A novel GIP-Oxyntomodulin hybrid peptide acting through GIP, glucagon and GLP-1 receptors exhibits weight reducing and anti-diabetic properties.

VK Bhat, BD Kerr, Peter Flatt, Victor Gault

Research output: Contribution to journalArticle

42 Citations (Scopus)

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 dA2GIP molecule to generate a novel GIP-Oxm peptide (dA2GIP-Oxm). dA2GIP-Oxm was resistant to DPP-IV and significantly stimulated in vitro insulin release. dA2GIP-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 dA2GIP-Oxm to HFF mice resulted in reduced plasma glucose (45% reduction) and increased insulin concentrations (1.7-fold increase). Furthermore, dA2GIP-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 dA2GIP-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. dA2GIP-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.
LanguageEnglish
Pages1655-1662
JournalBIiochemical Pharmacology
Volume85
Issue number11
DOIs
Publication statusPublished - 18 Mar 2013

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Oxyntomodulin
Glucagon
Weights and Measures
Peptides
Insulin
Plasmas
Glucose
Glucagon-Like Peptide 1
Medical problems
Glucagon-Like Peptide-1 Receptor
Obesity
Body Weight
Molecules

Cite this

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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 dA2GIP molecule to generate a novel GIP-Oxm peptide (dA2GIP-Oxm). dA2GIP-Oxm was resistant to DPP-IV and significantly stimulated in vitro insulin release. dA2GIP-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 dA2GIP-Oxm to HFF mice resulted in reduced plasma glucose (45{\%} reduction) and increased insulin concentrations (1.7-fold increase). Furthermore, dA2GIP-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 dA2GIP-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. dA2GIP-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.",
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A novel GIP-Oxyntomodulin hybrid peptide acting through GIP, glucagon and GLP-1 receptors exhibits weight reducing and anti-diabetic properties. / Bhat, VK; Kerr, BD; Flatt, Peter; Gault, Victor.

Vol. 85, No. 11, 18.03.2013, p. 1655-1662.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A novel GIP-Oxyntomodulin hybrid peptide acting through GIP, glucagon and GLP-1 receptors exhibits weight reducing and anti-diabetic properties.

AU - Bhat, VK

AU - Kerr, BD

AU - Flatt, Peter

AU - Gault, Victor

PY - 2013/3/18

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N2 - 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 dA2GIP molecule to generate a novel GIP-Oxm peptide (dA2GIP-Oxm). dA2GIP-Oxm was resistant to DPP-IV and significantly stimulated in vitro insulin release. dA2GIP-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 dA2GIP-Oxm to HFF mice resulted in reduced plasma glucose (45% reduction) and increased insulin concentrations (1.7-fold increase). Furthermore, dA2GIP-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 dA2GIP-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. dA2GIP-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.

AB - 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 dA2GIP molecule to generate a novel GIP-Oxm peptide (dA2GIP-Oxm). dA2GIP-Oxm was resistant to DPP-IV and significantly stimulated in vitro insulin release. dA2GIP-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 dA2GIP-Oxm to HFF mice resulted in reduced plasma glucose (45% reduction) and increased insulin concentrations (1.7-fold increase). Furthermore, dA2GIP-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 dA2GIP-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. dA2GIP-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.

U2 - 10.1016/j.bcp.2013.03.009

DO - 10.1016/j.bcp.2013.03.009

M3 - Article

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