OVEREXPRESSION OF HEXOKINASE-II IN TRANSGENIC MICE - EVIDENCE THAT INCREASED PHOSPHORYLATION AUGMENTS MUSCLE GLUCOSE-UPTAKE

Hexokinase II (HKII) is the predominant isozyme expressed in periphera l insulin-responsive tissues, To explore the role of HKII in muscle gl ucose metabolism, two lines of transgenic mice were generated where ov erexpression was restricted to striated muscle; HKII protein levels an d activity were increased by 3-8-fold, Oral glucose tolerance, intrave nous insulin tolerance, and insulin and lactate levels were unaffected in transgenic mice, There was a trend toward increased levels of musc le glycogen; however, glucose-6-phosphate levels were increased by 43% in transgenic skeletal muscle following in vivo glucose and insulin a dministration, Using 2-[H-3]deoxyglucose as a tracer, in. vitro basal and insulin-stimulated glucose uptake were determined in extensor digi torum longus, soleus, and epitrochlearis muscles. Maximal insulin-stim ulated glucose uptake was increased by 17% (extensor digitorum longus) , 34% (soleus), and 90% (epitrochlearis) in transgenic muscles; basal and submaximal glucose uptake was also modestly increased in soleus an d epitrochlearis. These data suggest that increased muscle HKII (corre sponding to the upper end of the physiologic range) may not be suffici ent to augment net in vivo glucose homeostasis, However, glucose phosp horylation can represent a rate-limiting step for skeletal muscle gluc ose utilization since muscle glucose-6-phosphate levels are increased during in vivo hyperinsulinemia and hyperglycemia; furthermore, basal and insulin-mediated muscle glucose uptake can be increased by a selec tive increase in HKII expression.