Treatment of type 2 diabetes by adenoviral-mediated overexpression of the glucokinase regulatory protein.
The enzyme glucokinase (GK) plays a central role in glucose homeostasis. Hepatic GK activity is acutely controlled by the action of the GK regulatory protein (GKRP). In vitro evidence suggests that GKRP reversibly binds to GK and inhibits its activity; however, less is known about the in vivo function of GKRP. To further explore the physiological role of GKRP in vivo, we used an E1/E2a/E3-deficient adenoviral vector containing the cDNA encoding human GKRP (Av3hGKRP). High fat diet-induced diabetic mice were administered Av3hGKRP or a control vector lacking a transgene (Av3Null). Surprisingly, the Av3hGKRP-treated mice showed a significant improvement in glucose tolerance and had lower fasting blood glucose levels than Av3Null-treated mice. A coincident decrease in insulin levels indicated that the Av3hGKRP-treated mice had sharply improved insulin sensitivity. These mice also exhibited lower leptin levels, reduced body weight, and decreased liver GK activity. In vitro experiments indicated that GKRP was able to increase both GK protein and enzymatic activity levels, suggesting that another role for GKRP is to stabilize and/or protect GK. These data are the first to indicate the ability of GKRP to treat type 2 diabetes and therefore have significant implications for future therapies of this disease.
Slosberg
E D
ED
Novartis Institute for Biomedical Research, Metabolic and Cardiovascular Diseases, Summit, New Jersey 07901, USA. eric.slosberg@pharma.novartis.com
Desai
U J
UJ
Fanelli
B
B
St  Denny
I
I
Connelly
S
S
Kaleko
M
M
Boettcher
B R
BR
Caplan
S L
SL
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001358:Avian Sarcoma Viruses / Q000235:genetics; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D002352:Carrier Proteins; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000628:therapy*; D004041:Dietary Fats / Q000009:adverse effects; D005215:Fasting; D015316:Genetic Therapy; D005822:Genetic Vectors; D005941:Glucokinase / Q000037:antagonists & inhibitors; D018149:Glucose Intolerance / Q000209:etiology / Q000628:therapy; D005951:Glucose Tolerance Test; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000502:physiology; D008112:Liver Glycogen / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size; D011506:Proteins / Q000235:genetics* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013539:Simian virus 40 / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; D001786:Blood Glucose; D002352:Carrier Proteins; D004041:Dietary Fats; C485100:GCKR protein, human; C499483:Gckr protein, mouse; C499484:Gckr protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008112:Liver Glycogen; D011506:Proteins; C080906:glucokinase regulatory protein; D005941:Glucokinase