SHORT-TERM EXPOSURE TO HUMOR NECROSIS FACTOR-ALPHA DOES NOT AFFECT INSULIN-STIMULATED GLUCOSE-UPTAKE IN SKELETAL-MUSCLE

It has been hypothesized that increased production of tumor necrosis f actor-alpha (TNF-alpha) plays a role in causing the insulin resistance associated with obesity. Obesity with insulin resistance is associate d with increased production of TNF-alpha by fat cells. Exposure of 3T3 -L1 adipocytes to TNF-alpha for 3-4 days makes them insulin resistant. TNF-alpha has also been reported to rapidly (15-60 min) cause insulin resistance, with a decrease in insulin-stimulated tyrosine phosphoryl ation, in a number of cultured cell lines. Because skeletal muscle is the major tissue responsible for insulin-stimulated glucose disposal, we performed the present study to determine if acute exposure to TNF-a lpha causes insulin resistance in muscle, We found that exposure of so leus muscles to 6 nmol/l TNF-alpha for 45 min in vitro had no inhibito ry effect on insulin-stimulated tyrosine phosphorylation of the insuli n receptor or insulin receptor substrate 1 (IRS-1) or on phosphatidyli nositol 3-kinase association with IRS-1, Incubation of epitrochlearis and soleus muscles with 6 nmol/l TNF-alpha for 45 min or 4 h had no ef fect on insulin-stimulated 2-deoxyglucose (2-DG) uptake. Treatment of epitrochlearis muscles with 2 nmol/l TNF-alpha for 8 h also had no eff ect on insulin-stimulated 2-DG uptake, We conclude that in contrast to Fao hepatoma cells and 3T3-L1 fibroblasts, skeletal muscle does not b ecome insulin resistant in response to short-term exposure to TNF-alph a.