Development and Characterization of a Glucagon-Like Peptide 1-Albumin Conjugate: The Ability to Activate the Glucagon-Like Peptide 1 Receptor In Vivo Export

@article{citeulike:785488, 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.}, author = {Kim, Jung-Guk and Baggio, Laurie L. and Bridon, Dominique P. and Castaigne, Jean-Paul and Robitaille, Martin F. and Jette, Lucie and Benquet, Corinne and Drucker, Daniel J.}, citeulike-article-id = {785488}, citeulike-linkout-0 = {http://diabetes.diabetesjournals.org/cgi/content/abstract/52/3/751}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/12606517}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=12606517}, day = {1}, journal = {Diabetes}, keywords = {1, 200, albugon, albumin, biosci353, conjugate, diabetes, fusion, glucagon-like, hybrid, peptide, protein, therapies}, month = {March}, number = {3}, pages = {751--759}, posted-at = {2006-08-04 04:04:46}, priority = {2}, title = {Development and Characterization of a Glucagon-Like Peptide 1-Albumin Conjugate: The Ability to Activate the Glucagon-Like Peptide 1 Receptor In Vivo}, url = {http://diabetes.diabetesjournals.org/cgi/content/abstract/52/3/751}, volume = {52}, year = {2003} }

TY - JOUR ID - citeulike:785488 L3 - citeulike-article-id:785488 N2 - 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. IS - 3 JF - Diabetes EP - 759 TI - Development and Characterization of a Glucagon-Like Peptide 1-Albumin Conjugate: The Ability to Activate the Glucagon-Like Peptide 1 Receptor In Vivo VL - 52 SP - 751 KW - 1 KW - 200 KW - albugon KW - albumin KW - biosci353 KW - conjugate KW - diabetes KW - fusion KW - glucagon-like KW - hybrid KW - peptide KW - protein KW - therapies AU - Kim, Jung-Guk AU - Baggio, Laurie AU - Bridon, Dominique AU - Castaigne, Jean-Paul AU - Robitaille, Martin AU - Jette, Lucie AU - Benquet, Corinne AU - Drucker, Daniel PY - 2003/03/01/ UR - http://diabetes.diabetesjournals.org/cgi/content/abstract/52/3/751 ER -