Development and characterization of a glucagon-like peptide 1-albumin conjugate: The ability to activate the glucagon-like peptide 1 receptor in vivo

• Published in: Diabetes (New York, N.Y.) Vol. 52; no. 3; pp. 751 - 759
• Main Authors: KIM, Jung-Guk, BAGGIO, Laurie L, BRIDON, Dominique P, CASTAIGNE, Jean-Paul, ROBITAILLE, Martin F, JETTE, Lucie, BENQUET, Corinne, DRUCKER, Daniel J
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.03.2003
• Subjects: Animals; Biological and medical sciences; Blood Glucose - analysis; Body Weight - drug effects; Care and treatment; CHO Cells; Cricetinae; Cyclic AMP - metabolism; Diabetes; Diabetes Mellitus - blood; Diabetes Mellitus - drug therapy; Diabetes therapy; Dipeptidyl Peptidase 4 - metabolism; Enzymes; Experiments; Fibroblasts - metabolism; Fundamental and applied biological sciences. Psychology; Glucagon; Glucagon - agonists; Glucagon - chemistry; Glucagon - metabolism; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucose; Glucose Tolerance Test; Human subjects; Humans; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - metabolism; Hypoglycemic Agents - pharmacology; Insulin; Maleimides - chemistry; Maleimides - metabolism; Maleimides - pharmacology; Mice; Mice, Inbred C57BL; Mice, Knockout; Ovaries; Peptide Fragments - agonists; Peptide Fragments - chemistry; Peptide Fragments - metabolism; Peptides; Peptides - chemistry; Peptides - metabolism; Peptides - pharmacology; Physiological aspects; Proinsulin - genetics; Protein Precursors - agonists; Protein Precursors - chemistry; Protein Precursors - metabolism; Receptors, Glucagon - deficiency; Receptors, Glucagon - genetics; Receptors, Glucagon - metabolism; Recombinant Proteins - metabolism; RNA, Messenger - analysis; Serum Albumin - chemistry; Serum Albumin - metabolism; Transfection; Type 2 diabetes; Canada
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.52.3.751

The rapid degradation of native glucagon-like peptide 1 (GLP-1) by dipeptidyl peptidase-IV (DPP-IV) has fostered new approaches for generation of degradation-resistant GLP-1 analogues. We examined the biological activity of CJC-1131, a DPP-IV-resistant drug affinity complex (DAC) GLP-1 compound that conjugates to albumin in vivo. The CJC-1131 albumin conjugate bound to the GLP-1 receptor (GLP-1R) and activated cAMP formation in heterologous fibroblasts expressing a GLP-1R. CJC-1131 lowered glucose in wild-type mice, but not in GLP-1R-/- mice. Basal glucose and glycemic excursion following glucose challenge remained significantly reduced 10-12 h following a single injection of CJC-1131. Twice daily administration of CJC-1131 to db/db mice significantly reduced glycemic excursion following oral and IP glucose challenge (P < 0.01 to 0.05) but did not significantly lower body weight during the 4-week study period. Levels of random fed glucose were significantly lower in CJC-1131-treated +/+ and db/db mice and remained significantly lower even 1 week following discontinuation of CJC-1131 administration. CJC-1131 increased levels of pancreatic proinsulin mRNA transcripts, percent islet area, and the number of bromodeoxyuridine-positive islet cells. These findings demonstrate that an albumin-conjugated DAC:GLP-1 mimics the action of native GLP-1 and represents a new approach for prolonged activation of GLP-1R signaling.