Effects of overexpressed, constitutively-active glycogen synthase on whole body glucose tolerance and insulin-stimulated glucose metabolism

Using the GSL3 transgenic mouse model, we have provided evidence that muscle glycogen concentration, per se, does not affect post-exercise insulin action in vivo or in muscle using an in situ preparation. Transgenic gastrocnemius muscle had significantly greater (7-fold) muscle glycogen concentration compared to wildtype. Glycogen concentration was unchanged 24 h following exhaustive exercise. In vivo insulin action during an intraperitoneal glucose tolerance test was improved 24 h following exercise regardless of the muscle glycogen concentration. Resting insulin-stimulated muscle glucose uptake was 30% lower in non-exercised transgenic versus wildtype muscle. Insulinstimulated muscle glucose uptake was improved 24 h following exercise in transgenic (84%) only. PI3-kinase and PKB/Akt activation was similar in nonand post-exercise wildtype and transgenic muscle. However, insulin-stimulated muscle glucose uptake and PKB/Akt activation were reduced in wildtype muscle with elevated muscle glycogen levels. Thirty minutes of contraction via in situ electrical stimulation of the sciatic nerve significantly reduced gastrocnemius muscle glycogen concentration in wildtype (49%) and transgenic (27%) mice although transgenic mice retained significantly more glycogen than wildtype mice. Muscle of transgenic and wildtype mice demonstrated similar pre- and postcontraction insulin-stimulated glucose uptakes. However, the percentage of [14C] glucose incorporated into glycogen was greater in non-contracted (151%) and contracted transgenic muscle (157%) versus muscle of wildtype mice. PKB/Akt Ser473 phosphorylation was greater in transgenic mice as compared to wildtype mice post-contraction. Taken together, these results demonstrate that glycogen concentration appears to influence post-exercise muscle insulin signaling and insulin-stimulated glucose uptake in wildtype muscle when elevated above normal. However, the insulin signaling results indicate that the normal inverse relationship between muscle glycogen concentration and insulin-stimulated glucose uptake is absent in GSL3 transgenic muscle. Therefore, there may be additional mechanisms influencing the rate of insulin-stimulated muscle glucose uptake.