INSULIN STIMULATION OF GLYCOGEN-SYNTHESIS AND GLYCOGEN-SYNTHASE ACTIVITY IS BLOCKED BY WORTMANNIN AND RAPAMYCIN IN 3T3-L1 ADIPOCYTES - EVIDENCE FOR THE INVOLVEMENT OF PHOSPHOINOSITIDE 3-KINASE AND P70 RIBOSOMAL PROTEIN-S6 KINASE

We have investigated the involvement of phosphoinositide (PI) 3-kinase and p70 ribosomal protein-S6 kinase (p70(s6k)) in mediating insulin stimulation of glycogen synthesis in 3T3-L1 adipocytes using specific inhibitors. Wortmannin inhibited PI 3-kinase activity (IC50 approximate to 16 nM), inhibition being complete at 100 nm. Wortmannin (100 nM) completely blocked the ability of insulin to activate glycogen synthase in 3T3-L1 adipocytes and the ability of insulin to stimulate glucose incorporation into glycogen in 3T3-L1 fibroblasts. Rapamycin, which blocks insulin-stimulated activation of p70(s6k), decreased insulin activation of glycogen synthase in a dose-dependent manner (IC50 similar to 0.8 ng/ml), with a maximum approx. 75% inhibition of insulin's stimulatory effect. Rapamycin inhibited insulin-stimulated glucose incorporation into glycogen to a similar extent and with similar dose-dependency, while having no effect on insulin-stimulated glucose transport. We conclude that PI 3-kinase and p70(s6k) are involved in the signalling pathways by which insulin stimulates glycogen synthase in 3T3-L1 adipocytes.