title: desHis¹Glu⁹-glucagon-[mPEG] and desHis¹Glu⁹(Lys³⁰PAL)-glucagon: long-acting peptide-based PEGylated and acylated glucagon receptor antagonists with potential antidiabetic activity.
abstract: Glucagon is hormone secreted from the pancreatic alpha-cells that is involved in blood glucose regulation. As such, antagonism of glucagon receptor signalling represents an exciting approach for treating diabetes. To harness these beneficial metabolic effects, two novel glucagon analogues, desHis¹Glu⁹-glucagon-[mPEG] and desHis¹Glu⁹(Lys³⁰PAL)-glucagon, has been evaluated for potential glucagon receptor antagonistic properties. Both novel peptides were completely resistant to enzymatic breakdown and significantly (P<0.05 to P<0.001) inhibited glucagon-mediated elevations of cAMP production in glucagon receptor transfected cells. Similarly, desHis¹Glu⁹-glucagon-[mPEG] and desHis¹Glu⁹(Lys³⁰PAL)-glucagon effectively antagonised glucagon-induced increases of insulin secretion from BRIN BD11 cells. When administered acutely to normal, high fat fed or ob/ob mice, both analogues had no significant effects on overall blood glucose or plasma insulin levels when compared to saline treated controls. However, desHis¹Glu⁹-glucagon-[mPEG] significantly (P<0.05) annulled glucagon-induced increases in blood glucose and plasma insulin levels in normal mice and had similar non-significant tendencies in high fat and ob/ob mice. In addition, desHis¹Glu⁹(Lys³⁰PAL)-glucagon effectively (P<0.05 to P<0.001) antagonised glucagon-mediated elevations of blood glucose levels in high fat fed and ob/ob mice, but was less efficacious in normal mice. Further studies confirmed the significant persistent glucagon receptor antagonistic properties of both novel enzyme-resistant analogues 4h post administration in normal mice. These studies emphasise the potential of longer-acting peptide-based glucagon receptor antagonists, and particularly acylated versions, for the treatment of diabetes.
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland BT52 1SA, UK. n.irwin@ulster.ac.uk
authors.forename: Nigel
authors.initials: N
authors.lastname: Irwin
authors.forename: Zara J
authors.initials: ZJ
authors.lastname: Franklin
authors.forename: Finbarr P M
authors.initials: FP
authors.lastname: O'Harte
mesh_terms: D000215:Acylation; D000818:Animals; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D004355:Drug Stability; D005934:Glucagon / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D057809:HEK293 Cells; D006801:Humans; D006943:Hyperglycemia / Q000150:complications / Q000517:prevention & control*; D006946:Hyperinsulinism / Q000150:complications / Q000517:prevention & control*; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000150:complications; D011092:Polyethylene Glycols / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015290:Second Messenger Systems / Q000187:drug effects
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D018027:Receptors, Glucagon; D011994:Recombinant Proteins; C584424:glucagon, deshistidyl(1)-glutamyl(9)(lysyl(30)PAL)-; C584423:glucagon-mPEG, deshistidyl(1)-glutamyl(9)-; D011092:Polyethylene Glycols; D005934:Glucagon; D000242:Cyclic AMP; D018819:Dipeptidyl Peptidase 4