Development and Characterization of a Glucagon-Like Peptide 1-Albumin Conjugate
The Ability to Activate the Glucagon-Like Peptide 1 Receptor In Vivo
- Jung-Guk Kim1,
- Laurie L. Baggio1,
- Dominique P. Bridon2,
- Jean-Paul Castaigne2,
- Martin F. Robitaille2,
- Lucie Jetté2,
- Corinne Benquet2 and
- Daniel J. Drucker1
- 1Banting and Best Diabetes Centre, Department of Medicine, University of Toronto, Toronto General Hospital, Toronto, Ontario
- 2Conjuchem, Montreal, Quebec
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.
Address correspondence and reprint requests to Dr. Daniel J Drucker, 200 Elizabeth St., MBRW-4R-402, Toronto, Ontario, Canada M5G 2C4. E-mail:.
Received for publication 16 July 2002 and accepted in revised form 6 November 2002.
AUC, area under the curve; CHO, Chinese hamster ovary; DAC, drug affinity complex; DPP-IV, dipeptidyl peptidase-IV; GIP, glucose-dependent insulinotropic peptide; GLP-1, glucagon-like peptide 1; GLP-1R, GLP-1 receptor; HSA, human serum albumin.