title: Ablation of glucagon receptor signaling by peptide-based glucagon antagonists improves glucose tolerance in high fat fed mice.
abstract: Modification to the structure of glucagon has provided a number of glucagon receptor antagonists with possible therapeutic application for diabetes. These novel peptide analogs include desHis(1)Pro(4)Glu(9)-glucagon and desHis(1)Pro(4)Glu(9)(Lys(30)PAL)-glucagon. This study has evaluated the metabolic benefits of once daily administration of desHis(1)Pro(4)Glu(9)-glucagon and desHis(1)Pro(4)Glu(9)(Lys(30)PAL)-glucagon in high fat (45%) fed mice for 15 days. Administration of desHis(1)Pro(4)Glu(9)-glucagon and desHis(1)Pro(4)Glu(9)(Lys(30)PAL)-glucagon had no significant effect on body weight, food intake or circulating glucose concentrations during the treatment period. However, both peptides significantly (P<0.05 to P<0.01) reduced circulating plasma insulin concentrations from day 6 onwards. Oral glucose tolerance and insulin sensitivity, as assessed by exogenous insulin administration, were significantly (P<0.01 to P<0.001) improved by both desHis(1)Pro(4)Glu(9)-glucagon and desHis(1)Pro(4)Glu(9)(Lys(30)PAL)-glucagon. These metabolic benefits were accompanied by significantly (P<0.01) increased pancreatic insulin stores. No significant differences in blood triacylglycerol or cholesterol levels were noted with desHis(1)Pro(4)Glu(9)-glucagon, however desHis(1)Pro(4)Glu(9)(Lys(30)PAL)-glucagon treatment significantly (P<0.01) increased HDL-cholesterol levels. Glucagon-mediated elevations of glucose and insulin were effectively (P<0.01 to P<0.001) annulled in both treatment groups on day 15. Interestingly, glucose levels during an intraperitoneal glucose tolerance test were not altered by either desHis(1)Pro(4)Glu(9)-glucagon or desHis(1)Pro(4)Glu(9)(Lys(30)PAL)-glucagon treatment. These data provide further evidence that glucagon antagonism could provide an effective means of treating T2DM.
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, UK.
authors.forename: Laura M
authors.initials: LM
authors.lastname: McShane
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, UK.
authors.forename: Zara J
authors.initials: ZJ
authors.lastname: Franklin
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, UK.
authors.forename: Finbarr P M
authors.initials: FP
authors.lastname: O'Harte
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, UK. Electronic address: n.irwin@ulster.ac.uk.
authors.forename: Nigel
authors.initials: N
authors.lastname: Irwin
mesh_terms: D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects*; D005934:Glucagon / Q000008:administration & dosage / Q000494:pharmacology*; D005951:Glucose Tolerance Test; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D010455:Peptides; D018027:Receptors, Glucagon; D005934:Glucagon
keywords: Diabetes; Glucagon antagonist; Glucose tolerance; Insulin sensitivity