Glucose- and metabolically regulated hepatic insulin gene therapy for diabetes
Journal
Pharmaceutical Research
Journal Volume
25
Journal Issue
6
Pages
1460-1468
Date Issued
2008
Author(s)
Hsu P.Y.-J.
Kotin R.M.
YA-WUN YANG
Abstract
Purpose. The purpose of this study was to examine glucose- and metabolically modulation of insulin secretion by rAAV-mediated gene delivery in vitro and in vivo. Materials and methods. A recombinant adeno-associated virus vector (rAAV) containing a furin-mutated human insulin gene, driven by the rat insulin I promoter, was used in this study. Glucose-responsive secretion of human insulin was determined by treating rAAV-transduced Huh7 human hepatoma cells with varying concentrations of glucose, with or without insulin secretagogues. Glucose- and metabolically modulated secretion of human insulin in the streptozotocin (STZ)-induced diabetic mice was assessed by intrahepatic administration of rAAV-polyethylenimine (PEI) complexes, followed by intraperitoneal glucose tolerance test (IPGTT), with or without theophylline. Results. Glucose- and metabolically controlled human insulin secretion was obtained in the rAAV-transduced Huh7 cells. Treatment of STZ-induced diabetic animals with rAAV-polyethylenimine (rAAV-PEI) complexes resulted in production of human insulin and amelioration of hyperglycemia. Co-administration of glucose and theophylline in these animals augmented the secretion of human insulin, demonstrating metabolic modulation of insulin secretion in vivo. Immunohistochemical examination of the liver sections of rAAV-treated mice confirmed the production of human insulin. Conclusions. Glucose- and metabolically controlled hepatic insulin gene therapy was obtained both in vitro and in vivo. ? 2008 Springer Science+Business Media, LLC.
Subjects
Diabetes mellitus; Insulin; Polyethylenimine; Recombinant adeno-associated virus; Regulated gene therapy
SDGs
Other Subjects
glucose; insulin; parvovirus vector; polyethyleneimine; streptozocin; theophylline; animal experiment; animal model; article; cell line; controlled study; diabetes mellitus; gene therapy; glucose metabolism; glucose tolerance test; hepatoma cell; human; human cell; hyperglycemia; immunohistochemistry; in vitro study; in vivo study; insulin metabolism; insulin release; liver; male; mouse; nonhuman; priority journal; promoter region; viral gene delivery system; Animals; Bucladesine; Dependovirus; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Forskolin; Gene Therapy; Glucose; Imines; Immunohistochemistry; Insulin; Liver; Male; Mice; Mice, Inbred C57BL; Polyethylenes; Streptozocin; Theophylline
Type
journal article