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

被引:172
作者
Kim, JG
Baggio, LL
Bridon, DP
Castaigne, JP
Robitaille, MF
Jetté, L
Benquet, C
Drucker, DJ
机构
[1] Univ Toronto, Toronto Gen Hosp, Banting & Best Diabet Ctr, Dept Med, Toronto, ON M5G 1L7, Canada
[2] Conjuchem, Montreal, PQ, Canada
关键词
D O I
10.2337/diabetes.52.3.751
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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-lR) and activated cAMP formation in heterologous fibroblasts expressing a GLP1R. 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.
引用
收藏
页码:751 / 759
页数:9
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