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.

Abstract

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.

• Authors: Hyo-Eun Kim, Sung-E Choi, Soo-Jin Lee, Ji-Hyun Lee, Youn-Jung Lee, Sang Sun Kang, Jaesun Chun, Yup Kang
• Journal: The Journal of endocrinology (J Endocrinol) Vol. 198 Issue 3 Pg. 549-60 (Sep 2008) ISSN: 1479-6805 [Electronic] England
• PMID: 18593820 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP-Binding Cassette Transporters
• Calcium Channels
• Glucose Transporter Type 2
• Homeodomain Proteins
• Insulin
• Kir6.2 channel
• NF-kappa B
• Potassium Channels, Inwardly Rectifying
• Receptors, Drug
• Slc2a2 protein, rat
• Sulfonylurea Receptors
• Trans-Activators
• Tumor Necrosis Factor-alpha
• pancreatic and duodenal homeobox 1 protein
• Adenosine Triphosphate
• Nitric Oxide Synthase Type II
• Glucokinase
• JNK Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases
• MAP Kinase Kinase Kinase 3
• Glucose
• Calcium

Topics

• ATP-Binding Cassette Transporters (genetics)
• Adenosine Triphosphate (metabolism)
• Animals
• Biological Transport (drug effects)
• Calcium (metabolism)
• Calcium Channels (genetics)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Gene Expression (drug effects)
• Glucokinase (genetics)
• Glucose (pharmacology)
• Glucose Transporter Type 2 (genetics)
• Homeodomain Proteins (genetics)
• Immunoblotting
• Insulin (metabolism)
• Insulin Secretion
• Insulinoma
• JNK Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)
• MAP Kinase Kinase Kinase 3 (genetics, physiology)
• NF-kappa B (antagonists & inhibitors, metabolism)
• Nitric Oxide Synthase Type II (genetics)
• Potassium Channels, Inwardly Rectifying (genetics)
• Radioimmunoassay
• Rats
• Receptors, Drug (genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Sulfonylurea Receptors
• Trans-Activators (genetics)
• Tumor Necrosis Factor-alpha (pharmacology)
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)