Endocrine Abstracts (2011) 26 P661

Effect of amino acid residues on N-terminal extension of GLP-1/IgG-Fc fusion protein

C Lee1, J Boyineni1, H-S Chung2 & S-H Jang1


1Daegu University, Gyeongsan 712-714, Republic of Korea; 2Hannam University, Daejeon 305-811, Republic of Korea.


Glucagon-like peptide-1 (GLP-1) is an incretin hormone playing an important role in glucose-dependent insulin secretion and β-cell growth. However, GLP-1 is rapidly degraded by dipeptidyl peptidase IV (DPP-IV) in vivo. Many attempts have been made to develop long-acting GLP-1 analogs with chemical modification, amino acid substitution, and fusion protein technology. We previously showed that the N-terminal Ala- or Gly-extended GLP-1 and human immunoglobulin gamma heavy chain (IgG-Fc) fusion protein is resistant to DPP-IV in vitro and induces expression of insulin receptor substrate-2 in INS-1 cells (Bull. Korean Chem. Soc. 2009 30 2471–2474). In this study, we substituted a polar, aliphatic, charged, or aromatic amino acid (Ser, Leu, Lys, Asp, or Phe) for Ala or Gly, which was tethered on the N-terminus of GLP-1/IgG-Fc fusion protein, and compared the effects on the GLP-1 receptor-mediated signaling in INS-1 cells, in vivo half-life, and blood glucose level. The fusion proteins expressed in CHO-K1 cells were secreted into medium and purified by Protein A affinity chromatography. Our data show that all of the N-terminal-extended GLP-1/IgG-Fc fusion proteins by a single amino acid are resistant to DPP-IV. We will discuss the use of N-terminal-extended GLP-1/IgG-Fc fusion proteins for the treatment of insulin-resistant type 2 diabetes.

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