HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (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 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.

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.