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, 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.
Kim
Hyo-Eun
HE
Institute for Medical Science, Ajou University School of Medicine, 442-749 Suwon, Republic of Korea.
Choi
Sung-E
SE
Lee
Soo-Jin
SJ
Lee
Ji-Hyun
JH
Lee
Youn-Jung
YJ
Kang
Sang Sun
SS
Chun
Jaesun
J
Kang
Yup
Y
D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D005941:Glucokinase / Q000235:genetics; D005947:Glucose / Q000494:pharmacology*; D051273:Glucose Transporter Type 2 / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D015151:Immunoblotting; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007340:Insulinoma; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D048748:MAP Kinase Kinase Kinase 3 / Q000235:genetics / Q000502:physiology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics; D011863:Radioimmunoassay; D051381:Rats; D011955:Receptors, Drug / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D064233:Sulfonylurea Receptors; D015534:Trans-Activators / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000099161:Kcnj11 Channel
D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate; D002118:Calcium; D015220:Calcium Channels; D005941:Glucokinase; D005947:Glucose; D051273:Glucose Transporter Type 2; D018398:Homeodomain Proteins; D007328:Insulin; D048031:JNK Mitogen-Activated Protein Kinases; D048748:MAP Kinase Kinase Kinase 3; D016328:NF-kappa B; D052247:Nitric Oxide Synthase Type II; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000099161:Kcnj11 Channel; C495683:Slc2a2 protein, rat; C084010:pancreatic and duodenal homeobox 1 protein