A novel GLP-1/glucagon hybrid peptide with triple-acting agonist activity at GIP, GLP-1 and glucagon receptors and therapeutic potential in high-fat fed mice.

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Abstract

Glucagon-like-peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon bind to related members of the same receptor superfamily and exert important effects on glucose homeostasis, insulin secretion and energy regulation. The present study assessed the biological actions and therapeutic utility of novel GIP/glucagon/GLP-1 hybrid peptides. Nine novel peptides were synthesized and exhibited complete DPP-IV resistance and enhanced in vitro insulin secretion. The most promising peptide, [DA2]GLP-1/GcG, stimulated cAMP production in GIP-, GLP-1- and glucagon-R transfected cells. Acute administration of [DA2]GLP-1/GcG in combination with glucose significantly lowered plasma glucose and increased plasma insulin in normal and obese diabetic (ob/ob) mice. Furthermore, [DA2]GLP-1/GcG elicited a protracted glucose-lowering and insulinotropic effect in high-fat fed mice. Twice-daily administration of [DA2]GLP-1/GcG for 21 days decreased body weight, non-fasting plasma glucose and increased circulating plasma insulin concentrations in high-fat fed mice. Furthermore, [DA2]GLP-1/GcG significantly improved glucose tolerance and insulin sensitivity by day 21. Interestingly, locomotor activity was increased in [DA2]GLP-1/GcG mice, without appreciable changes in aspects of metabolic rate. Studies in knockout mice confirmed the biological action of [DA2]GLP-1/GcG via multiple targets including GIP-, GLP-1- and glucagon-Rs. The data suggests significant promise for novel triple-acting hybrid peptides as therapeutic options for obesity-diabetes.
LanguageEnglish
Pages35581-35591
JournalJournal of Biological Chemistry
Volume288
Issue number49
DOIs
Publication statusPublished - 6 Dec 2013

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Glucagon Receptors
Glucagon-Like Peptide 1
Polypeptides
Glucagon
Fats
Glucose
Peptides
Insulin
Therapeutics
Plasmas
Glucagon-Like Peptide-1 Receptor
Locomotion
Medical problems
Knockout Mice
Insulin Resistance

Cite this

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title = "A novel GLP-1/glucagon hybrid peptide with triple-acting agonist activity at GIP, GLP-1 and glucagon receptors and therapeutic potential in high-fat fed mice.",
abstract = "Glucagon-like-peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon bind to related members of the same receptor superfamily and exert important effects on glucose homeostasis, insulin secretion and energy regulation. The present study assessed the biological actions and therapeutic utility of novel GIP/glucagon/GLP-1 hybrid peptides. Nine novel peptides were synthesized and exhibited complete DPP-IV resistance and enhanced in vitro insulin secretion. The most promising peptide, [DA2]GLP-1/GcG, stimulated cAMP production in GIP-, GLP-1- and glucagon-R transfected cells. Acute administration of [DA2]GLP-1/GcG in combination with glucose significantly lowered plasma glucose and increased plasma insulin in normal and obese diabetic (ob/ob) mice. Furthermore, [DA2]GLP-1/GcG elicited a protracted glucose-lowering and insulinotropic effect in high-fat fed mice. Twice-daily administration of [DA2]GLP-1/GcG for 21 days decreased body weight, non-fasting plasma glucose and increased circulating plasma insulin concentrations in high-fat fed mice. Furthermore, [DA2]GLP-1/GcG significantly improved glucose tolerance and insulin sensitivity by day 21. Interestingly, locomotor activity was increased in [DA2]GLP-1/GcG mice, without appreciable changes in aspects of metabolic rate. Studies in knockout mice confirmed the biological action of [DA2]GLP-1/GcG via multiple targets including GIP-, GLP-1- and glucagon-Rs. The data suggests significant promise for novel triple-acting hybrid peptides as therapeutic options for obesity-diabetes.",
author = "Victor Gault and VK Bhat and Nigel Irwin and Peter Flatt",
year = "2013",
month = "12",
day = "6",
doi = "10.1074/jbc.M113.512046",
language = "English",
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journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology",
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T1 - A novel GLP-1/glucagon hybrid peptide with triple-acting agonist activity at GIP, GLP-1 and glucagon receptors and therapeutic potential in high-fat fed mice.

AU - Gault, Victor

AU - Bhat, VK

AU - Irwin, Nigel

AU - Flatt, Peter

PY - 2013/12/6

Y1 - 2013/12/6

N2 - Glucagon-like-peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon bind to related members of the same receptor superfamily and exert important effects on glucose homeostasis, insulin secretion and energy regulation. The present study assessed the biological actions and therapeutic utility of novel GIP/glucagon/GLP-1 hybrid peptides. Nine novel peptides were synthesized and exhibited complete DPP-IV resistance and enhanced in vitro insulin secretion. The most promising peptide, [DA2]GLP-1/GcG, stimulated cAMP production in GIP-, GLP-1- and glucagon-R transfected cells. Acute administration of [DA2]GLP-1/GcG in combination with glucose significantly lowered plasma glucose and increased plasma insulin in normal and obese diabetic (ob/ob) mice. Furthermore, [DA2]GLP-1/GcG elicited a protracted glucose-lowering and insulinotropic effect in high-fat fed mice. Twice-daily administration of [DA2]GLP-1/GcG for 21 days decreased body weight, non-fasting plasma glucose and increased circulating plasma insulin concentrations in high-fat fed mice. Furthermore, [DA2]GLP-1/GcG significantly improved glucose tolerance and insulin sensitivity by day 21. Interestingly, locomotor activity was increased in [DA2]GLP-1/GcG mice, without appreciable changes in aspects of metabolic rate. Studies in knockout mice confirmed the biological action of [DA2]GLP-1/GcG via multiple targets including GIP-, GLP-1- and glucagon-Rs. The data suggests significant promise for novel triple-acting hybrid peptides as therapeutic options for obesity-diabetes.

AB - Glucagon-like-peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon bind to related members of the same receptor superfamily and exert important effects on glucose homeostasis, insulin secretion and energy regulation. The present study assessed the biological actions and therapeutic utility of novel GIP/glucagon/GLP-1 hybrid peptides. Nine novel peptides were synthesized and exhibited complete DPP-IV resistance and enhanced in vitro insulin secretion. The most promising peptide, [DA2]GLP-1/GcG, stimulated cAMP production in GIP-, GLP-1- and glucagon-R transfected cells. Acute administration of [DA2]GLP-1/GcG in combination with glucose significantly lowered plasma glucose and increased plasma insulin in normal and obese diabetic (ob/ob) mice. Furthermore, [DA2]GLP-1/GcG elicited a protracted glucose-lowering and insulinotropic effect in high-fat fed mice. Twice-daily administration of [DA2]GLP-1/GcG for 21 days decreased body weight, non-fasting plasma glucose and increased circulating plasma insulin concentrations in high-fat fed mice. Furthermore, [DA2]GLP-1/GcG significantly improved glucose tolerance and insulin sensitivity by day 21. Interestingly, locomotor activity was increased in [DA2]GLP-1/GcG mice, without appreciable changes in aspects of metabolic rate. Studies in knockout mice confirmed the biological action of [DA2]GLP-1/GcG via multiple targets including GIP-, GLP-1- and glucagon-Rs. The data suggests significant promise for novel triple-acting hybrid peptides as therapeutic options for obesity-diabetes.

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DO - 10.1074/jbc.M113.512046

M3 - Article

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SP - 35581

EP - 35591

JO - Journal of Biological Chemistry

T2 - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

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