Administration of an acylated GLP-I and GIP preparation provides added beneficial glucose-lowering and insulinotropic actions over single incretins in mice with Type 2 diabetes and obesity

Victor Gault, Barry D. Kerr, Patrick Harriott, Peter Flatt

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Abstract

The present study examined the glucose-lowering and insulinotropic properties of acylated GLP-1 (glucagon-like peptide-l) and GIP (glucose-dependent insulinotropic polypeptide) peptides in Type 2 diabetes and obesity. GLP-1, GIP, Liraglutide, N-AcGIP(Lys(37)Myr) (N-acetylGIP with myristic acid conjugated at Lys(37)), a simple combination of both peptides and a Lira-AcGIP preparation [overnight preparation of Liraglutide and N-AcGIP(Lys(37)Myr)] were incubated with DPP-IV (dipeptidyl peptidase-IV) to assess peptide stability, and BRIN-BD11 cells were used to evaluate cAMP production and insulin secretion. Acute glucose-lowering and insulinotropic actions were evaluated in Swiss TO mice. Subchronic studies on glucose homoeostasis, insulin secretion, food intake and bodyweight were evaluated in ob/ob mice. Liraglutide, N-AcGIP(Lys(37)Myr), a simple combination of both peptides and the Lira-AcGIP preparation demonstrated improved DPP-IV resistance (P < 0.001). while stimulating cAMP production and insulin secretion (1.4-2-fold; P < 0.001). The Lira-AcGIP preparation was more potent at lowering plasma glucose (20-51% reduction; P < 0.05-P < 0.001) and stimulating insulin secretion (1.5-1.8-fold; P < 0.05 P < 0.001) compared with Liraglutide and N-AcGIP(Lys(37)Myr) or a simple peptide combination. Daily administration of the Lira-AcGIP preparation to ob/ob mice lowered bodyweight (7-9%; P < 0.05), food intake (23%; P < 0.05) and plasma glucose (46% reduction; P < 0.001), while increasing plasma insulin (1.5-1.6-fold; P < 0.001). The Lira-AcGIP preparation enhanced glucose tolerance, insulin response to glucose and insulin content (P < 0.05 P < 0.001). These findings demonstrate that a combined preparation of the acylated GLP-1 and GIP peptides Liraglutide and N-AcGIP(Lys(37)Myr) markedly improved glucose-lowering and insulinotropic properties in diabetic obesity compared with either incretin mimetic given individually.
LanguageEnglish
Pages107-117
JournalClinical Science
Volume121
Issue number3-4
DOIs
Publication statusPublished - Aug 2011

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Incretins
Type 2 Diabetes Mellitus
Obesity
Glucose
Peptides
Insulin
Glucagon-Like Peptide 1
Gastric Inhibitory Polypeptide
Dipeptidyl Peptidase 4
Eating
Glucagon-Like Peptides
Myristic Acid
Homeostasis
Liraglutide

Cite this

@article{422c4a9ba3ee45ada4c5fead65b44348,
title = "Administration of an acylated GLP-I and GIP preparation provides added beneficial glucose-lowering and insulinotropic actions over single incretins in mice with Type 2 diabetes and obesity",
abstract = "The present study examined the glucose-lowering and insulinotropic properties of acylated GLP-1 (glucagon-like peptide-l) and GIP (glucose-dependent insulinotropic polypeptide) peptides in Type 2 diabetes and obesity. GLP-1, GIP, Liraglutide, N-AcGIP(Lys(37)Myr) (N-acetylGIP with myristic acid conjugated at Lys(37)), a simple combination of both peptides and a Lira-AcGIP preparation [overnight preparation of Liraglutide and N-AcGIP(Lys(37)Myr)] were incubated with DPP-IV (dipeptidyl peptidase-IV) to assess peptide stability, and BRIN-BD11 cells were used to evaluate cAMP production and insulin secretion. Acute glucose-lowering and insulinotropic actions were evaluated in Swiss TO mice. Subchronic studies on glucose homoeostasis, insulin secretion, food intake and bodyweight were evaluated in ob/ob mice. Liraglutide, N-AcGIP(Lys(37)Myr), a simple combination of both peptides and the Lira-AcGIP preparation demonstrated improved DPP-IV resistance (P < 0.001). while stimulating cAMP production and insulin secretion (1.4-2-fold; P < 0.001). The Lira-AcGIP preparation was more potent at lowering plasma glucose (20-51{\%} reduction; P < 0.05-P < 0.001) and stimulating insulin secretion (1.5-1.8-fold; P < 0.05 P < 0.001) compared with Liraglutide and N-AcGIP(Lys(37)Myr) or a simple peptide combination. Daily administration of the Lira-AcGIP preparation to ob/ob mice lowered bodyweight (7-9{\%}; P < 0.05), food intake (23{\%}; P < 0.05) and plasma glucose (46{\%} reduction; P < 0.001), while increasing plasma insulin (1.5-1.6-fold; P < 0.001). The Lira-AcGIP preparation enhanced glucose tolerance, insulin response to glucose and insulin content (P < 0.05 P < 0.001). These findings demonstrate that a combined preparation of the acylated GLP-1 and GIP peptides Liraglutide and N-AcGIP(Lys(37)Myr) markedly improved glucose-lowering and insulinotropic properties in diabetic obesity compared with either incretin mimetic given individually.",
author = "Victor Gault and Kerr, {Barry D.} and Patrick Harriott and Peter Flatt",
year = "2011",
month = "8",
doi = "10.1042/CS20110006",
language = "English",
volume = "121",
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journal = "Clinical Science",
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T1 - Administration of an acylated GLP-I and GIP preparation provides added beneficial glucose-lowering and insulinotropic actions over single incretins in mice with Type 2 diabetes and obesity

AU - Gault, Victor

AU - Kerr, Barry D.

AU - Harriott, Patrick

AU - Flatt, Peter

PY - 2011/8

Y1 - 2011/8

N2 - The present study examined the glucose-lowering and insulinotropic properties of acylated GLP-1 (glucagon-like peptide-l) and GIP (glucose-dependent insulinotropic polypeptide) peptides in Type 2 diabetes and obesity. GLP-1, GIP, Liraglutide, N-AcGIP(Lys(37)Myr) (N-acetylGIP with myristic acid conjugated at Lys(37)), a simple combination of both peptides and a Lira-AcGIP preparation [overnight preparation of Liraglutide and N-AcGIP(Lys(37)Myr)] were incubated with DPP-IV (dipeptidyl peptidase-IV) to assess peptide stability, and BRIN-BD11 cells were used to evaluate cAMP production and insulin secretion. Acute glucose-lowering and insulinotropic actions were evaluated in Swiss TO mice. Subchronic studies on glucose homoeostasis, insulin secretion, food intake and bodyweight were evaluated in ob/ob mice. Liraglutide, N-AcGIP(Lys(37)Myr), a simple combination of both peptides and the Lira-AcGIP preparation demonstrated improved DPP-IV resistance (P < 0.001). while stimulating cAMP production and insulin secretion (1.4-2-fold; P < 0.001). The Lira-AcGIP preparation was more potent at lowering plasma glucose (20-51% reduction; P < 0.05-P < 0.001) and stimulating insulin secretion (1.5-1.8-fold; P < 0.05 P < 0.001) compared with Liraglutide and N-AcGIP(Lys(37)Myr) or a simple peptide combination. Daily administration of the Lira-AcGIP preparation to ob/ob mice lowered bodyweight (7-9%; P < 0.05), food intake (23%; P < 0.05) and plasma glucose (46% reduction; P < 0.001), while increasing plasma insulin (1.5-1.6-fold; P < 0.001). The Lira-AcGIP preparation enhanced glucose tolerance, insulin response to glucose and insulin content (P < 0.05 P < 0.001). These findings demonstrate that a combined preparation of the acylated GLP-1 and GIP peptides Liraglutide and N-AcGIP(Lys(37)Myr) markedly improved glucose-lowering and insulinotropic properties in diabetic obesity compared with either incretin mimetic given individually.

AB - The present study examined the glucose-lowering and insulinotropic properties of acylated GLP-1 (glucagon-like peptide-l) and GIP (glucose-dependent insulinotropic polypeptide) peptides in Type 2 diabetes and obesity. GLP-1, GIP, Liraglutide, N-AcGIP(Lys(37)Myr) (N-acetylGIP with myristic acid conjugated at Lys(37)), a simple combination of both peptides and a Lira-AcGIP preparation [overnight preparation of Liraglutide and N-AcGIP(Lys(37)Myr)] were incubated with DPP-IV (dipeptidyl peptidase-IV) to assess peptide stability, and BRIN-BD11 cells were used to evaluate cAMP production and insulin secretion. Acute glucose-lowering and insulinotropic actions were evaluated in Swiss TO mice. Subchronic studies on glucose homoeostasis, insulin secretion, food intake and bodyweight were evaluated in ob/ob mice. Liraglutide, N-AcGIP(Lys(37)Myr), a simple combination of both peptides and the Lira-AcGIP preparation demonstrated improved DPP-IV resistance (P < 0.001). while stimulating cAMP production and insulin secretion (1.4-2-fold; P < 0.001). The Lira-AcGIP preparation was more potent at lowering plasma glucose (20-51% reduction; P < 0.05-P < 0.001) and stimulating insulin secretion (1.5-1.8-fold; P < 0.05 P < 0.001) compared with Liraglutide and N-AcGIP(Lys(37)Myr) or a simple peptide combination. Daily administration of the Lira-AcGIP preparation to ob/ob mice lowered bodyweight (7-9%; P < 0.05), food intake (23%; P < 0.05) and plasma glucose (46% reduction; P < 0.001), while increasing plasma insulin (1.5-1.6-fold; P < 0.001). The Lira-AcGIP preparation enhanced glucose tolerance, insulin response to glucose and insulin content (P < 0.05 P < 0.001). These findings demonstrate that a combined preparation of the acylated GLP-1 and GIP peptides Liraglutide and N-AcGIP(Lys(37)Myr) markedly improved glucose-lowering and insulinotropic properties in diabetic obesity compared with either incretin mimetic given individually.

U2 - 10.1042/CS20110006

DO - 10.1042/CS20110006

M3 - Article

VL - 121

SP - 107

EP - 117

JO - Clinical Science

T2 - Clinical Science

JF - Clinical Science

SN - 0143-5221

IS - 3-4

ER -