title: Two novel glucagon receptor antagonists prove effective therapeutic agents in high-fat-fed and obese diabetic mice.
abstract: OBJECTIVE
  To examine the effect of two novel, enzymatically stable, glucagon receptor peptide antagonists, on metabolic control in two mouse models of obesity/diabetes.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  These data indicate that peptide-based glucagon receptor antagonists can reverse aspects of genetically and dietary-induced obesity-related diabetes.
authors: The Saad Centre for Pharmacy & Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, UK.
authors: F P M
authors: FP
authors: O'Harte
authors: Z J
authors: ZJ
authors: Franklin
authors: N
authors: N
authors: Irwin
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000209:etiology; D059305:Diet, High-Fat; D004334:Drug Administration Schedule; D004435:Eating / Q000187:drug effects*; D005934:Glucagon / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008820:Mice, Obese; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors*
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D018027:Receptors, Glucagon; C000600505:glucagon, deshistidyl(1)-prolyl(4)-glutamyl(9)-; D005934:Glucagon
keywords: acylated peptide analogues; animal models of diabetes; chronic effects of peptide antagonists; glucagon receptor antagonist; glucose tolerance