title: A Novel Long-Acting Glucagon-Like Peptide-1 Agonist with Improved Efficacy in Insulin Secretion and β-Cell Growth.
abstract: BACKGROUND
  Glucagon-like peptide-1 (GLP-1) is an incretin hormone produced by cleavage of proglucagon in intestinal L-cells. In the pancreas, GLP-1 stimulates post-prandial insulin secretion, promotes insulin biosynthesis, and improves insulin sensitivity. Because of its insulinotropic activity, GLP-1 has been considered a good candidate drug for treatment of diabetes mellitus. However, clinical use of GLP-1 has been limited by its short half-life, as a result of rapid degradation by dipeptidyl peptidase-IV (DPP-IV).
  
  
  METHODS
  We designed a novel GLP-1 analog, Xenopus GLP-1 (xGLP)-E4. The Ala residue in the second position of xGLP was replaced with a Ser residue to increase the half-life in the body. The C-terminal tail of exendin-4 was added to enhance the binding affinity for the GLP-1 receptor (GLP1R). The potency of GLP-1 and its analogs was determined by luciferase assay. The stability of GLP1R agonists was evaluated by determining the activity of agonists that had been preincubated in the presence of fetal bovine serum, which contains innate DPP-IV activity. The effects of xGLP-E4 on insulin secretion and β-cell growth were investigated using insulin enzyme-linked immunosorbent assay and cell counting.
  
  
  RESULTS
  xGLP-E4 exhibited improved stability against DPP-IV activity and increased potency to GLP1R, compared with GLP-1. An increase in glucose-dependent insulin secretion was observed in xGLP-E4-treated pancreatic β-cells. The effect of xGLP-E4 on β-cell growth was greater than that of GLP-1.
  
  
  CONCLUSIONS
  We developed a novel GLP-1 analog, xGLP-E4, that shows prolonged longevity and improved efficacy. This analog is a potential candidate for treatment of type 2 diabetes.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea.
authors.forename: Hee Young
authors.initials: HY
authors.lastname: Kim
authors.affiliation: Korea University Graduate School of Medicine, Seoul, Korea.
authors.forename: Jong-Ik
authors.initials: JI
authors.lastname: Hwang
authors.affiliation: Korea University Graduate School of Medicine, Seoul, Korea.
authors.forename: Mi Jin
authors.initials: MJ
authors.lastname: Moon
authors.affiliation: Korea University Graduate School of Medicine, Seoul, Korea.
authors.forename: Jae Young
authors.initials: JY
authors.lastname: Seong
keywords: Analog; Diabetes; Exenatide; Glucagon-like peptide 1; xGLP-E4