Ectopic expression of glucagon-like peptide 1 for gene therapy of type II diabetes

Gene Ther. 2007 Jan;14(1):38-48. doi: 10.1038/sj.gt.3302842. Epub 2006 Aug 24.

Abstract

Glucagon-like peptide 1 (GLP-1) is a promising candidate for the treatment of type II diabetes. However, the short in vivo half-life of GLP-1 has made peptide-based treatments challenging. Gene therapy aimed at achieving continuous GLP-1 expression presents one way to circumvent the rapid turnover of GLP-1. We have created a GLP-1 minigene that can direct the secretion of active GLP-1 (amino acids 7-37). Plasmid and adenoviral expression vectors encoding the 31-amino-acid peptide linked to leader sequences required for secretion of GLP-1 yielded sustained levels of active GLP-1 that were significantly greater than endogenous levels. Systemic administration of expression vectors to animals using two diabetic rodent models, db/db mice and Zucker Diabetic Fatty (ZDF) rats, yielded elevated GLP-1 levels that lowered both the fasting and random-fed hyperglycemia present in these animals. Because the insulinotropic actions of GLP-1 are glucose dependent, no evidence of hypoglycemia was observed. Improved glucose homeostasis was demonstrated by improvements in %HbA1c (glycated hemoglobin) and in glucose tolerance tests. GLP-1-treated animals had higher circulating insulin levels and increased insulin immunostaining of pancreatic sections. GLP-1-treated ZDF rats showed diminished food intake and, in the first few weeks following vector administration, a diminished weight gain. These results demonstrate the feasibility of gene therapy for type II diabetes using GLP-1 expression vectors.

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / therapy*
  • Female
  • Gene Expression
  • Genetic Engineering
  • Genetic Therapy / methods*
  • Genetic Vectors / administration & dosage
  • Glucagon-Like Peptide 1 / analysis
  • Glucagon-Like Peptide 1 / genetics
  • Glucagon-Like Peptide 1 / metabolism*
  • Glucose Tolerance Test
  • Glycated Hemoglobin A / analysis
  • Insulin / analysis
  • Insulin / blood
  • Insulin-Secreting Cells / chemistry
  • Insulin-Secreting Cells / metabolism*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Obese
  • Plasmids / administration & dosage
  • Rats
  • Rats, Zucker
  • Transduction, Genetic / methods
  • Transfection / methods

Substances

  • Glycated Hemoglobin A
  • Insulin
  • Glucagon-Like Peptide 1