Preincubation of rat soleus muscle with 1 and 10 μM monensin for 2h increased the subsequent basal 2-deoxyglucose uptake by muscle 76 and 121% respectively. Under the same conditions, monensin decreased the insulin- stimulated (1 mU/ml) 2-deoxyglucose uptake by 29 and 37% respectively. The monensin-induced augmentation of basal 2-deoxyglucose uptake was inhibited 92% by cytochalasin B suggesting that the uptake in mediated by glucose transporters. Monensin did not increase the cellular accumulation L-glucose in muscle indicating that it does not affect the cell membrane integrity. Neither the stimulatory effect of monensin on basal 2-deoxyglucose uptake nor the opposite, inhibitory action of monensin on the insulin-stimulated 2- deoxyglucose uptake were influenced by the removal of Ca21 from the medium or be dantrolene, an inhibitor of Ca21 release from the sarcoplasmic reticulum, suggesting that the actions of monensin are not mediated by calcium. Monensin had no effect on muscle ATP concentration. The monensin- induced augmentation of basal 2-deoxyglucose uptake was neither associated with stimulation of muscle phosphatidylinositol 3-kinase activity nor inhibited by wortmannin, demonstrating that the increase in basal 2- deoxyglucose uptake is not mediated by activation of phosphatidylinositol 3- kinase. The inhibition of insulin-stimulated 2-deoxyglucose uptake by monensin was associated with a 31% decrease in the abundance of insulin receptors in muscles, a 64% decrease in the insulin-induced autophosphorylation of the insulin receptor β-subunit, and a 44% reduction of the insulin-stimulated phosphatidylinositol 3-kinase activity. Addition of monensin into the phosphatidylinositol 3-kinase reaction had no effect on the activity of the enzyme, demonstrating that the inhibition in monensin- treated muscles is indirect and occurs upstream of phosphatidylinositol 3- kinase. It is concluded that monensin has a dual effect on 2-deoxyglucose uptake by skeletal muscle: it stimulates basal uptake but inhibits the insulin-stimulated uptake. The primary cause of the latter, inhibitory effect of monensin is at the level of the insulin receptor.
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism