title: A DPP-IV-resistant triple-acting agonist of GIP, GLP-1 and glucagon receptors with potent glucose-lowering and insulinotropic actions in high-fat-fed mice.
abstract: OBJECTIVE
  We designed a chemically modified, enzyme-resistant peptide with triple-acting properties based on human glucagon with amino acid substitutions aligned to strategic positions in the sequence of glucose-dependent insulinotropic polypeptide (GIP).
  
  
  METHODS
  Y(1)-dA(2)-I(12)-N(17)-V(18)-I(27)-G(28,29)-glucagon (termed YAG-glucagon) was incubated with dipeptidylpeptidase IV (DPP-IV) to assess stability, BRIN-BD11 cells to evaluate insulin secretion, and receptor-transfected cells to examine cAMP production. Acute glucose-lowering and insulinotropic properties of YAG-glucagon were assessed in National Institutes of Health (NIH) Swiss mice, while longer-term actions on glucose homeostasis, insulin secretion, food intake and body weight were examined in high-fat-fed mice.
  
  
  RESULTS
  YAG-glucagon was resistant to DPP-IV, increased in vitro insulin secretion (1.5-3-fold; p < 0.001) and stimulated cAMP production in GIP receptor-, glucagon-like peptide-1 (GLP-1) receptor- and glucagon receptor-transfected cells. Plasma glucose levels were significantly reduced (by 51%; p < 0.01) and insulin concentrations increased (1.2-fold; p < 0.01) after acute injection of YAG-glucagon in NIH Swiss mice. Acute actions were countered by established GIP, GLP-1 and glucagon antagonists. In high-fat-fed mice, twice-daily administration of YAG-glucagon for 14 days reduced plasma glucose (40% reduction; p < 0.01) and increased plasma insulin concentrations (1.8-fold; p < 0.05). Glycaemic responses were markedly improved (19-48% reduction; p < 0.05) and insulin secretion enhanced (1.5-fold; p < 0.05) after a glucose load, which were independent of changes in insulin sensitivity, food intake and body weight.
  
  
  CONCLUSIONS
  YAG-glucagon is a DPP-IV-resistant triple agonist of GIP, GLP-1 and glucagon receptors and exhibits beneficial biological properties suggesting that it may hold promise for treatment of type 2 diabetes.
authors.affiliation: The SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Cromore Road, Coleraine, BT52 1SA, Northern Ireland, UK.
authors.forename: V K
authors.initials: VK
authors.lastname: Bhat
authors.forename: B D
authors.initials: BD
authors.lastname: Kerr
authors.forename: S
authors.initials: S
authors.lastname: Vasu
authors.forename: P R
authors.initials: PR
authors.lastname: Flatt
authors.forename: V A
authors.initials: VA
authors.lastname: Gault
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D001835:Body Weight; D006224:Cricetinae; D003412:Cricetulus; D059305:Diet, High-Fat; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism; D005934:Glucagon / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D011964:Receptors, Gastrointestinal Hormone / Q000819:agonists*; D018027:Receptors, Glucagon / Q000819:agonists*
chemical_list: D001786:Blood Glucose; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D010455:Peptides; D011964:Receptors, Gastrointestinal Hormone; D018027:Receptors, Glucagon; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; C041086:gastric inhibitory polypeptide receptor; D018819:Dipeptidyl Peptidase 4