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
A. M. Lynch; N. Pathak; V. Pathak; F. P. M. O’Harte; P. R. Flatt; N. Irwin; V. A. Gault
Year of publication
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-Ser2)glucagon and an analogue of (d-Ser2)glucagon with the addition of nine amino acids from the C-terminal of exendin(1-39), namely (d-Ser2)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-Ser2)glucagon and (d-Ser2)glucagon-exe evoked significant (p < 0.001) insulin release. (d-Ser2)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-Ser2)glucagon retained glucagon-like effects of increasing (p < 0.001) plasma glucose and insulin levels. (d-Ser2)glucagon-exe was devoid of hyperglycaemic actions but substantially (p < 0.001) increased plasma insulin levels. (d-Ser2)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-Ser2)glucagon-exe. Twice-daily administration of (d-Ser2)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. Conclusions/interpretation: This study emphasises the potential of (d-Ser2)glucagon-exe for the treatment of obesity-related diabetes.