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

Abstract

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.

• Authors: F P M O'Harte, Z J Franklin, N Irwin
• Journal: Diabetes, obesity & metabolism (Diabetes Obes Metab) Vol. 16 Issue 12 Pg. 1214-22 (Dec 2014) ISSN: 1463-1326 [Electronic] England
• PMID: 25060150 (Publication Type: Journal Article)
• Copyright: © 2014 John Wiley & Sons Ltd.

Chemical References

• Blood Glucose
• Hypoglycemic Agents
• Receptors, Glucagon
• glucagon, deshistidyl(1)-prolyl(4)-glutamyl(9)-
• Glucagon

Topics

• Animals
• Blood Glucose (drug effects)
• Body Weight (drug effects)
• Diabetes Mellitus, Experimental (drug therapy, etiology)
• Diet, High-Fat
• Drug Administration Schedule
• Eating (drug effects)
• Glucagon (administration & dosage, analogs & derivatives, pharmacology)
• Hypoglycemic Agents (administration & dosage, pharmacology)
• Mice
• Mice, Obese
• Receptors, Glucagon (antagonists & inhibitors)