期刊
PLOS ONE
卷 5, 期 9, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0012734
关键词
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资金
- Juvenile Diabetes Research Foundation
- St Michael's Hospital
- Canadian Institute for Health Research (CIHR)
- Canadian Diabetes association
GLP-1 has a variety of anti-diabetic effects. However, native GLP-1 is not suitable for therapy of diabetes due to its short half-life (t1/2<2 min). To circumvent this, we developed a long-lasting GLP-1 receptor agonist by the fusion of GLP-1 with human IgG2 Fc (GLP-1/hlgG2). ELISA-based receptor binding assay demonstrated that GLP-1/hlgG2 had high binding affinity to the GLP-1R in INS-1 cells (Kd = 13.90 +/- 1.52 nM). Upon binding, GLP-1/hlgG2 was rapidly internalized by INS-1 cells in a dynamin-dependent manner. Insulin RIA showed that GLP-1/IgG2 dose-dependently stimulated insulin secretion from INS-1 cells. Pharmacokinetic studies in CD1 mice showed that with intraperitoneal injection (i.p.), the GLP-1/hlgG2 peaked at 30 minutes in circulation and maintained a plateau for >168 h. Intraperitoneal glucose tolerance test (IPGTT) in mice showed that GLP-1/hlgG2 significantly decreased glucose excursion. Furthermore, IPGTT performed on mice one week after a single drug-injection also displayed significantly reduced glucose excursion, indicating that GLP-1/hlgG2 fusion protein has long-lasting effects on the modulation of glucose homeostasis. GLP-1/hlgG2 was found to be effective in reducing the incidence of diabetes in multiple-low-dose streptozotocin-induced type 1 diabetes in mice. Together, the long-lasting bioactive GLP-1/hlgG2 retains native GLP-1 activities and thus may serve as a potent GLP-1 receptor agonist.
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