Adiponectin gene therapy of streptozotocin-induced diabetic mice using hydrodynamic injection.
BACKGROUND
Adiponectin (Adipo), an adipocyte hormone involved in the regulation of glucose and lipid metabolism, has already been identified as a potential therapeutic target for the treatment of diabetes. However, successful delivery of Adipo to the receptors is difficult due to their peptide characteristics. Receptors for Adipo are abundantly expressed in the liver and skeletal muscle.


METHODS
Uptake of 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose (2-NBDG) in hepatoblastoma HepG2 cells expressing Adipo was examined. Adipo-expressing plasmid DNA (10-50 microg) in saline solution (0.1 ml/g body weight) was rapidly injected into the tail vein of 4-week-old diabetic mice after 4-6 weeks of treatment with streptozotocin (STZ). Uptake of glucose in diabetic mice also was measured using a planar positron imaging system featuring 18-fluorodeoxyglucose.


RESULTS
HepG2 cells expressing Adipo exhibited significantly increased 2-NBDG uptake compared with cells transfected with control plasmid even in the absence of insulin. STZ-induced diabetic mice showed decreased serum Adipo levels compared with non-diabetic mice. A single hydrodynamic injection of 10-50 microg Adipo-expressing plasmid DNA into diabetic mice led to approximately 10-15-fold elevation in serum Adipo levels, and resulted in decreased serum levels of glucose and triglyceride. As well as exhibiting higher levels of Adipo expression, diabetic mice also had higher hepatic glucose uptake than similar mice injected with control plasmid.


CONCLUSIONS
We report that STZ-induced diabetic mice exhibited decreased Adipo levels and hyperglycemia which may be alleviated by hydrodynamic injection of the Adipo gene. This type of gene delivery system to the liver offers a different approach in developing novel treatments for type 1 and 2 diabetes.
Fukushima
Masayoshi
M
Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan.
Hattori
Yoshiyuki
Y
Tsukada
Hideo
H
Koga
Kimiko
K
Kajiwara
Eiichi
E
Kawano
Kumi
K
Kobayashi
Tsuneo
T
Kamata
Katsuo
K
Maitani
Yoshie
Y
D009327:4-Chloro-7-nitrobenzofurazan / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D052242:Adiponectin / Q000008:administration & dosage* / Q000235:genetics / Q000493:pharmacokinetics; D000818:Animals; D045744:Cell Line, Tumor; D003847:Deoxyglucose / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D003921:Diabetes Mellitus, Experimental / Q000628:therapy*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism / Q000637:transplantation*; D006801:Humans; D007267:Injections / Q000379:methods; D008099:Liver / Q000378:metabolism; D051379:Mice; D013311:Streptozocin
D052242:Adiponectin; D013311:Streptozocin; D003847:Deoxyglucose; D009327:4-Chloro-7-nitrobenzofurazan; C098340:2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose