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

FP O'Harte*, ZJ Franklin, N Irwin

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)

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 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.
Original languageEnglish
Article number12360
Pages (from-to)1214-1222
Number of pages8
JournalDiabetes, Obesity & Metabolism
Volume16
Issue number12
DOIs
Publication statusPublished - Dec 2014

Keywords

  • acylated peptide analogues
  • animal models of diabetes
  • chronic effects of peptide antagonists
  • glucagon receptor antagonist
  • Glucose tolerance

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