title: Glucoregulatory, endocrine and morphological effects of [P5K]hymenochirin-1B in mice with diet-induced glucose intolerance and insulin resistance.
abstract: The frog skin host-defence peptide hymenochirin-1B has been shown to stimulate insulin release in vitro from isolated pancreatic islets and BRIN-BD11 clonal β-cells. This study examines the effects of 28-day administration of a more potent analogue [P5K]hymenochirin-1B ([P5K]hym-1B) (75 nmol·kg(-1) body weight) to high-fat-fed mice with obesity, glucose intolerance and insulin resistance. Treatment with [P5K]hym-1B significantly decreased plasma glucose concentrations and improved glucose tolerance, insulin secretion, insulin sensitivity and increased the magnitude of the incretin effect (difference in response to oral vs intraperitoneal glucose loads). Responses to established insulin secretagogues were greater in islets isolated from treated animals compared with saline-treated controls. [P5K]hym-1B administration significantly decreased total islet area and β- and α-cell areas, and resulted in lower concentrations of circulating triglycerides and plasma and pancreatic glucagon. Peptide treatment had no effect on food intake, body weight, indirect calorimetry or circulating concentrations of amylase and marker enzymes of liver and kidney function. RT-PCR demonstrated that the Insr (insulin receptor) gene and genes involved in insulin signalling (Slc2a4, Irs1, Pik3ca, Akt1 and Pkd1) were significantly up-regulated in skeletal muscle from animals treated with [P5K]hym-1B. Expression of the Glp1r (GLP-1 receptor) and Gipr (GIP receptor) genes was significantly elevated in islets from peptide-treated mice. These data suggest that [P5K]hym-1B shows potential for development into an agent for treating patients with type 2 diabetes.
authors.affiliation: SAAD Centre for Pharmacy and 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 and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, BT52 1SA, UK.|School of Health, Sport and Bioscience, University of East London, Stratford, E15 4LZ, UK.
authors.forename: Opeolu O
authors.initials: OO
authors.lastname: Ojo
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, BT52 1SA, UK.
authors.forename: Dinesh K
authors.initials: DK
authors.lastname: Srinivasan
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, BT52 1SA, UK. m.conlon@ulster.ac.uk.
authors.forename: J Michael
authors.initials: JM
authors.lastname: Conlon
authors.affiliation: SAAD Centre for Pharmacy and 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 and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, BT52 1SA, UK.
authors.forename: Yasser H A
authors.initials: YH
authors.lastname: Abdel-Wahab
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D048430:Cell Shape / Q000187:drug effects*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D018149:Glucose Intolerance / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood*; D007333:Insulin Resistance / Q000235:genetics; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008055:Lipids / Q000097:blood; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D046509:Tissue Culture Techniques
chemical_list: D023181:Antimicrobial Cationic Peptides; D015415:Biomarkers; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D008055:Lipids; C000614436:hymenochirin-1B, Lys(5)-
keywords: Glucose tolerance; Hymenochrin-1B; Insulin resistance; Insulin secretion; Type 2 diabetes