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This Article Accepted manuscript (PDF) All Versions of this Article: JOE-08-0131v1 198/3/549    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kim, H.-E. Articles by Kang, Y. Search for Related Content PubMed PubMed Citation Articles by Kim, H.-E. Articles by Kang, Y.

H Kim, Institute for Medical Science, Ajou University School of Medicine, Suwon, Korea, Republic of
S Choi, Institute for Medical Science, Ajou University School of Medicine, Suwon, Korea, Republic of
S Lee, Institute for Medical Science, Ajou University School of Medicine, Suwon, Korea, Republic of
J Lee, Institute for Medical Science, Ajou University School of Medicine, Suwon, Korea, Republic of
Y Lee, Institute for Medical Science, Ajou University School of Medicine, Suwon, Korea, Republic of
S Kang, Division of Science Education, Chungbuk National University, Chongju, Korea, Republic of
J Chun, Korea National University of Education, Korea National University of Education, Chungwon, Korea, Republic of
Y Kang, Institute for Medical Science, Ajou University School of Medicine, Suwon, 442-749, Korea, Republic of

Correspondence: Yup Kang, Email: kangy{at}ajou.ac.kr

Abstract

The present study was undertaken to determine how TNF- elicits glucose-stimulated insulin secretion (GSIS) inhibition in INS-1 β cells. TNF- pretreatment did not change the expression levels of insulin, PDX-1, glucose transporter 2, glucokinase, KATP 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 Ca2+ influx. TNF-a treatment was thought to activate c-Jun N-terminal kinase (JNK) stress, p38 stress, and NFkB inflammatory signals, since TNF-a increased phospho-JNK and phosphor-p38 and reduced IkB level. In particular, inhibitor of these stress/inflammatory signals prevented the TNF--induced reduction of the Ca2+ influx and inhibition of GSIS. Overexpression of MEKK3, a possible mediator from the TNF- receptor to stress/inflammatory signals, increased the level of phospho-JNK, phosphor-p38, and NFkB, and reduced the glucose-stimulated Ca2+ influx and GSIS. The reduction of the Ca2+ influx and insulin secretion was restored by treatment of stress/inflammatory signal inhibitors. These data demonstrate that TNF-a inhibits GSIS by reducing the glucose-stimulated Ca2+ influx, possibly through activation of stress/inflammatory signals. Thus, our findings suggest that the activation of stress/inflammatory signals can be a contributor for the inhibition of GSIS in the development of diabetes.

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