Long-term overexpression of glucokinase in the liver of transgenic mice leads to insulin resistance.
OBJECTIVE
Glucokinase overexpression in the liver increases glucose uptake and utilization, and improves glucose tolerance in young transgenic mice. Here, we examined the long-term effects of hepatic overexpression of glucokinase on glucose homeostasis. Moreover, we determined whether glucokinase overexpression counteracted high-fat diet-induced insulin resistance.


METHODS
Transgenic mice overexpressing glucokinase in liver under the control of the phosphoenolpyruvate carboxykinase promoter, fed either a standard diet or a high-fat diet, were studied. We used non-transgenic littermates as controls.


RESULTS
Transgenic mice over 6 months old developed impaired glucose tolerance. In addition, at 12 months of age, transgenic mice showed mild hyperglycaemia, hyperinsulinaemia and hypertriglyceridaemia. In spite of increased glucokinase activity, the liver of these mice accumulated less glycogen and increased triglyceride deposition. When 2-month-old glucose-tolerant mice were fed a high-fat diet, transgenic mice gained more body weight and became hyperglycaemic and hyperinsulinaemic. This was concomitant to glucose intolerance, liver steatosis and whole-body insulin resistance.


CONCLUSIONS
Long-term overexpression of glucokinase increases hepatic lipogenesis and circulating lipids, which lead to insulin resistance. Our results also suggest that the liver plays a key role in the onset of diabetes.
Ferre
T
T
Department of Biochemistry and Molecular Biology, School of Veterinary Medicine and Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, 08193, Bellaterra, Spain.
Riu
E
E
Franckhauser
S
S
Agudo
J
J
Bosch
F
F
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D004041:Dietary Fats; D004435:Eating; D005215:Fasting; D005941:Glucokinase / Q000235:genetics* / Q000378:metabolism*; D005951:Glucose Tolerance Test; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics*; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D051379:Mice; D008822:Mice, Transgenic; D014280:Triglycerides / Q000097:blood; D015430:Weight Gain
D001786:Blood Glucose; D004041:Dietary Fats; D007328:Insulin; D014280:Triglycerides; D005941:Glucokinase