title: A novel GIP-oxyntomodulin hybrid peptide acting through GIP, glucagon and GLP-1 receptors exhibits weight reducing and anti-diabetic properties.
abstract: Oxyntomodulin (Oxm) is a 37-amino acid peptide linked to alleviation of obesity-diabetes through a dual mode of action mediated at both glucagon and GLP-1 receptors. GIP is the principle physiological regulator of postprandial insulin secretion. Therefore, the primary aim was to design a novel GIP-Oxm peptide incorporating the actions of GIP, GLP-1 and glucagon in a single molecule. The first 11 N-terminal residues of Oxm were substituted with the sequence of stable dA(2)GIP molecule to generate a novel GIP-Oxm peptide (dA(2)GIP-Oxm). dA(2)GIP-Oxm was resistant to DPP-IV and significantly stimulated in vitro insulin release. dA(2)GIP-Oxm stimulated cAMP production in GIP-R, glucagon-R and GLP-1-R transfected cells by up to 95%, 83% and 77% of that elicited by respective native ligands. Acute administration of dA(2)GIP-Oxm to HFF mice resulted in reduced plasma glucose (45% reduction) and increased insulin concentrations (1.7-fold increase). Furthermore, dA(2)GIP-Oxm lowered plasma glucose (42% reduction) and increased plasma insulin (1.6-fold increase) when administered to HFF mice four hours prior to a glucose load. Once-daily administration of dA(2)GIP-Oxm for 15 days in HFF mice lowered body weight (13% reduction), reduced plasma glucose (40% reduction) and increased plasma insulin (1.7-fold increase). Furthermore, glycemic responses were improved (38% reduction) and glucose-mediated plasma insulin concentrations enhanced (2-fold increase). These improvements in metabolic control were independent of changes in food intake and insulin sensitivity. dA(2)GIP-Oxm exerts positive beneficial actions on glucose homeostasis, beta-cell insulin secretion and body weight, mediated through GIP, glucagon and GLP-1 receptors. Such multiple-acting peptides may hold promise as novel therapies for obesity-diabetes.
authors.affiliation: School of Biomedical Sciences, University of Ulster, Coleraine, UK.
authors.forename: Vikas K
authors.initials: VK
authors.lastname: Bhat
authors.forename: Barry D
authors.initials: BD
authors.lastname: Kerr
authors.forename: Peter R
authors.initials: PR
authors.lastname: Flatt
authors.forename: Victor A
authors.initials: VA
authors.lastname: Gault
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002460:Cell Line; D006224:Cricetinae; D000242:Cyclic AMP / Q000096:biosynthesis; D005749:Gastric Inhibitory Polypeptide / Q000737:chemistry*; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D053772:Oxyntomodulin / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D011964:Receptors, Gastrointestinal Hormone / Q000378:metabolism*; D018027:Receptors, Glucagon / Q000378:metabolism*; D015431:Weight Loss / Q000187:drug effects*
chemical_list: D001786:Blood Glucose; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D007328:Insulin; D053772:Oxyntomodulin; D010455:Peptides; D011964:Receptors, Gastrointestinal Hormone; D018027:Receptors, Glucagon; D005749:Gastric Inhibitory Polypeptide; C041086:gastric inhibitory polypeptide receptor; D000242:Cyclic AMP