Two novel glucagon receptor antagonists prove effective therapeutic agents in high-fat-fed and obese diabetic mice

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 desHis1Pro4Glu9‐glucagon or desHis1Pro4Glu9Lys12FA‐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 desHis1Pro4Glu9Lys12FA‐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 desHis1Pro4Glu9Lys12FA‐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 desHis1Pro4Glu9‐glucagon or desHis1Pro4Glu9Lys12FA‐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.