Ectopic expression of glucagon-like peptide 1 for gene therapy of type II diabetes.
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.
Parsons
G B
GB
Department of Molecular Biology, Genzyme Corporation, Framingham, MA 01701, USA. geoffrey.parsons@genzyme.com
Souza
D W
DW
Wu
H
H
Yu
D
D
Wadsworth
S G
SG
Gregory
R J
RJ
Armentano
D
D
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000628:therapy*; D005260:Female; D015870:Gene Expression; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D052216:Glucagon-Like Peptide 1 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006442:Glycated Hemoglobin / Q000032:analysis; D007328:Insulin / Q000032:analysis / Q000097:blood; D050417:Insulin-Secreting Cells / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008820:Mice, Obese; D010957:Plasmids / Q000008:administration & dosage; D051381:Rats; D011924:Rats, Zucker; D014161:Transduction, Genetic / Q000379:methods; D014162:Transfection / Q000379:methods
D052216:Glucagon-Like Peptide 1; D006442:Glycated Hemoglobin; D007328:Insulin