Gene therapy of diabetes using a novel GLP-1/IgG1-Fc fusion construct normalizes glucose levels in db/db mice

Gene Ther. 2007 Jan;14(2):162-72. doi: 10.1038/ Epub 2006 Aug 31.


Glucagon-like peptide (GLP-1), a major physiological incretin, plays numerous important roles in modulating blood glucose homeostasis and has been proposed for the treatment of type 2 diabetes. The major obstacles for using native GLP-1 as a therapeutic agent are that it must be delivered by a parenteral route and has a short half-life. In an attempt to develop a strategy to prolong the physiological t(1/2) and enhance the potency of GLP-1, a fusion protein consisting of active human GLP-1 and mouse IgG(1) heavy chain constant regions (GLP-1/Fc) was generated. A plasmid encoding an IgK leader peptide-driven secretable fusion protein of the active GLP-1 and IgG(1)-Fc was constructed for mammalian expression. This plasmid allows for expression of bivalent GLP-1 peptide ligands as a result of IgG-Fc homodimerization. In vitro studies employing purified GLP-1/Fc indicate that the fusion protein is functional and elevates cAMP levels in insulin-secreting INS-1 cells. In addition, it stimulates insulin secretion in a glucose concentration-dependent manner. Intramuscular gene transfer of the plasmid in db/db mice demonstrated that expression of the GLP-1/Fc peptide normalizes glucose tolerance by enhancing insulin secretion and suppressing glucagon release. This strategy of using a bivalent GLP-1/Fc fusion protein as a therapeutic agent is a novel approach for the treatment of diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bioreactors
  • Blood Glucose / analysis
  • COS Cells
  • Cell Line
  • Chlorocebus aethiops
  • Cyclic AMP / blood
  • Diabetes Mellitus, Type 2 / therapy*
  • Genetic Therapy / methods*
  • Glucagon / blood
  • Glucagon-Like Peptide 1 / genetics*
  • Half-Life
  • Immunoglobulin Fc Fragments / genetics*
  • Immunoglobulin G / genetics*
  • Insulin / blood
  • Mice
  • Mice, Obese
  • Models, Animal
  • Recombinant Fusion Proteins / isolation & purification
  • Recombinant Fusion Proteins / metabolism
  • Recombinant Fusion Proteins / therapeutic use*
  • Transfection / methods


  • Blood Glucose
  • Immunoglobulin Fc Fragments
  • Immunoglobulin G
  • Insulin
  • Recombinant Fusion Proteins
  • Glucagon-Like Peptide 1
  • Glucagon
  • Cyclic AMP