Glucagon-like peptide-1（GLP-1） is an endogenous insulinotropic hormone with excellent blood glucose-lowering activity, however, it is rapidly inactivated in the plasma mainly by dipeptidyl peptidase IV（DPP-IV）. To overcome this problem, various N-terminal modifications of GLP-1 have been performed to prolong the in vivo biological activity, by improving the DPP-IV resistance while retaining receptor affinity and receptor activation. These studies have included modifications of His7, Ala8 or Glu9 at the N-terminus of GLP-1 and some other modifications. Among them, Ala8 substitutions with glycine（Gly8） and α-aminoisobutyric acid（Aib8） have been clinically applied in the development of diabetic therapy, such as Exenatide, Semaglutide, Albiglutide and Taspoglutide. In this review, we introduce N-terminal modifications of GLP-1 that have been reported, and discuss their potential and challenges for the treatment of type 2 diabetes.
