title: Magainin-related peptides stimulate insulin-release and improve glucose tolerance in high fat fed mice.
abstract: Earlier peptidomic analysis of the skin secretion of Xenopus amieti led to the identification of orthologs of magainins and other peptides. This study investigated the degradation, in vitro insulin-releasing and acute metabolic effects of magainin-AM1 (GIKEFAHSLGKFG KAFVGGILNQ) and magainin-AM2 (GVSKILHSAGKFGKAFLGEIMKS). Plasma degradation was investigated using reversed-phase HPLC and MALDI-TOF mass spectroscopy. Insulin-releasing effects were determined using BRIN-BD11 clonal beta cells and mouse islets. Effects of magainin peptides on cytosolic enzyme lactate dehydrogenase release, membrane potential and intracellular Ca(2+) concentration were assessed using BRIN-BD11 cells while their in vivo effects on glucose tolerance and insulin release were assessed in obese, insulin-resistant Swiss National Institute of Health (NIH) mice. Both peptides were resistant to degradation by plasma enzymes in vitro for up to 8 h. Though magainin-AM1 elicited non-toxic, concentration-dependent stimulation of insulin-release from clonal BRINBD11 cells at concentrations ≥ 100nM, magainin-AM2 produced a higher stimulation of insulin-release from BRIN-BD11 cells and isolated mouse islets. Membrane depolarization and intracellular [Ca(2+)]i in BRIN-BD11 cells were significantly (P<0.05) induced by both peptides and chelation of extracellular Ca(2+), addition of diazoxide or verapamil significantly (P<0.01) reduced the insulinotropic actions of the peptides. Administration of magainin-AM2 (75 nmol/kg body weight) to high-fat fed mice significantly enhanced insulin-release (P<0.01) and improved glucose tolerance (P<0.05). These data indicate magainin-AM2 peptides have potential for development into agents for treatment of type 2 diabetes.
authors.forename: Opeolu Oyejide
authors.initials: OO
authors.lastname: Ojo
authors.forename: Dinesh Kumar
authors.initials: DK
authors.lastname: Srinivasan
authors.forename: Bosede Olayinka
authors.initials: BO
authors.lastname: Owolabi
authors.forename: Peter Raymond
authors.initials: PR
authors.lastname: Flatt
authors.affiliation: School of Biomedical Sciences, University of Ulster, Coleraine, BT52 1SA, Northern Ireland, UK. y.abdel-wahab@ulster.ac.uk.
authors.forename: Yasser Hassan Atef
authors.initials: YH
authors.lastname: Abdel-Wahab
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D001835:Body Weight / Q000187:drug effects; D002478:Cells, Cultured; D059305:Diet, High-Fat; D007328:Insulin / Q000097:blood*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D054806:Magainins / Q000008:administration & dosage / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D051381:Rats; D029867:Xenopus Proteins / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D007328:Insulin; D054806:Magainins; D029867:Xenopus Proteins; C582630:magainin-AM1, Xenopus; C582631:magainin-AM2, Xenopus