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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

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Gault, Victor, Kerr, Barry D., Harriott, Patrick and Flatt, Peter (2011) 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. CLINICAL SCIENCE, 121 (3-4). pp. 107-117. [Journal article]

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DOI: 10.1042/CS20110006

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.

Item Type:Journal article
Faculties and Schools:Faculty of Life and Health Sciences
Faculty of Life and Health Sciences > School of Biomedical Sciences
Research Institutes and Groups:Biomedical Sciences Research Institute
Biomedical Sciences Research Institute > Diabetes
ID Code:20372
Deposited By:Dr Nigel Irwin
Deposited On:28 Oct 2011 12:01
Last Modified:28 Oct 2011 12:01

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