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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.

Kim, HE; Choi, SE; Lee, SJ; Lee, JH; Lee, YJ; Kang, SS; Chun, J; Kang, Y
The Journal of endocrinology, 198(3):549-560, 2008
Journal Title
The Journal of endocrinology
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, Ca(2)(+) 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 Ca(2)(+). The TNF-alpha treatment was thought to activate c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and NF-kappaB inflammatory signals, since TNF-alpha increased phospho-JNK and phospho-p38 and reduced I kappaB levels. Inhibitors of these signaling pathways prevented the TNF-alpha-induced reduction of the Ca(2)(+) influx and GSIS. Overexpression of MEKK3, a possible mediator from the TNF-alpha receptor to the JNK/p38 and NK-kappaB signaling cascade, increased the levels of phospho-JNK, phospho-p38, and NF-kappaB, and reduced the glucose-stimulated Ca(2)(+) influx and GSIS. The reduction of the Ca(2)(+) influx and GSIS in MEKK3-overexpressing INS-1 cells was also prevented by inhibitors of JNK, p38, and NF-kappaB. These data demonstrate that TNF-alpha inhibits GSIS by reducing the glucose-stimulated Ca(2)(+) influx, possibly through the activation of JNK and p38 MAPK and NF-kappaB 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.
MeSH terms
ATP-Binding Cassette Transporters/geneticsAdenosine Triphosphate/metabolismAnimalsBiological Transport/drug effects*Calcium/metabolism*Calcium Channels/geneticsCell Line, TumorCell Survival/drug effectsGene Expression/drug effectsGlucokinase/geneticsGlucose/pharmacology*Glucose Transporter Type 2/geneticsHomeodomain Proteins/geneticsImmunoblottingInsulin/metabolismInsulin/secretion*InsulinomaJNK Mitogen-Activated Protein Kinases/antagonists & inhibitorsJNK Mitogen-Activated Protein Kinases/metabolismMAP Kinase Kinase Kinase 3/geneticsMAP Kinase Kinase Kinase 3/physiologyNF-kappa B/antagonists & inhibitorsNF-kappa B/metabolismNitric Oxide Synthase Type II/geneticsPotassium Channels, Inwardly Rectifying/geneticsRadioimmunoassayRatsReceptors, Drug/geneticsReverse Transcriptase Polymerase Chain ReactionTrans-Activators/geneticsTumor Necrosis Factor-alpha/pharmacology*p38 Mitogen-Activated Protein Kinases/antagonists & inhibitorsp38 Mitogen-Activated Protein Kinases/metabolism
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Journal Papers > Research Organization > Chronic Inflammatory Disease Research Center
Journal Papers > School of Medicine / Graduate School of Medicine > Physiology
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