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

Gault, Victor A.; Kerr, Barry D.; Harriott, Patrick; Flatt, Peter R.

doi:10.1042/cs20110006

Cited by 125Diabetes Treatment and ManagementPancreatic function and diabetesDiabetes Management and Research

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

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Gault, Victor A., Kerr, Barry D., Harriott, Patrick, Flatt, Peter R.·2011·Clinical Science

DOI 10.1042/cs20110006

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Abstract

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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Simultaneous activation of GLP-1 and GIP receptors in preclinical models results in greater weight loss and glucose-lowering efficacy compared to activation of each receptor alone.
“as the simultaneous activation of GLP-1 and GIP receptors in preclinical models results in greater WL and glucose-lowering efficacy compared to activation of each receptor alone [38–40]”
From What is the pipeline for future medications for obesity? (2025) · cites this paper as [38]
In preclinical studies, simultaneous activation of GLP-1 and GIP receptors leads to enhanced glucose-lowering effects and more WL compared to activating either receptor alone.
“Studies in animals have also shown an anorexigenic effect of the GIP and in preclinical studies, the simultaneous activation of GLP-1 and GIP receptors leads to enhanced glucose-lowering effects and more WL compared to activating either receptor alone [21,38,39].”
From Oral glucagon-like peptide-1 receptor agonists and combinations of entero-pancreatic hormones as treatments for adults with type 2 diabetes: where are we now? (2024) · cites this paper as [39]
Studies in animals have shown an anorexigenic effect of the GIP.
“Studies in animals have also shown an anorexigenic effect of the GIP and in preclinical studies, the simultaneous activation of GLP-1 and GIP receptors leads to enhanced glucose-lowering effects and more WL compared to activating either receptor alone [21,38,39].”
From Oral glucagon-like peptide-1 receptor agonists and combinations of entero-pancreatic hormones as treatments for adults with type 2 diabetes: where are we now? (2024) · cites this paper as [39]

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Authors: Gault, V. A., Kerr, B. D., Harriott, P., & Flatt, P. R.
Affiliations: University of Ulster (GB)
Queen's University Belfast (GB)
ORCID: Gault, Victor A.
Flatt, Peter R.
Venue: Clinical Science
Publisher: Portland Press Ltd.
Published: 2011-04-15
Volume: 121
Issue: 3
Pages: 107-117
ISSN: 0143-5221 (ISSN-L)
1470-8736
DOI: 10.1042/cs20110006
OpenAlex: W1982526723
Cited by: 125
References: 48
Citations by year: 2026: 1 · 2025: 7 · 2024: 11 · 2023: 7 · 2022: 4 · 2021: 14 · 2020: 8 · 2019: 14 · 2018: 15 · 2017: 8 · 2016: 11 · 2015: 9 · 2014: 5 · 2013: 7 · 2012: 2
FWCI: 3.93
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Clinical Science (publishedVersion)
PubMed (publishedVersion)
HAL (submittedVersion, other-oa)
Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion)
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
Keywords: glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, liraglutide, insulin secretion, glucose tolerance, type 2 diabetes, obesity, ob/ob mice, insulinotropic effect, dietary intake, body weight, cAMP signaling, BRIN-BD11 cells, peptide stability
MeSH terms: Liraglutide, Animals, Diabetes Mellitus, Type 2, Gastric Inhibitory Polypeptide, Glucose, Insulin, Male, Mice, Obese, Models, Biological, Obesity, Insulin-Secreting Cells, Mice, Glucagon-Like Peptide 1, Incretins

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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

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