlotte
authors.initials: RC
authors.lastname: Moffett
authors.affiliation: Centre for Experimental Medicine, Queen's University of Belfast, Belfast, BT9 7BL, UK.
authors.forename: Mary K
authors.initials: MK
authors.lastname: McGahon
authors.affiliation: Centre for Experimental Medicine, Queen's University of Belfast, Belfast, BT9 7BL, UK.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Curtis
authors.affiliation: SAAD Centre for Pharmacy & Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, BT52 1SA, UK. Electronic address: m.conlon@ulster.ac.uk.
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, UK.
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, UK.
authors.forename: Yasser H A
authors.initials: YHA
authors.lastname: Abdel-Wahab
mesh_terms: D029845:Amphibian Proteins / Q000627:therapeutic use*; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000627:therapeutic use*; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D010884:Pipidae; D051381:Rats; D015398:Signal Transduction; D029867:Xenopus Proteins / Q000627:therapeutic use*
chemical_list: D029845:Amphibian Proteins; D023181:Antimicrobial Cationic Peptides; D007004:Hypoglycemic Agents; D007328:Insulin; C000621671:Lys(14)-PGLa-AM1 peptide, Xenopus amieti; C000621672:Lys(20)-PGLa-AM1 peptide, Xenopus amieti; C000603829:PGLa-AM1 peptide, Xenopus amieti; D029867:Xenopus Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D002118:Calcium
keywords: Amphibian skin peptide; Anti-apoptotic peptide; Insulin-release; PGLa-AM1; Type 2 diabetes; β-Cell proliferation