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Biochem Mol Med. 1996 Oct;59(1):80-6.

Abnormal regulation of hexokinase in insulin-resistant skeletal muscle.

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Department of Biochemistry, University of Oxford, United Kingdom.


The present study has assessed the potential involvement of hexokinase in the control of insulin-mediated glucose metabolism in insulin-sensitive and -resistant skeletal muscle. Soleus muscle strips from lean (insulin-sensitive) and obese (insulin-resistant) Zucker rats were incubated with 10 or 10,000 microU and then homogenized using a protocol to maintain the location of hexokinase in situ. Hexokinase is inhibited by glucose 6-phosphate, a metabolic intermediate which may have a central role in the regulation of glycogen synthesis. Two separate measurements of hexokinase activity were made on each muscle homogenate: the total hexokinase activity (glucose 6-phosphate was metabolized immediately by glucose 6-phosphate dehydrogenase) and the fractional hexokinase activity (glucose 6-phosphate accumulated so as to regulate the enzyme as in vivo). The total hexokinase activity was equal in insulin-sensitive and -resistant muscle and was unaffected by the extracellular insulin concentration. The fractional hexokinase activity was significantly increased by insulin (10,000 in all muscles (lean, 82%; obese, 52%; P < 0.05) although the stimulated fractional hexokinase activity was lower in the muscle from obese Zucker rats compared to lean (P < 0.05). These results provide evidence that insulin decreases the inhibition of hexokinase by glucose 6-phosphate in insulin-sensitive but not in insulin-resistant muscle. This study has revealed short-term regulation of hexokinase by insulin which is defective in insulin-resistant skeletal muscle. Thus, the study has identified hexokinase as a potential regulatory site of insulin action that is abnormal in insulin resistance. The altered regulation of hexokinase may be a major contributing factor to the reduced insulin-mediated glucose fluxes in insulin-resistant skeletal muscle.

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