A recombinant human glucagon-like peptide (GLP)-1-albumin protein (albugon) mimics peptidergic activation of GLP-1 receptor-dependent pathways coupled with satiety, gastrointestinal motility, and glucose homeostasis.
Peptide hormones exert unique actions via specific G protein-coupled receptors; however, the therapeutic potential of regulatory peptides is frequently compromised by rapid enzymatic inactivation and clearance from the circulation. In contrast, recombinant or covalent coupling of smaller peptides to serum albumin represents an emerging strategy for extending the circulating t(1/2) of the target peptide. However, whether larger peptide-albumin derivatives will exhibit the full spectrum of biological activities encompassed by the native peptide remains to be demonstrated. We report that Albugon, a human glucagon-like peptide (GLP)-1-albumin recombinant protein, activates GLP-1 receptor (GLP-1R)-dependent cAMP formation in BHK-GLP-1R cells, albeit with a reduced half-maximal concentration (EC(50)) (0.2 vs. 20 nmol/l) relative to the GLP-1R agonist exendin-4. Albugon decreased glycemic excursion and stimulated insulin secretion in wild-type but not GLP-1R(-/-) mice and reduced food intake after both intracerebroventricular and intraperitoneal administration. Moreover, intraperitoneal injection of Albugon inhibited gastric emptying and activated c-FOS expression in the area postrema, the nucleus of the solitary tract, the central nucleus of the amygdala, the parabrachial, and the paraventricular nuclei. These findings illustrate that peripheral administration of a larger peptide-albumin recombinant protein mimics GLP-1R-dependent activation of central and peripheral pathways regulating energy intake and glucose homeostasis in vivo.
Baggio
Laurie L
LL
Toronto General Hospital, Banting and Best Diabetes Centre, 200 Elizabeth St., MBRW4R-402, Toronto, Canada.
Huang
Qingling
Q
Brown
Theodore J
TJ
Drucker
Daniel J
DJ
D000418:Albumins / Q000235:genetics / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D006224:Cricetinae; D004435:Eating / Q000187:drug effects / Q000502:physiology; D005746:Gastric Emptying / Q000187:drug effects / Q000502:physiology; D005769:Gastrointestinal Motility / Q000187:drug effects / Q000502:physiology; D005934:Glucagon / Q000235:genetics / Q000494:pharmacology*; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007668:Kidney / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010446:Peptide Fragments / Q000235:genetics / Q000494:pharmacology*; D011498:Protein Precursors / Q000235:genetics / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D018027:Receptors, Glucagon / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology*; D012528:Satiety Response / Q000187:drug effects* / Q000502:physiology*
D000418:Albumins; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D010446:Peptide Fragments; D011498:Protein Precursors; D016760:Proto-Oncogene Proteins c-fos; D018027:Receptors, Glucagon; D011994:Recombinant Proteins; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D005947:Glucose