title: Dogfish glucagon analogues counter hyperglycaemia and enhance both insulin secretion and action in diet-induced obese diabetic mice.
abstract: 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.
  
  
  
  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-Lys(30) -γ-glutamyl-PAL (25 nmol/kg body weight) for 51 days.
  
  
  
  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).
  
  
  
  Overall, dogfish glucagon co-agonist analogues had several beneficial metabolic effects, showing therapeutic potential for type 2 diabetes.
authors.affiliation: School of Biomedical Sciences, Saad Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, UK. fpm.oharte@ulster.ac.uk.
authors.forename: F P M
authors.initials: FP
authors.lastname: O'Harte
authors.affiliation: School of Biomedical Sciences, Saad Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, UK.
authors.forename: M T
authors.initials: MT
authors.lastname: Ng
authors.affiliation: School of Biomedical Sciences, Saad Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, UK.
authors.forename: A M
authors.initials: AM
authors.lastname: Lynch
authors.affiliation: School of Biomedical Sciences, Saad Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, UK.
authors.forename: J M
authors.initials: JM
authors.lastname: Conlon
authors.affiliation: School of Biomedical Sciences, Saad Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, UK.
authors.forename: P R
authors.initials: PR
authors.lastname: Flatt
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism*; D059305:Diet, High-Fat; D004284:Dogfish / Q000378:metabolism; D005934:Glucagon / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D005951:Glucose Tolerance Test; D006943:Hyperglycemia / Q000150:complications / Q000517:prevention & control*; D007328:Insulin / Q000378:metabolism* / Q000502:physiology*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000209:etiology / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D007328:Insulin; D005934:Glucagon
keywords: chronic study; co-agonist; diabetic mice; dogfish glucagon; glucagon-like peptide-1; peptide analogues; therapy