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Institute for Medical Science, Ajou University School of Medicine, 442-749 Suwon, Republic of Korea¹ Division of Science Education, Chungbuk National University, 361-763 Chongju, Republic of Korea² Korea National University of Education, 363-791 Chungbuk, Republic of Korea

(Correspondence should be addressed to Y Kang; Email: kangy{at}ajou.ac.kr)

^* (H-E Kim and S-E Choi contributed equally to this work)

The present study was undertaken to determine how tumour necrosis factor- (TNF-) elicits the inhibition of glucose-stimulated insulin secretion (GSIS) in rat insulinoma cells (INS)-1 β-cells. TNF- 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- reduced the glucose-stimulated influx of Ca²⁺. The TNF- treatment was thought to activate c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and NF-B inflammatory signals, since TNF- increased phospho-JNK and phospho-p38 and reduced IB levels. Inhibitors of these signaling pathways prevented the TNF--induced reduction of the Ca²⁺ influx and GSIS. Overexpression of MEKK3, a possible mediator from the TNF- receptor to the JNK/p38 and NK-B signaling cascade, increased the levels of phospho-JNK, phospho-p38, and NF-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-B. These data demonstrate that TNF- inhibits GSIS by reducing the glucose-stimulated Ca²⁺ influx, possibly through the activation of JNK and p38 MAPK and NF-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.

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