Development and characterization of a glucagon-like peptide 1-albumin conjugate: the ability to activate the glucagon-like peptide 1 receptor in vivo.
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.
Kim
Jung-Guk
JG
Banting and Best Diabetes Centre, Department of Medicine, University of Toronto, Toronto General Hospital, 200 Elizabeth Street, Toronto, Ontario, Canada M5G 2C4.
Baggio
Laurie L
LL
Bridon
Dominique P
DP
Castaigne
Jean-Paul
JP
Robitaille
Martin F
MF
Jetté
Lucie
L
Benquet
Corinne
C
Drucker
Daniel J
DJ
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D003920:Diabetes Mellitus / Q000097:blood / Q000188:drug therapy; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005934:Glucagon / Q000819:agonists / Q000737:chemistry* / Q000378:metabolism; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D005951:Glucose Tolerance Test; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008301:Maleimides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000819:agonists / Q000737:chemistry* / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011384:Proinsulin / Q000235:genetics; D011498:Protein Precursors / Q000819:agonists / Q000737:chemistry* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D018027:Receptors, Glucagon / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D012709:Serum Albumin / Q000737:chemistry* / Q000378:metabolism; D014162:Transfection
D001786:Blood Glucose; C473712:CJC 1131; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D008301:Maleimides; D010446:Peptide Fragments; D010455:Peptides; D011498:Protein Precursors; D012333:RNA, Messenger; D018027:Receptors, Glucagon; D011994:Recombinant Proteins; D012709:Serum Albumin; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D011384:Proinsulin; D000242:Cyclic AMP; D018819:Dipeptidyl Peptidase 4