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

O'Harte, Finbarr, Ng, Tony, Lynch, AM, Conlon, J. Michael and Flatt, Peter (2016) Dogfish glucagon analogues counter hyperglycaemia and enhance both insulin secretion and action in diet-induced obese diabetic mice. Diabetes Obesity and Metabolism, 18 (10). pp. 1013-1024. [Journal article]

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DOI: 10.1111/dom.12713

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.

Item Type:Journal article
Keywords:Dogfish glucagon; chronic study; co-agonist; diabetic mice; glucagon like peptide-1; peptide analogues; therapy
Faculties and Schools: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:35059
Deposited By: Dr Nigel Irwin
Deposited On:05 Jul 2016 08:41
Last Modified:17 Oct 2017 16:24

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