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

作者：Lynch Aisling M; Pathak Nupur; Pathak Varun; O' Harte Finbarr P M; Flatt Peter R; Irwin Nigel^*; Gault Victor A

来源：Diabetologia, 2014, 57(9): 1927-1936.

DOI：10.1007/s00125-014-3296-7

• Diabetes
• GLP-1
• Glucagon
• Glucagon-like peptide-1
• Glucose tolerance
• Obesity

Aim/hypothesis Modification of the structure of glucagon could provide useful compounds for the potential treatment of obesity-related diabetes. %26lt;br%26gt;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. %26lt;br%26gt;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 %26lt; 0.001)insulin release. (D-Ser(2))glucagon-exe stimulated cAMP production (p %26lt; 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 %26lt; 0.001) plasma glucose and insulin levels. (D-Ser(2))glucagon-exe was devoid of hyperglycaemic actions but substantially (p %26lt; 0.001) increased plasma insulin levels. (D-Ser(2))glucagon-exe reduced the glycaemic excursion (p %26lt; 0.01) and increased the insulin secretory (p %26lt; 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 %26lt; 0.05 to p %26lt; 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 %26lt; 0.01) improved and energy expenditure, O-2 consumption and locomotor activity were (p %26lt; 0.05 to p %26lt; 0.001) augmented. The metabolic benefits were accompanied by increases in pancreatic islet number (p %26lt; 0.001) and area (p %26lt; 0.05), as well as beta cell area (p %26lt; 0.05). Beneficial effects were largely retained for 14 days following cessation of treatment. %26lt;br%26gt;Conclusions/interpretation This study emphasises the potential of (D-Ser(2))glucagon-exe for the treatment of obesity-related diabetes.

• 出版日期2014-9