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Exp Clin Endocrinol Diabetes 2015; 123(06): 371-375
DOI: 10.1055/s-0035-1548797
Article
© Georg Thieme Verlag KG Stuttgart · New York

GLP-1-Exendin-4/IgG4 (Fc) Fusion Protein as a Novel Drug for Diabetes Treatment

Y. Gan   *
1   Jinan Central Hospital Affiliated to Shandong University, Jinan Shandong Province, People’s Republic of China
2   Medical School of Shandong University, Jinan Shandong Province, People’s Republic of China
3   Tengzhou Central Hospital, Shandong Province, People’s Republic of China
,
N. Dang   *
1   Jinan Central Hospital Affiliated to Shandong University, Jinan Shandong Province, People’s Republic of China
,
Z. Qu
1   Jinan Central Hospital Affiliated to Shandong University, Jinan Shandong Province, People’s Republic of China
,
R. Shi
1   Jinan Central Hospital Affiliated to Shandong University, Jinan Shandong Province, People’s Republic of China
4   Department of Medicine, Taishan Medical University, Shandong Province, People’s Republic of China
,
L. Ding
1   Jinan Central Hospital Affiliated to Shandong University, Jinan Shandong Province, People’s Republic of China
2   Medical School of Shandong University, Jinan Shandong Province, People’s Republic of China
,
L. Wang
1   Jinan Central Hospital Affiliated to Shandong University, Jinan Shandong Province, People’s Republic of China
2   Medical School of Shandong University, Jinan Shandong Province, People’s Republic of China
,
S. Pang
1   Jinan Central Hospital Affiliated to Shandong University, Jinan Shandong Province, People’s Republic of China
2   Medical School of Shandong University, Jinan Shandong Province, People’s Republic of China
› Author Affiliations
Further Information

Publication History

received 16 October 2014
first decision 23 December 2014

accepted 11 March 2015

Publication Date:
21 April 2015 (online)

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Abstract

In this paper, we aimed to look for a potent long acting GLP-1 receptor agonist for diabetes treatment. In this work, we constructed the eukaryotic expression vector of GLP-1-Exendin-4/IgG4 (Fc)-pOptiVEC™-TOPO® and then transfected it into Chinese hamster ovary DG44 (CHO/DG44) cells using liposome method. Then the beta-cell line INS-1 cells were treated with purified GLP-1-Exendin-4/IgG4 (Fc) fusion protein (0.01, 0.1, 1.0 mM respectively) and randomly assigned to 2 groups, each group were then grown in KRB buffer in the presence of 2.8 mM or 16.8 mM glucose for 2 h separately. In addition, single dose of fusion protein was intraperitoneally injected into male CD1 mice for pharmacokinetic study. Besides, multiple low doses of streptozotozin (STZ) induced diabetes mice were used to evaluate the effect of fusion protein for anti-diabetes in male CD1 mice. GLP-1-Exendin-4/IgG4 (Fc) had stimulatory effect on insulin secretion glucose-dependently from INS-1 cells in a dose-dependent manner. Pharmacokinetic studies showed that the GLP-1 level increased significantly after injecting fusion protein and maintained a higher level for 200 h. Besides, multiple-low-dose STZ-induced diabetes mice which received intraperitoneal injections of fusion protein did not show sign of diabetes. Our results indicated that GLP-1-Exendin-4/IgG4 (Fc) fusion protein retained native GLP-1 activities and had effect on long-term glucose regulation. All the results suggest that this fusion protein may serve as a potent long acting GLP-1 receptor agonist.

Key words

glucagon-like peptide-1 - exendin-4 - GLP-1-Exendin-4/IgG4 (Fc) fusion protein - pharmacokinetic study - streptozotocin (STZ)-induced diabetes mice

* Yizhang Gan and Ningning Dang contributed equally to this work.


 

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