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Two novel glucagon receptor antagonists prove effective therapeutic agents in high‐fat‐fed and obese diabetic mice
Author(s) -
O'Harte F. P. M.,
Franklin Z. J.,
Irwin N.
Publication year - 2014
Publication title -
diabetes, obesity and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.445
H-Index - 128
eISSN - 1463-1326
pISSN - 1462-8902
DOI - 10.1111/dom.12360
Subject(s) - medicine , endocrinology , glucagon , insulin , basal (medicine) , glucagon like peptide 1 , glucagon receptor , chemistry , receptor , diabetes mellitus , type 2 diabetes
Aims To examine the effect of two novel, enzymatically stable, glucagon receptor peptide antagonists, on metabolic control in two mouse models of obesity/diabetes. Method The effects of twice daily i.p. administration of desHis 1 Pro 4 Glu 9 ‐glucagon or desHis 1 Pro 4 Glu 9 Lys 12 FA ‐glucagon for 10 days on metabolic control in high‐fat‐fed ( HFF ; 45% fat) and obese diabetic ( ob/ob ) mice were compared with saline‐treated controls. Results Neither analogue altered body weight or food intake in either model over 10 days; however, treatment with each peptide restored non‐fasting blood glucose towards normal control values in HFF mice. Basal glucose was also reduced (p < 0.01) in desHis 1 Pro 4 Glu 9 Lys 12 FA ‐glucagon treated ob/ob mice by day 10, coinciding with increases (p < 0.001) in circulating insulin. At the end of the treatment period, both analogues significantly (p < 0.05–0.01) improved oral and i.p. glucose tolerance (p < 0.05) and peripheral insulin sensitivity, increased pancreatic insulin and glucagon content (p < 0.05–0.01) and decreased (p < 0.05) cholesterol levels in HFF mice. Similarly beneficial metabolic effects on oral glucose tolerance (p < 0.01) and pancreatic insulin content (p < 0.05) were observed in ob/ob mice, especially after desHis 1 Pro 4 Glu 9 Lys 12 FA ‐glucagon treatment. No significant differences in circulating triglycerides or aspects of indirect calorimetry were noted between peptide treatment groups and respective control HFF and ob/ob mice. Finally, glucagon‐mediated elevations of glucose and insulin were significantly (p < 0.05–0.01) annulled after 10 days of desHis 1 Pro 4 Glu 9 ‐glucagon or desHis 1 Pro 4 Glu 9 Lys 12 FA ‐glucagon treatment in both animal models. Conclusion These data indicate that peptide‐based glucagon receptor antagonists can reverse aspects of genetically and dietary‐induced obesity‐related diabetes.