Dogfish glucagon analogues counter hyperglycaemia and enhance both insulin secretion and action in diet-induced obese diabetic mice

Aims: To investigate the antidiabetic actions of three dogfish glucagon peptide analogues [known glucagon-like peptide-1 and glucagon receptor co-agonists] after chronic administration in diet-induced high-fat-diet-fed diabetic mice. Materials and methods: National Institutes of Health Swiss mice were pre-conditioned to a high-fat diet (45% fat) for 100 days, and control mice were fed a normal diet (10% fat). Normal diet control and high-fat-fed control mice received twice-daily intraperitoneal (i.p.) saline injections, while the high-fat-fed treatment groups (n = 8) received twice-daily injections of exendin-4(1-39), [S2a]dogfish glucagon, [S2a]dogfish glucagon exendin-4(31-39) or [S2a]dogfish glucagon-Lys³⁰-γ-glutamyl-PAL (25 nmol/kg body weight) for 51 days. Results: After dogfish glucagon analogue treatment, there was a rapid and sustained decrease in non-fasting blood glucose and an associated insulinotropic effect (analysis of variance, p <.05 to <.001) compared with saline-treated high-fat-fed controls. All peptide treatments significantly improved i.p. and oral glucose tolerance with concomitant increased insulin secretion compared with saline-treated high-fat-fed controls (p <.05 to <.001). After chronic treatment, no receptor desensitization was observed but insulin sensitivity was enhanced for all peptide-treated groups (p <.01 to <.001) except [S2a]dogfish glucagon. Both exendin-4 and [S2a]dogfish glucagon exendin-4(31-39) significantly reduced plasma triglyceride concentrations compared with those found in lean controls (p =.0105 and p =.0048, respectively). Pancreatic insulin content was not affected by peptide treatments but [S2a]dogfish glucagon and [S2a]dogfish glucagon exendin-4(31-39) decreased pancreatic glucagon by 28%-34% (p =.0221 and p =.0075, respectively). The percentage of β-cell area within islets was increased by exendin-4 and peptide analogue treatment groups compared with high-fat-fed controls and the β-cell area decreased (p <.05 to <.01). Conclusions: Overall, dogfish glucagon co-agonist analogues had several beneficial metabolic effects, showing therapeutic potential for type 2 diabetes.