Ulster University Logo

A novel DPP IV-resistant C-terminally extended glucagon analogue exhibits weight-lowering and diabetes-protective effects in high-fat-fed mice mediated through glucagon and GLP-1 receptor activation.

Lynch, AM, Pathak, N, Pathak, V, O'Harte, Finbarr, Flatt, Peter, Irwin, Nigel and Gault, Victor (2014) A novel DPP IV-resistant C-terminally extended glucagon analogue exhibits weight-lowering and diabetes-protective effects in high-fat-fed mice mediated through glucagon and GLP-1 receptor activation. Diabetologia, 57 (9). pp. 1927-1936. [Journal article]

Full text not available from this repository.

DOI: 10.1007/s00125-014-3296-7

Abstract

AIMS/HYPOTHESIS: Modification of the structure of glucagon could provide useful compounds for the potential treatment of obesity-related diabetes.METHODS: This study evaluated N-acetyl-glucagon, (D-Ser(2))glucagon and an analogue of (D-Ser(2))glucagon with the addition of nine amino acids from the C-terminal of exendin(1-39), namely (D-Ser(2))glucagon-exe.RESULTS: All analogues were resistant to dipeptidyl peptidase IV degradation. N-Acetyl-glucagon lacked acute insulinotropic effects in BRIN BD11 cells, whereas (D-Ser(2))glucagon and (D-Ser(2))glucagon-exe evoked significant (p < 0.001) insulin release. (D-Ser(2))glucagon-exe stimulated cAMP production (p < 0.001) in glucagon- and GLP-1-receptor (GLP-1R)-transfected cells but not in glucose-dependent insulinotropic polypeptide-receptor-transfected cells. In normal mice, N-acetyl-glucagon and (D-Ser(2))glucagon retained glucagon-like effects of increasing (p < 0.001) plasma glucose and insulin levels. (D-Ser(2))glucagon-exe was devoid of hyperglycaemic actions but substantially (p < 0.001) increased plasma insulin levels. (D-Ser(2))glucagon-exe reduced the glycaemic excursion (p < 0.01) and increased the insulin secretory (p < 0.01) response following a glucose challenge 12 h after administration. Studies in GLP-1R knockout mice confirmed involvement of the GLP-1R pathway in the biological actions of (D-Ser(2))glucagon-exe. Twice-daily administration of (D-Ser(2))glucagon-exe to high-fat-fed mice for 28 days significantly (p < 0.05 to p < 0.001) reduced body weight, energy intake and non-fasting glucose levels, as well as increasing insulin concentrations. Glucose tolerance and insulin sensitivity were significantly (p < 0.01) improved and energy expenditure, O2 consumption and locomotor activity were (p < 0.05 to p < 0.001) augmented. The metabolic benefits were accompanied by increases in pancreatic islet number (p < 0.001) and area (p < 0.05), as well as beta cell area (p < 0.05). Beneficial effects were largely retained for 14 days following cessation of treatment.

Item Type:Journal article
Faculties and Schools:Faculty of Life and Health Sciences > School of Pharmacy and Pharmaceutical Science
Faculty of Life and Health Sciences > School of Biomedical Sciences
Faculty of Life and Health Sciences
Research Institutes and Groups:Biomedical Sciences Research Institute
Biomedical Sciences Research Institute > Diabetes
ID Code:30010
Deposited By: Dr Nigel Irwin
Deposited On:05 Sep 2014 11:19
Last Modified:09 May 2016 11:20

Repository Staff Only: item control page