Tumour necrosis factor-alpha-induced glucose-stimulated insulin secretion inhibition in INS-1 cells is ascribed to a reduction of the glucose-stimulated Ca2+ influx.

The present study was undertaken to determine how tumour-necrosis factor-alpha (TNF-alpha) elicits the inhibition of glucose-stimulated insulin secretion (GSIS) in rat insulinoma cells (INS)-1 beta-cells. TNF-alpha pretreatment did not change the expression levels of insulin, PDX-1, glucose transporter 2, glucokinase, K-ATP channels, Ca2+ channels, and exocytotic molecules and, furthermore, did not reduce the glucose-stimulated ATP level. On the other hand, TNF-alpha reduced the glucose-stimulated influx of Ca2+. The TNF-alpha treatment was thought to activate c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and NF-kappa B inflammatory signals, since TNF-alpha increased phospho-JNK and phospho-p38 and reduced I kappa B levels. Inhibitors of these signaling pathways prevented the TNF-alpha-induced reduction of the Ca2+ influx and GSIS. Overexpression of MEKK3, a possible mediator from the TNF-alpha receptor to the JNK/p38 and NK-kappa B signaling cascade, increased the levels of phospho-JNK, phospho-p38, and NF-kappa B, and reduced the glucose-stimulated Ca2+ influx and GSIS. The reduction of the Ca2+ influx and GSIS in MEKK3-overexpressing INS-1 cells was also prevented by inhibitors of JNK, p38, and NF-kappa B. These data demonstrate that TNF-alpha inhibits GSIS by reducing the glucose-stimulated Ca2+ influx, possibly through the activation of JNK and p38 MAPK and NF-kappa B inflammatory signals. Thus, our findings suggest that the activation of stress and inflammatory signals can contribute to the inhibition of GSIS in the development of diabetes.