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

O'Harte, Finbarr, Franklin, ZJ and Irwin, Nigel (2014) Two novel glucagon receptor antagonists prove effective therapeutic agents in high-fat-fed and obese diabetic mice. Diabetes Obesity and Metabolism, 16 . pp. 1214-1222. [Journal article]

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DOI: 10.1111/dom.12360

Abstract

Aims: To examine the effect of two novel, enzymatically stable, glucagon receptor peptide antagonists, on metabolic control in two mouse models ofobesity/diabetes.Method: The effects of twice daily i.p. administration of desHis1Pro4Glu9-glucagon or desHis1Pro4Glu9Lys12FA-glucagon for 10 days on metaboliccontrol 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-fastingblood glucose towards normal control values in HFF mice. Basal glucose was also reduced (p<0.01) in desHis1Pro4Glu9Lys12FA-glucagon treatedob/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) andpancreatic insulin content (p<0.05) were observed in ob/ob mice, especially after desHis1Pro4Glu9Lys12FA-glucagon treatment. No significant differencesin 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 ordesHis1Pro4Glu9Lys12FA-glucagon treatment in both animal models.Conclusion: These data indicate that peptide-based glucagon receptor antagonists can reverse aspects of genetically and dietary-inducedobesity-related diabetes.

Item Type:Journal article
Faculties and Schools:Faculty of Life and Health Sciences > School of Pharmacy and Pharmaceutical Science
Faculty of Life and Health Sciences > School of Biomedical Sciences
Faculty of Life and Health Sciences
Research Institutes and Groups:Biomedical Sciences Research Institute
Biomedical Sciences Research Institute > Diabetes
ID Code:30568
Deposited By: Dr Nigel Irwin
Deposited On:15 Nov 2014 12:53
Last Modified:15 Nov 2014 12:53

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