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J Biol Chem, Vol. 274, Issue 45, 31833-31838, November 5, 1999
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From the Zucker diabetic fatty rats develop
type 2 diabetes concomitantly with peripheral insulin resistance.
Hepatocytes from these rats and their control lean counterparts have
been cultured, and a number of key parameters of glucose metabolism
have been determined. Glucokinase activity was 4.5-fold lower in
hepatocytes from diabetic rats than in hepatocytes from healthy ones.
In contrast, hexokinase activity was about 2-fold higher in hepatocytes
from diabetic animals than in healthy ones. Glucose-6-phosphatase
activity was not significantly different. Despite the altered ratios of
glucokinase to hexokinase activity, intracellular glucose 6-phosphate
concentrations were similar in the two types of cells when they where
incubated with 1-25 mM glucose. However, glycogen
levels and glycogen synthase activity ratio were lower in hepatocytes
from diabetic animals. Total pyruvate kinase activity and its activity
ratio as well as fructose 2,6-bisphosphate concentration and lactate
production were also lower in cells from diabetic animals. All of these
data indicate that glucose metabolism is clearly impaired in
hepatocytes from Zucker diabetic fatty rats.
Glucokinase overexpression using adenovirus restored glucose metabolism
in diabetic hepatocytes. In glucokinase-overexpressing cells, glucose
6-phosphate levels increased. Moreover, glycogen deposition was greatly
enhanced due to the activation of glycogen synthase. Pyruvate kinase
was also activated, and fructose-2,6-bisphosphate concentration and
lactate production were increased in glucokinase-overexpressing diabetic hepatocytes. Overexpression of hexokinase I did not increase glycogen deposition. In conclusion, hepatocytes from Zucker diabetic fatty rats showed depressed glycogen and glycolytic metabolism, but
glucokinase overexpression improved their glucose utilization and storage.
Department of Biochemistry and Molecular
Biology, University of Barcelona, E-08028 Barcelona, Spain and the
Gifford Laboratories for Diabetes Research, Departments of
Biochemistry and Internal Medicine, University of Texas
Southwestern Medical Center, Dallas, Texas 75235
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