Endocrine Abstracts

Recent acute in vivo studies have shown that structural modifications of dogfish glucagon improves peptide stability and these analogues can act as dual agonists at both glucagon and GLP-1 receptors. Here, we compared the effects of chronic (51 days) twice daily administration of [D-Ala²]dogfish glucagon (Pep-N) and [D-Ala²]dogfish glucagon-exendin-4(31–39) construct (Pep-C), exendin-4(1–39) or saline treated controls on metabolic status in groups (4×n=8) of male (Swiss TO) diet induced (4 months pre-conditioned on 45% high fat diet) diabetic mice. Non-fasting blood glucose was significantly reduced in all treatment groups vs saline controls after one week and remained lower throughout the remaining study period (P<0.05 to P<0.001). Peptide therapies had no significant effect on cumulative food intake but the increase in body weight gain was lower (P<0.05) following Pep-N and Pep-C administration vs saline treated controls. Plasma insulin concentrations progressively increased (P<0.05 to P<0.01) in all three peptide treated groups vs high fat fed saline treated controls. After day 51, Pep-N and Pep-C showed an improved overall glycaemic response (0-120 min, area under curve AUC) to i.p. glucose (18 mmol/kg body weight) (P<0.001), along with exendin-4 (P<0.05) compared to saline treated controls. Also a significant rise in plasma insulin concentration was noted over 120 min within all peptide treatment groups with Pep-C being the most effective insulinotropic peptide (P<0.001). Following chronic treatment, an insulin sensitivity test (25 U/kg body weight) showed that exendin-4 (P<0.05) and Pep-C (P<0.001) had enhanced insulin sensitivity vs saline treated controls. Terminal DEXA scan densitometry analysis revealed that percentage body fat mass was significantly decreased (P<0.001) in Pep-N and Pep-C treated mice but not following exendin-4 treatment. Pep-C effectively lowered plasma triglyceride concentrations (P<0.01). Pep-N and Pep-C caused a reduction in the terminal circulating plasma glucagon concentrations (P<0.01) compared to saline treated controls. Finally, pancreatic insulin content was unchanged in all of the peptide treated groups compared to saline treated control mice. In conclusion, chronic twice daily treatment with the novel dual agonist Pep-C demonstrated improved glycaemic control and lipid profiles compared with exendin-4 therapy in diet induced obese diabetic mice.

Disclosure: Invest NI (Proof of Concept) POC308 funding

PhD Studentship from DEL in N. Ireland.