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Reported discrepancies in the effects of tumor necrosis factor (TNF)-alpha in modulating insulin sensitivity of cultured cells may relate both to cell types studied and to the time course of exposure to the cytokine. Additionally, the relationship of effects on glucose metabolism to changes in the insulin signaling pathway cannot be assumed. For in vitro study, the cell type most relevant to insulin resistance in humans is the cultured human muscle cell. In the present study, TNF brought about no change in the rate of glycogen synthesis in cultured human muscle cells unless present during differentiation. The presence of TNF (5 ng/ml) during the process of differentiation of myoblasts into mature myotubes diminished the response of glycogen synthesis to acute insulin stimulation. This finding was associated with an impairment of differentiation-dependent increases in total cellular glycogen synthase (GS) activity. Under the same conditions of TNF exposure, there was no effect on the response to acute insulin stimulation of the fractional activity of GS. Similarly, there was no effect on the insulin stimulation of protein kinase B (PKB) and inhibition of glycogen synthase kinase 3 (GSK-3). Acute insulin stimulation brought about a 4.08 +/- 0.44-fold stimulation of activity of PKB in the absence of TNF, with 4.81 +/- 0.70-fold stimulation in cells exposed to TNF. GSK-3 activity decreased to 74.0 +/- 5.8% of basal after insulin stimulation without TNF and 78.3 +/- 5.0% after TNF exposure. However, differentiation of myocytes, as defined by an increase in the acetylcholine receptor, myogenin, and mature creatine kinase isoform expression, was impaired in TNF-treated cells. These studies demonstrate that TNF, if present during differentiation, decreases insulin-stimulated rates of storage of glucose as glycogen and total GS activity but does not downregulate the insulin-signaling system to GS. More generally, TNF also inhibits differentiation of human muscle cells in culture. [ABSTRACT FROM AUTHOR]