Glucagon-like peptide-1 plasmid construction and delivery for the treatment of type 2 diabetes

Abstract

Glucagon like peptide-1 (GLP-1) is a potent insulinotrophic hormone, which makes GLP-1 an attractive candidate for the treatment of type 2 diabetes. However, GLP-1 is not immediately clinically applicable because of its extremely short half-life. In this study, we evaluated the effect of GLP-1 gene delivery both in vitro and in vivo using a new plasmid constructed with a modified GLP-1 (7-37) cDNA. This cDNA contains a furin cleavage site between the start codon and the GLP-1 coding region. The expression of the GLP-1 gene was driven by the chicken β-actin promoter (p GLP1) or SV40 promoter (pSV-GLP1-NF B). The level of the GLP-1 mRNA was evaluated by RT-PCR 24 hours after transfection. The in vitro results showed a dose dependent expression of GLP-1. Co-culture assay of the GLP-1 plasmid transfected cells with isolated rat islet cells demonstrated that GLP-1 increased insulin secretion by two-fold, compared to controls during a hyperglycemic challenge. A single injection of polyethylenimine (PEI)/GLP1 plasmid complex into animal model resulted in increasing insulin secretion and decreasing blood glucose level that was maintained for 2 weeks. This GLP-1 gene delivery system may provide an effective and safe treatment modality for type 2 diabetes.