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

Abstract

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.

• Authors: Jung-Guk Kim, Laurie L Baggio, Dominique P Bridon, Jean-Paul Castaigne, Martin F Robitaille, Lucie Jetté, Corinne Benquet, Daniel J Drucker
• Journal: Diabetes (Diabetes) Vol. 52 Issue 3 Pg. 751-9 (Mar 2003) ISSN: 0012-1797 [Print] United States
• PMID: 12606517 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Glucose
• CJC 1131
• GLP1R protein, human
• Glp1r protein, mouse
• Glucagon-Like Peptide-1 Receptor
• Hypoglycemic Agents
• Maleimides
• Peptide Fragments
• Peptides
• Protein Precursors
• RNA, Messenger
• Receptors, Glucagon
• Recombinant Proteins
• Serum Albumin
• Glucagon-Like Peptide 1
• Glucagon
• Proinsulin
• Cyclic AMP
• Dipeptidyl Peptidase 4

Topics

• Animals
• Blood Glucose (analysis)
• Body Weight (drug effects)
• CHO Cells
• Cricetinae
• Cyclic AMP (metabolism)
• Diabetes Mellitus (blood, drug therapy)
• Dipeptidyl Peptidase 4 (metabolism)
• Fibroblasts (metabolism)
• Glucagon (agonists, chemistry, metabolism)
• Glucagon-Like Peptide 1
• Glucagon-Like Peptide-1 Receptor
• Glucose Tolerance Test
• Humans
• Hypoglycemic Agents (chemistry, metabolism, pharmacology)
• Maleimides (chemistry, metabolism, pharmacology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Peptide Fragments (agonists, chemistry, metabolism)
• Peptides (chemistry, metabolism, pharmacology)
• Proinsulin (genetics)
• Protein Precursors (agonists, chemistry, metabolism)
• RNA, Messenger (analysis)
• Receptors, Glucagon (deficiency, genetics, metabolism)
• Recombinant Proteins (metabolism)
• Serum Albumin (chemistry, metabolism)
• Transfection