Tumor necrosis factor alpha signaling pathway and apoptosis in pancreatic β cells

Ishizuka, Nobuko; Yagui, Kazuo; Tokuyama, Yoshiharu; Yamada, Kazuo; Suzuki, Yoshiyuki; Miyazaki, Jun‐ichi; Hashimoto, Naotake; Makino, Hideichi; Saitō, Yasushi; Kanatsuka, Azuma

doi:10.1016/s0026-0495(99)90234-2

Cited by 56 publications

(38 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…6) is consistent with our hypothesis. Ceramide has been implicated as a potential mediator of cytokine-induced beta cell death (35)(36)(37), although some reports have been controversial (19,38). However, the functional role of ceramide in beta cells has, to our knowledge, not been investigated, and our results represent the first demonstration of a role for ceramide as a mediator of palmitate inhibition of insulin gene expression (Fig.…”

Section: Discussionmentioning

confidence: 63%

Palmitate Inhibition of Insulin Gene Expression Is Mediated at the Transcriptional Level via Ceramide Synthesis

Kelpe

Moore

Parazzoli

et al. 2003

Journal of Biological Chemistry

218

171

View full text Add to dashboard Cite

Chronic exposure to elevated levels of fatty acids impairs pancreatic beta cell function, a phenomenon thought to contribute to the progressive deterioration of insulin secretion in type 2 diabetes. We have previously demonstrated that prolonged exposure of isolated islets to elevated levels of palmitate inhibits preproinsulin mRNA levels in the presence of high glucose concentrations. However, whether this occurs via transcriptional or post-transcriptional mechanisms has not been determined. In addition, the nature of the lipid metabolites involved in palmitate inhibition of insulin gene expression is unknown. In this study, we show that palmitate decreases glucose-stimulated preproinsulin mRNA levels in isolated rat islets, an effect that is not mediated by changes in preproinsulin mRNA stability, but is associated with inhibition of glucose-stimulated insulin promoter activity. Prolonged culture of isolated islets with palmitate is associated with increased levels of intracellular ceramide. Palmitate-induced ceramide generation is prevented by inhibitors of de novo ceramide synthesis. Further, exogenous ceramide inhibits insulin mRNA levels, whereas blockade of de novo ceramide synthesis prevents palmitate inhibition of insulin gene expression. We conclude that prolonged exposure to elevated levels of palmitate affects glucose-stimulated insulin gene expression via transcriptional mechanisms and ceramide synthesis.

show abstract

Section: Discussionmentioning

confidence: 63%

Palmitate Inhibition of Insulin Gene Expression Is Mediated at the Transcriptional Level via Ceramide Synthesis

Kelpe

Moore

Parazzoli

et al. 2003

Journal of Biological Chemistry

218

171

View full text Add to dashboard Cite

show abstract

“…31 The potential cytotoxic effects of TNFa on HIT-T15 cells has not been examined in our study. This possibility seems unlikely, however, given that the cytotoxic effects of TNFa on b-cells apparently require higher concentrations of TNFa, 35 or the simultaneous presence of other cytokines such as IFN-g andaor IL-1b, 36 ± 38 which was not the case in our system.…”

Section: Inhibition Of Insulin Transcription By Tnfa and Leptinmentioning

confidence: 79%

TNFα and leptin inhibit basal and glucose-stimulated insulin secretion and gene transcription in the HIT-T15 pancreatic cells

Tsiotra¹,

Tsigos²,

Raptis

2001

Int J Obes

View full text Add to dashboard Cite

BACKGROUND: Tumor necrosis factor a (TNFa), a cytokine produced at in¯ammatory sites and in adipose tissue, is known primarily for its detrimental effects on insulin action. There is evidence to suggest that TNFa may also in¯uence b-cell function. Leptin is another adipose tissue-derived hormone that might also act on b-cells. OBJECTIVE: We explored the independent and combined effects of TNFa and leptin upon basal and glucose-stimulated insulin transcription and secretion in the HIT-T15 pancreatic b cell line. METHODS: Cells were cultured for 40 h in the presence of near-normal basal (7 mM) or high (16.7 mM) glucose and treated with either TNFa (1, 10 and 50 ngaml) or leptin (10, 50 and 100 ngaml) or both together. Insulin concentrations were measured by radioimmunoassay. Insulin mRNA levels were evaluated by a semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) method, after normalization with b-actin mRNA. RESULTS: TNFa signi®cantly suppressed basal and glucose-stimulated insulin secretion and proinsulin mRNA transcription in a dose-dependent manner, an effect that was more powerful in the presence of high glucose. Leptin also inhibited dosedependent insulin mRNA and protein at both glucose concentrations, but did not appear to further potentiate the suppressive effects of TNFa. CONCLUSION: TNFa suppresses both basal and glucose-stimulated insulin transcription and secretion in HIT-T15 cells, an effect that is enhanced signi®cantly by high glucose. Leptin also independently inhibits basal and glucose-stimulated insulin secretion and transcription but does not modify TNFa effects. These effects might contribute to the abnormalities of glucose metabolism that characterize conditions of increased TNFa andaor leptin production.

show abstract

“…Ishizuka et al (1999) demonstrated TNF-alpha induced time-and dose-dependent apoptotic nuclear changes in these betacells and further suggested that TNF-alpha can cause apoptosis in pancreatic beta-cells through TNFR1-linked apoptotic factors, TRADD, FADD, and FLICE, and TNF-induced ceramide production may be involved in the pathways.…”

Section: Pathways Of Caspase Activation In Apoptosismentioning

confidence: 81%

Role of caspases in the regulation of apoptotic pancreatic islet beta‐cells death

Hui

Dotta

Mario

et al. 2004

Journal Cellular Physiology

View full text Add to dashboard Cite

The homeostatic control of beta-cell mass in normal and pathological conditions is based on the balance of proliferation, differentiation, and death of the insulinsecreting cells. A considerable body of evidence, accumulated during the last decade, has emphasized the significance of the disregulation of the mechnanisms regulating the apoptosis of beta-cells in the sequence of events that lead to the development of diabetes. The identification of agents capable of interfering with this process needs to be based on a better understanding of the beta-cell specific pathways that are activated during apoptosis. The aim of this article is fivefold: (1) a review of the evidence for beta-cell apoptosis in Type I diabetes, Type II diabetes, and islet transplantation, (2) to review the common stimuli and their mechanisms in pancreatic beta-cell apoptosis, (3) to review the role of caspases and their activation pathway in beta-cell apoptosis, (4) to review the caspase cascade and morphological cellular changes in apoptotic beta-cells, and (5) to highlight the putative strategies for preventing pancreatic beta-cells from apoptosis.

show abstract

Tumor necrosis factor alpha signaling pathway and apoptosis in pancreatic β cells

Cited by 56 publications

References 37 publications

Palmitate Inhibition of Insulin Gene Expression Is Mediated at the Transcriptional Level via Ceramide Synthesis

Palmitate Inhibition of Insulin Gene Expression Is Mediated at the Transcriptional Level via Ceramide Synthesis

TNFα and leptin inhibit basal and glucose-stimulated insulin secretion and gene transcription in the HIT-T15 pancreatic cells

Role of caspases in the regulation of apoptotic pancreatic islet beta‐cells death

Contact Info

Product

Resources

About