scholarly journals Pro-inflammatory cytokines increase glucose, alanine and triacylglycerol utilization but inhibit insulin secretion in a clonal pancreatic β-cell line

2007 ◽  
Vol 195 (1) ◽  
pp. 113-123 ◽  
Author(s):  
Aoife Kiely ◽  
Neville H McClenaghan ◽  
Peter R Flatt ◽  
Philip Newsholme
Keyword(s):  
Insulin Secretion ◽  
Inflammatory Cytokines ◽  
Prolonged Exposure ◽  
Cell Metabolism ◽  
Glutamate Release ◽  
Β Cell ◽  
Catabolic State ◽  
Stimulus Secretion Coupling ◽  
Factor Α ◽  
Pro Inflammatory Cytokines

We have investigated the effects of prolonged exposure (24 h) to pro-inflammatory cytokines on β-cell metabolism and insulin secretion using clonal BRIN-BD11 β cells. Addition of IL-1β, tumour necrosis factor-α and IFN-γ (at concentrations that did not induce apoptosis) inhibited chronic (24 h) and acute stimulated levels of insulin release (by 59 and 93% respectively), increased cellular glucose and alanine consumption, and also elevated lactate and glutamate release. However, ATP levels and cellular triacylglycerol were decreased while glutathione was increased. We conclude that sub-lethal concentrations of pro-inflammatory cytokines appear to shift β-cell metabolism away from a key role in energy generation and stimulus–secretion coupling and towards a catabolic state which may be related to cell defence.

scholarly journals Overexpression of the malate–aspartate NADH shuttle member Aralar1 in the clonal β-cell line BRIN-BD11 enhances amino-acid-stimulated insulin secretion and cell metabolism

2009 ◽  
Vol 117 (9) ◽  
pp. 321-330 ◽  
Author(s):  
Katrin Bender ◽  
Pierre Maechler ◽  
Neville H. McClenaghan ◽  
Peter R. Flatt ◽  
Philip Newsholme
Keyword(s):  
Insulin Secretion ◽  
Amino Acid ◽  
Cell Line ◽  
Recombinant Adenovirus ◽  
Cell Metabolism ◽  
Glutamate Release ◽  
Lactate Production ◽  
Control Site ◽  
Β Cell ◽  
Insulin Secreting Cells

In the present study, we have investigated the effects of the transduction with recombinant adenovirus AdCA-Aralar1 (aspartate–glutamate carrier 1) on the metabolism, function and secretory properties of the glucose- and amino-acid-responsive clonal insulin-secreting cell line BRIN-BD11. Aralar1 overexpression increased long-term (24 h) and acute (20 min) glucose- and amino-acid-stimulated insulin secretion, cellular glucose metabolism, L-alanine and L-glutamine consumption, cellular ATP and glutamate concentrations, and stimulated glutamate release. However, cellular triacylglycerol and glycogen contents were decreased as was lactate production. These findings indicate that increased malate–aspartate shuttle activity positively shifted β-cell metabolism, thereby increasing glycolysis capacity, stimulus–secretion coupling and, ultimately, enhancing insulin secretion. We conclude that Aralar1 is a key metabolic control site in insulin-secreting cells.

scholarly journals Pancreatic β-Cell Death in Response to Pro-Inflammatory Cytokines Is Distinct from Genuine Apoptosis

PLoS ONE ◽  
2011 ◽  
Vol 6 (7) ◽  
pp. e22485 ◽  
Author(s):  
J. Jason Collier ◽  
Susan J. Burke ◽  
Mary E. Eisenhauer ◽  
Danhong Lu ◽  
Renee C. Sapp ◽  
...  
Keyword(s):  
Cell Death ◽  
Inflammatory Cytokines ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Pro Inflammatory Cytokines

Effects of pharmacological inhibition of NADPH oxidase or iNOS on pro-inflammatory cytokine, palmitic acid or H2O2-induced mouse islet or clonal pancreatic β-cell dysfunction

2010 ◽  
Vol 30 (6) ◽  
pp. 445-453 ◽  
Author(s):  
Marta Michalska ◽  
Gabriele Wolf ◽  
Reinhard Walther ◽  
Philip Newsholme
Keyword(s):  
Fatty Acids ◽  
Insulin Secretion ◽  
Nadph Oxidase ◽  
Inflammatory Cytokine ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Mouse Islets ◽  
Pro Inflammatory Cytokines

Various pancreatic β-cell stressors including cytokines and saturated fatty acids are known to induce oxidative stress, which results in metabolic disturbances and a reduction in insulin secretion. However, the key mechanisms underlying dysfunction are unknown. We investigated the effects of prolonged exposure (24 h) to pro-inflammatory cytokines, H2O2 or PA (palmitic acid) on β-cell insulin secretion, ATP, the NADPH oxidase (nicotinamide adenine dinucleotide phosphate oxidase) component p47phox and iNOS (inducible nitric oxide synthase) levels using primary mouse islets or clonal rat BRIN-BD11 β-cells. Addition of a pro-inflammatory cytokine mixture [IL-1β (interleukin-1β), TNF-α (tumour necrosis factor-α) and IFN-γ (interferon-γ)] or H2O2 (at sub-lethal concentrations) inhibited chronic (24 h) levels of insulin release by at least 50% (from islets and BRIN-BD11 cells), while addition of the saturated fatty acid palmitate inhibited acute (20 min) stimulated levels of insulin release from mouse islets. H2O2 decreased ATP levels in the cell line, but elevated p47phox and iNOS levels as did cytokine addition. Similar effects were observed in mouse islets with respect to elevation of p47phox and iNOS levels. Addition of antioxidants SOD (superoxide dismutase), Cat (catalase) and NAC (N-acetylcysteine) attenuated H2O2 or the saturated fatty acid palmitate-dependent effects, but not cytokine-induced dysfunction. However, specific chemical inhibitors of NADPH oxidase and/or iNOS appear to significantly attenuate the effects of cytokines, H2O2 or fatty acids in islets. While pro-inflammatory cytokines are known to increase p47phox and iNOS levels in β-cells, we now report that H2O2 can increase levels of the latter two proteins, suggesting a key role for positive-feedback redox sensitive regulation of β-cell dysfunction.

Time-resolved metabolomics analysis of β-cells implicates the pentose phosphate pathway in the control of insulin release

2013 ◽  
Vol 450 (3) ◽  
pp. 595-605 ◽  
Author(s):  
Peter Spégel ◽  
Vladimir V. Sharoyko ◽  
Isabel Goehring ◽  
Anders P. H. Danielsson ◽  
Siri Malmgren ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Pentose Phosphate Pathway ◽  
Metabolic Response ◽  
Cell Metabolism ◽  
Pentose Phosphate ◽  
Β Cells ◽  
Β Cell ◽  
Time Resolved ◽  
Atp Production ◽  
Rat Islets

Insulin secretion is coupled with changes in β-cell metabolism. To define this process, 195 putative metabolites, mitochondrial respiration, NADP+, NADPH and insulin secretion were measured within 15 min of stimulation of clonal INS-1 832/13 β-cells with glucose. Rapid responses in the major metabolic pathways of glucose occurred, involving several previously suggested metabolic coupling factors. The complexity of metabolite changes observed disagreed with the concept of one single metabolite controlling insulin secretion. The complex alterations in metabolite levels suggest that a coupling signal should reflect large parts of the β-cell metabolic response. This was fulfilled by the NADPH/NADP+ ratio, which was elevated (8-fold; P<0.01) at 6 min after glucose stimulation. The NADPH/NADP+ ratio paralleled an increase in ribose 5-phosphate (>2.5-fold; P<0.001). Inhibition of the pentose phosphate pathway by trans-dehydroepiandrosterone (DHEA) suppressed ribose 5-phosphate levels and production of reduced glutathione, as well as insulin secretion in INS-1 832/13 β-cells and rat islets without affecting ATP production. Metabolite profiling of rat islets confirmed the glucose-induced rise in ribose 5-phosphate, which was prevented by DHEA. These findings implicate the pentose phosphate pathway, and support a role for NADPH and glutathione, in β-cell stimulus-secretion coupling.

scholarly journals Sudachinoid- and Ichangensin-Type Limonoids from Citrus junos Downregulate Pro-Inflammatory Cytokines

2020 ◽  
Vol 21 (18) ◽  
pp. 6963
Author(s):  
Jihun Shin ◽  
Hwa Young Song ◽  
Mina Lee
Keyword(s):  
Inflammatory Cytokines ◽  
Human Colon ◽  
Dominant Group ◽  
Citrus Junos ◽  
Mouse Macrophages ◽  
Inflammatory Bowel ◽  
Anti Inflammatory ◽  
Factor Α ◽  
Necrosis Factor ◽  
Pro Inflammatory Cytokines

Limonoids, a dominant group of phytochemicals in the Rutaceae family, are known to exhibit several pharmacological activities. To identify natural products having efficacy against inflammatory bowel disease (IBD), we isolated 13 limonoids including a new compound, methyl sudachinoid A, from the seeds of Citrus junos and investigated their anti-inflammatory effects by assessing the expression of pro-inflammatory cytokines in lipopolysaccharide-stimulated RAW 264.7 mouse macrophages and HT-29 human colon epithelial cells. Our findings revealed that limonoids significantly downregulated the pro-inflammatory cytokines, such as interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor-α, and nuclear transcription factor κB. In particular, sudachinoid-type compounds, methyl sudachinoid A and sudachinoid B, and ichangensin-type compound, 1-O-methyichangensin downregulated the expression of pro-inflammatory cytokines more potently than other limonoids, nomilin and limonin, which have been previously reported to exhibit anti-inflammatory activities in other cells; nomilin and limonin were therefore employed as positive controls in this study. Herein, we reveal that the anti-inflammatory activities of limonoids including a new compound methyl sudachinoid A from C. junos were mediated via the downregulation of pro-inflammatory cytokines and these limonoids can be employed as potential therapeutic phytochemicals for IBD.

scholarly journals Reduced Insulin Secretion in Protein Malnourished Mice Is Associated with Multiple Changes in the β-Cell Stimulus-Secretion Coupling

Endocrinology ◽  
2010 ◽  
Vol 151 (8) ◽  
pp. 3543-3554 ◽  
Author(s):  
Sergi Soriano ◽  
Alejandro Gonzalez ◽  
Laura Marroquí ◽  
Eva Tudurí ◽  
Elaine Vieira ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Β Cell ◽  
Stimulus Secretion Coupling

scholarly journals UPR-mediated TRIB3 expression correlates with reduced AKT phosphorylation and inability of interleukin 6 to overcome palmitate-induced apoptosis in RINm5F cells

2010 ◽  
Vol 206 (2) ◽  
pp. 183-193 ◽  
Author(s):  
José Edgar Nicoletti-Carvalho ◽  
Tatiane C Araújo Nogueira ◽  
Renata Gorjão ◽  
Carla Rodrigues Bromati ◽  
Tatiana S Yamanaka ◽  
...  
Keyword(s):  
Cell Death ◽  
Inflammatory Cytokines ◽  
Interleukin 6 ◽  
Common Mechanism ◽  
Rinm5f Cells ◽  
Β Cell ◽  
Induced Apoptosis ◽  
Unconditional Stimulation ◽  
Stimulation Of ◽  
Pro Inflammatory Cytokines

Unfolded protein response (UPR)-mediated pancreatic β-cell death has been described as a common mechanism by which palmitate (PA) and pro-inflammatory cytokines contribute to the development of diabetes. There are evidences that interleukin 6 (IL6) has a protective action against β-cell death induced by pro-inflammatory cytokines; the effects of IL6 on PA-induced apoptosis have not been investigated yet. In the present study, we have demonstrated that PA selectively disrupts IL6-induced RAC-alpha serine/threonine-protein kinase (AKT) activation without interfering with signal transducer and activator of transcription 3 phosphorylation in RINm5F cells. The inability of IL6 to activate AKT in the presence of PA correlated with an inefficient protection against PA-induced apoptosis. In contrast to PA, IL6 efficiently reduced apoptosis induced by pro-inflammatory cytokines. In addition, we have demonstrated that IL6 is unable to overcome PA-stimulated UPR, as assessed by activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP) expression, X-box binding protein-1 gene mRNA splicing, and pancreatic eukaryotic initiation factor-2α kinase phosphorylation, whereas no significant induction of UPR by pro-inflammatory cytokines was detected. This unconditional stimulation of UPR and apoptosis by PA was accompanied by the stimulation of CHOP and tribble3 (TRIB3) expression, irrespective of the presence of IL6. These findings suggest that IL6 is unable to protect pancreatic β-cells from PA-induced apoptosis because it does not repress UPR activation. In this way, CHOP and ATF4 might mediate PA-induced TRIB3 expression and, by extension, the suppression of IL6 activation of pro-survival kinase AKT.

scholarly journals Toll-like receptor agonist induced changes in clonal rat BRIN-BD11 β-cell insulin secretion and signal transduction

2009 ◽  
Vol 202 (3) ◽  
pp. 365-373 ◽  
Author(s):  
Aoife Kiely ◽  
Aisling Robinson ◽  
Neville H McClenaghan ◽  
Peter R Flatt ◽  
Philip Newsholme
Keyword(s):  
Insulin Secretion ◽  
Insulin Signalling ◽  
Cell Metabolism ◽  
Saturated Fatty Acids ◽  
Insulin Content ◽  
Β Cell ◽  
Akt Phosphorylation ◽  
Tlr4 Ligand ◽  
Induced Changes

Evidence for involvement of toll-like receptors (TLRs) (e.g. TLR4 and TLR2, whose agonists include lipopolysaccharides (LPS) and saturated fatty acids) in altered patterns of signalling in adipose, liver and muscle from animal models of insulin resistance and obesity has been published. We have now extended this area of research and have determined the effects of LPS on cell viability, insulin secretion, insulin signalling and metabolism in a clonal β-cell line. BRIN-BD11 β-cells were treated for 24 h with increasing concentrations of LPS. Chronic (24 h) and acute (20 min) insulin secretion, insulin content and parameters of cell metabolism and insulin signalling were determined. Incubation of BRIN-BD11 cells for 24 h in the presence of increasing concentrations of the TLR4 ligand LPS significantly decreased chronic (24 h) insulin secretion from 1.09±0.19 to 0.76±0.18 μg insulin/mg protein in the presence of 100 ng/ml LPS (P<0.05). There was no change in acute (20 min) stimulated insulin secretion or insulin content. Cell metabolism was not changed. Insulin receptor-β (IRβ) expression levels were increased significantly from 1±0.52 to 8.6±1.83 units (P<0.01), whereas calcineurin activity and Akt phosphorylation were significantly (P<0.01 and P<0.05 respectively) reduced in response to 24 h incubation in the presence of LPS. There was no change in IR substrate-1 protein expression or phosphorylation after 24 h. Further incubation for 24 h in the absence of LPS resulted in the recovery of chronic insulin secretion. The negative β-cell effects of LPS may contribute to hyperglycaemia in vivo.

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