THE EXPRESSION OF TNF-ALPHA BY HUMAN MUSCLE - RELATIONSHIP TO INSULIN-RESISTANCE

TNF alpha is overexpressed in the adipose tissue of obese rodents and humans, and is associated with insulin resistance. To more closely lin k TNF expression with whole body insulin action, we examined the expre ssion of TNF by muscle, which is responsible for the majority of gluco se uptake in vivo. Using RT-PCR, TNF was detected in human heart, in s keletal muscle from humans and Fats, and in cultured human myocytes. U sing competitive RT-PCR, TNF was quantitated in the muscle biopsy spec imens from 15 subjects whose insulin sensitivity had been characterize d using the glucose clamp technique. TNF expression in the insulin res istant subjects and the diabetic patients was fourfold higher than in the insulin sensitive subjects, and there was a significant inverse li near relationship between maximal glucose disposal rate and muscle TNF (r = -0.60, P < 0.02). In nine subjects, muscle cells from vastus lat eralis muscle biopsies were placed into tissue culture for 4 wk, and i nduced to differentiate into myotubes. TNF was secreted into the mediu m from these cells, and cells from diabetic patients expressed threefo ld more TNF than cells from nondiabetic subjects. Thus, TNF is express ed in human muscle, and is expressed at a higher level in the muscle t issue and in the cultured muscle cells from insulin resistant and diab etic subjects. These data suggest another mechanism by which TNF may p lay an important role in human insulin resistance.