Phenotypic correction of diabetic mice by adenovirus-mediated glucokinase expression.
Hyperglycemia of diabetes is caused in part by perturbation of hepatic glucose metabolism. Hepatic glucokinase (GK) is an important regulator of glucose storage and disposal in the liver. GK levels are lowered in patients with maturity-onset diabetes of the young and in some diabetic animal models. Here, we explored the adenoviral vector-mediated overexpression of GK in a diet-induced murine model of type 2 diabetes as a treatment for diabetes. Diabetic mice were treated by intravenous administration with an E1/E2a/E3-deleted adenoviral vector encoding human hepatic GK (Av3hGK). Two weeks posttreatment, the Av3hGK-treated diabetic mice displayed normalized fasting blood glucose levels (95 +/- 4.8 mg/dl; P < 0.001) when compared with Av3Null (135 +/- 5.9 mg/dl), an analogous vector lacking a transgene, and vehicle-treated diabetic mice (134 +/- 8 mg/dl). GK treatment also resulted in lowered insulin levels (632 +/- 399 pg/ml; P < 0.01) compared with the control groups (Av3Null, 1,803 +/- 291 pg/ml; vehicle, 1,861 +/- 392 pg/ml), and the glucose tolerance of the Av3hGK-treated diabetic mice was normalized. No significant increase in plasma or hepatic triglycerides, or plasma free fatty acids was observed in the Av3hGK-treated mice. These data suggest that overexpression of GK may have a therapeutic potential for the treatment of type 2 diabetes.
Desai
U J
UJ
Genetic Therapy, Inc., Gaithersburg, Maryland. Novartis Institute for Biomedical Research, Summit, New Jersey, USA.
Slosberg
E D
ED
Boettcher
B R
BR
Caplan
S L
SL
Fanelli
B
B
Stephan
Z
Z
Gunther
V J
VJ
Kaleko
M
M
Connelly
S
S
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003920:Diabetes Mellitus / Q000235:genetics* / Q000503:physiopathology; D004435:Eating; D005215:Fasting / Q000097:blood; D015870:Gene Expression / Q000502:physiology*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D005941:Glucokinase / Q000235:genetics* / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000097:blood; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D014280:Triglycerides / Q000378:metabolism
D001786:Blood Glucose; D007328:Insulin; D014280:Triglycerides; D006003:Glycogen; D005941:Glucokinase