title: A novel glucagon-like peptide-1 (GLP-1)/glucagon hybrid peptide with triple-acting agonist activity at glucose-dependent insulinotropic polypeptide, GLP-1, and glucagon receptors and therapeutic potential in high fat-fed mice.
abstract: Glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon bind to related members of the same receptor superfamily and exert important effects on glucose homeostasis, insulin secretion, and energy regulation. The present study assessed the biological actions and therapeutic utility of novel GIP/glucagon/GLP-1 hybrid peptides. Nine novel peptides were synthesized and exhibited complete DPP-IV resistance and enhanced in vitro insulin secretion. The most promising peptide, [dA(2)]GLP-1/GcG, stimulated cAMP production in GIP, GLP-1, and glucagon receptor-transfected cells. Acute administration of [dA(2)]GLP-1/GcG in combination with glucose significantly lowered plasma glucose and increased plasma insulin in normal and obese diabetic (ob/ob) mice. Furthermore, [dA(2)]GLP-1/GcG elicited a protracted glucose-lowering and insulinotropic effect in high fat-fed mice. Twice daily administration of [dA(2)]GLP-1/GcG for 21 days decreased body weight and nonfasting plasma glucose and increased circulating plasma insulin concentrations in high fat-fed mice. Furthermore, [dA(2)]GLP-1/GcG significantly improved glucose tolerance and insulin sensitivity by day 21. Interestingly, locomotor activity was increased in [dA(2)]GLP-1/GcG mice, without appreciable changes in aspects of metabolic rate. Studies in knock-out mice confirmed the biological action of [dA(2)]GLP-1/GcG via multiple targets including GIP, GLP-1, and glucagon receptors. The data suggest significant promise for novel triple-acting hybrid peptides as therapeutic options for obesity and diabetes.
authors.affiliation: From the SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, BT52 1SA Northern Ireland, United Kingdom.
authors.forename: Victor A
authors.initials: VA
authors.lastname: Gault
authors.forename: Vikas K
authors.initials: VK
authors.lastname: Bhat
authors.forename: Nigel
authors.initials: N
authors.lastname: Irwin
authors.forename: Peter R
authors.initials: PR
authors.lastname: Flatt
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D000242:Cyclic AMP / Q000096:biosynthesis; D059305:Diet, High-Fat; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D005934:Glucagon / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D052216:Glucagon-Like Peptide 1 / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin / Q000097:blood / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D008969:Molecular Sequence Data; D009765:Obesity / Q000188:drug therapy / Q000503:physiopathology; D011964:Receptors, Gastrointestinal Hormone / Q000819:agonists*; D018027:Receptors, Glucagon / Q000819:agonists*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D011964:Receptors, Gastrointestinal Hormone; D018027:Receptors, Glucagon; D011993:Recombinant Fusion Proteins; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; C041086:gastric inhibitory polypeptide receptor; D000242:Cyclic AMP; D018819:Dipeptidyl Peptidase 4
keywords: Diabetes; Glucose; Insulin; Insulin Secretion; Obesity