The present study examined the glucose-lowering and insulinotropic properties of acylated GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide) peptides in Type 2 diabetes and obesity. GLP-1, GIP, Liraglutide, N-AcGIP(Lys37Myr) (N-acetylGIP with myristic acid conjugated at Lys37), a simple combination of both peptides and a Lira–AcGIP preparation [overnight preparation of Liraglutide and N-AcGIP(Lys37Myr)] 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(Lys37Myr), 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(Lys37Myr) 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(Lys37Myr) markedly improved glucose-lowering and insulinotropic properties in diabetic obesity compared with either incretin mimetic given individually.
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Research Article|
April 15 2011
Administration of an acylated GLP-1 and GIP preparation provides added beneficial glucose-lowering and insulinotropic actions over single incretins in mice with Type 2 diabetes and obesity
Victor A. Gault;
*School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland, U.K.
Correspondence: Dr Victor A. Gault (email va.gault@ulster.ac.uk).
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Barry D. Kerr;
Barry D. Kerr
*School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland, U.K.
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Patrick Harriott;
Patrick Harriott
†School of Biological Sciences, Queen's University of Belfast, Belfast BT9 7BL, Northern Ireland, U.K.
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Peter R. Flatt
Peter R. Flatt
*School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland, U.K.
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Publisher: Portland Press Ltd
Received:
January 06 2011
Revision Received:
February 17 2011
Accepted:
February 18 2011
Accepted Manuscript online:
February 18 2011
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2011 Biochemical Society
2011
Clin Sci (Lond) (2011) 121 (3): 107–117.
Article history
Received:
January 06 2011
Revision Received:
February 17 2011
Accepted:
February 18 2011
Accepted Manuscript online:
February 18 2011
Citation
Victor A. Gault, Barry D. Kerr, Patrick Harriott, Peter R. Flatt; Administration of an acylated GLP-1 and GIP preparation provides added beneficial glucose-lowering and insulinotropic actions over single incretins in mice with Type 2 diabetes and obesity. Clin Sci (Lond) 1 August 2011; 121 (3): 107–117. doi: https://doi.org/10.1042/CS20110006
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