Journal
BIOCHEMICAL PHARMACOLOGY
Volume 85, Issue 11, Pages 1655-1662Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2013.03.009
Keywords
Glucose-dependent insulinotropic polypeptide (GIP); Glucagon-like peptide-1 (GLP-1); Oxyntomodulin (OXM); Obesity-diabetes; Insulin secretion
Categories
Funding
- Vice-Chancellors Research Scholarship
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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. (C) 2013 Elsevier Inc. All rights reserved.
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