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

Y. Gan; N. Dang; Z. Qu; R. Shi; L. Ding; L. Wang; S. Pang

doi:10.1055/s-0035-1548797

Experimental and Clinical Endocrinology & Diabetes, Table of Contents

Exp Clin Endocrinol Diabetes 2015; 123(06): 371-375
DOI: 10.1055/s-0035-1548797

Article

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

Authors

Y. Gan^*

¹Jinan Central Hospital Affiliated to Shandong University, Jinan Shandong Province, People’s Republic of China

²Medical School of Shandong University, Jinan Shandong Province, People’s Republic of China

³Tengzhou Central Hospital, Shandong Province, People’s Republic of China
N. Dang^*

¹Jinan Central Hospital Affiliated to Shandong University, Jinan Shandong Province, People’s Republic of China
Z. Qu

¹Jinan Central Hospital Affiliated to Shandong University, Jinan Shandong Province, People’s Republic of China
R. Shi

¹Jinan Central Hospital Affiliated to Shandong University, Jinan Shandong Province, People’s Republic of China

⁴Department of Medicine, Taishan Medical University, Shandong Province, People’s Republic of China
L. Ding

¹Jinan Central Hospital Affiliated to Shandong University, Jinan Shandong Province, People’s Republic of China

²Medical School of Shandong University, Jinan Shandong Province, People’s Republic of China
L. Wang

¹Jinan Central Hospital Affiliated to Shandong University, Jinan Shandong Province, People’s Republic of China

²Medical School of Shandong University, Jinan Shandong Province, People’s Republic of China
S. Pang

¹Jinan Central Hospital Affiliated to Shandong University, Jinan Shandong Province, People’s Republic of China

²Medical School of Shandong University, Jinan Shandong Province, People’s Republic of China

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

Full Text

References

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