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

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Abstract

AIMS: We investigated the antidiabetic actions of three dogfish glucagon peptide analogues (known GLP-1 and glucagon receptor co-agonists) following chronic administration to diet-induced high fat fed (HFD) diabetic mice.MATERIALS AND METHODS: NIH Swiss mice were pre-conditioned to a HFD (45% fat) for 100 days, or control mice were fed a normal diet (10% fat). Normal diet control and HFD control mice received twice daily i.p. saline and HFD groups (n = 8) received twice daily injections of or 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: Following dogfish glucagon analogue treatment, there was a rapid and sustained decrease in non-fasting blood glucose and associated insulinotropic effect (ANOVA, p <0.05-p <0.001) compared to saline-treated HFD controls. All peptide treatments significantly improved i.p. and oral glucose tolerance with concomitant increased insulin secretion compared to saline-treated HFD controls (p <0.05-p <0.001). Following chronic treatment, no receptor desensitisation was observed but insulin sensitivity was enhanced for all peptide treated groups (p <0.01-p <0.001) except [S2a]dogfish glucagon. Both exendin-4 and [S2a]dogfish glucagon exendin-4(31-39) significantly reduced plasma triglycerides concentrations compared to lean controls (p = 0.0105 and p = 0.0048, 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 = 0.0221 and p = 0.0075, respectively). The percentage β-cell area within islets was increased by exendin-4 and peptide analogue treatment groups compared with HFD controls and the α-cell area decreased (p <0.05-p <0.01) CONCLUSIONS: Overall, dogfish glucagon co-agonist analogues demonstrated several beneficial metabolic effects showing therapeutic potential for T2DM.
Original languageEnglish
Pages (from-to)1013-1024
Number of pages12
JournalDiabetes Obesity and Metabolism
Volume18
Issue number10
Early online date30 Jun 2016
DOIs
Publication statusPublished - 13 Sep 2016

Keywords

  • Dogfish glucagon
  • chronic study
  • co-agonist
  • diabetic mice
  • glucagon like peptide-1
  • peptide analogues
  • therapy

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    Finbarr O'Harte

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