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

• Published in: Diabetes (New York, N.Y.) Vol. 53; no. 9; pp. 2492 - 2500
• Main Authors: Baggio, Laurie L., Huang, Qingling, Brown, Theodore J., Drucker, Daniel J.
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.09.2004
• Subjects: Albumins - genetics; Albumins - pharmacology; Animals; Biological and medical sciences; Cells, Cultured; Cricetinae; Diabetes; Diabetes. Impaired glucose tolerance; Eating - drug effects; Eating - physiology; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Energy consumption; Food; Gastric Emptying - drug effects; Gastric Emptying - physiology; Gastrointestinal Motility - drug effects; Gastrointestinal Motility - physiology; Glucagon; Glucagon - genetics; Glucagon - pharmacology; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Glucose - metabolism; Homeostasis; Homeostasis - drug effects; Homeostasis - physiology; Human subjects; Humans; Insulin; Kidney - cytology; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Motility; Peptide Fragments - genetics; Peptide Fragments - pharmacology; Peptides; Plasma; Protein Precursors - genetics; Protein Precursors - pharmacology; Proteins; Proto-Oncogene Proteins c-fos - metabolism; Rats; Receptors, Glucagon - genetics; Receptors, Glucagon - metabolism; Recombinant Proteins - pharmacology; Satiety Response - drug effects; Satiety Response - physiology; Endocrinopathy; Human; Motility; Diabetes mellitus; Albumin; Homeostasis; Satiety; Glucose; Gastrointestinal; Protein; Biological receptor
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.53.9.2492

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 Laurie L. Baggio 1 , Qingling Huang 1 , Theodore J. Brown 2 and Daniel J. Drucker 1 1 Department of Medicine, Banting and Best Diabetes Centre, Toronto General Hospital, Toronto, Ontario, Canada 2 Division of Reproductive Science, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, and the University of Toronto, Toronto, Ontario, Canada Address correspondence and reprint requests to Dr. Daniel J. Drucker, Toronto General Hospital, Banting and Best Diabetes Centre, 200 Elizabeth St., MBRW4R-402, Toronto, Canada M5G 2C4. E-mail: d.drucker{at}utoronto.ca Abstract 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. CCK, cholecystokinin CNS, central nervous system DPP-IV, dipeptidyl peptidase-IV Ex-4, exendin-4 GLP, glucagon-like peptide GLP-1R, GLP-1 receptor HSA, human serum albumin ICV, intracerebroventricular IP, intraperitoneal NTS, nucleus of the solitary tract Footnotes Accepted May 28, 2004. Received December 4, 2003. DIABETES