The Xenopus proglucagon gene encodes novel GLP-1-like peptides with insulinotropic properties

被引:71
作者
Irwin, DM
Satkunarajah, M
Wen, Y
Brubaker, PL
Pederson, RA
Wheeler, MB
机构
[1] UNIV TORONTO,DEPT MED,TORONTO,ON M5G 1L5,CANADA
[2] UNIV TORONTO,DEPT PHYSIOL,TORONTO,ON M5G 1L5,CANADA
[3] UNIV TORONTO,BANTING & BEST DIABET CTR,TORONTO,ON M5G 1L5,CANADA
[4] UNIV BRITISH COLUMBIA,DEPT PHYSIOL,VANCOUVER,BC V6T 1Z3,CANADA
关键词
diabetes; insulinotropic peptides; GLP-1; receptor;
D O I
10.1073/pnas.94.15.7915
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The proglucagon gene encodes several hormones that have key roles in the regulation of metabolism, In particular, glucagon-like peptide (GLP-1), a potent stimulus of insulin secretion, is being developed as a therapy for the treatment of non-insulin-dependent diabetes mellitus, To define structural moieties of the molecule that convey its insulinotropic activity, we have cloned and characterized the proglucagon gene from the amphibian, Xenopus laevis, Unexpectedly, these cDNAs were found to encode three unique glucagon-like-1 peptides, termed xenGLP-1A, xenGLP-1B, and xenGLP-1C in addition to the typical proglucagon-derived hormones glucagon and GLP-2. xenGLP-1A, -1B, and -1C were synthesized and tested for their ability to bind and activate the human GLP-1 receptor (hGLP-IR), and to stimulate insulin release from rat pancreas, All three Xenopus GLP-1-like peptides bind effectively to the hGLP-1R and stimulate cAMP production. Surprisingly, xenGLP-1B(1-30) demonstrated higher affinity for the hGLP-1R than hGLP-1 (IC50 of 1.1 +/- 0.4 nM vs, 4.4 +/- 1.0 nM, respectively, P < 0.02) and was equipotent to hGLP-1 in stimulating cAMP production (EC50 of 0.17 +/- 0.02 nM vs, 0.6 +/- 0.2 nM, respectively, P > 0.05), Further studies demonstrated that hGLP-1, xenGLP-1A, -1B, and -1C stimulate comparable insulin release from the pancreas. These results demonstrate that despite an average of nine amino acid differences between the predicted Xenopus GLPs and hGLP-1, all act as hGLP-1R agonists.
引用
收藏
页码:7915 / 7920
页数:6
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