scholarly journals Free Fatty Acids Induce a Proinflammatory Response in Islets via the Abundantly Expressed Interleukin-1 Receptor I

Endocrinology ◽  
2009 ◽  
Vol 150 (12) ◽  
pp. 5218-5229 ◽  
Author(s):  
Marianne Böni-Schnetzler ◽  
Simone Boller ◽  
Sarah Debray ◽  
Karim Bouzakri ◽  
Daniel T. Meier ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Free Fatty Acids ◽  
Interleukin 1 ◽  
Human Islets ◽  
Type I ◽  
Β Cells ◽  
Mouse Tissues ◽  
Mouse Islets ◽  
Human And Mouse ◽  
Proinflammatory Factors

Abstract Islets of patients with type 2 diabetes mellitus (T2DM) display features of an inflammatory process including elevated levels of the cytokine IL-1β, various chemokines, and macrophages. IL-1β is a master regulator of inflammation, and IL-1 receptor type I (IL-1RI) blockage improves glycemia and insulin secretion in humans with T2DM and in high-fat-fed mice pointing to a pivotal role of IL-1RI activity in intra-islet inflammation. Given the association of dyslipidemia and T2DM, we tested whether free fatty acids (FFA) promote the expression of proinflammatory factors in human and mouse islets and investigated a role for the IL-1RI in this response. A comparison of 22 mouse tissues revealed the highest IL-1RI expression levels in islets and MIN6 β-cells. FFA induced IL-1β, IL-6, and IL-8 in human islets and IL-1β and KC in mouse islets. Elevated glucose concentrations enhanced FFA-induced proinflammatory factors in human islets. Blocking the IL-1RI with the IL-1R antagonist (IL-1Ra) strongly inhibited FFA-mediated expression of proinflammatory factors in human and mouse islets. Antibody inhibition of IL-1β revealed that FFA stimulated IL-1RI activity via the induction of the receptor ligand. FFA-induced IL-1β and KC expression in mouse islets was completely dependent on the IL-1R/Toll-like receptor (TLR) docking protein Myd88 and partly dependent on TLR2 and -4. Activation of TLR2 in purified human β-cells and islets stimulated the expression of proinflammatory factors, and IL-1RI activity increased the TLR2 response in human islets. We conclude that FFA and TLR stimulation induce proinflammatory factors in islets and that IL-1RI engagement results in signal amplification.

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.

Free fatty acids stimulate autophagy in pancreatic β-cells via JNK pathway

2010 ◽  
Vol 401 (4) ◽  
pp. 561-567 ◽  
Author(s):  
Koji Komiya ◽  
Toyoyoshi Uchida ◽  
Takashi Ueno ◽  
Masato Koike ◽  
Hiroko Abe ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Free Fatty Acids ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Jnk Pathway

Effects of palmitate on ER and cytosolic Ca2+ homeostasis in β-cells

2009 ◽  
Vol 296 (4) ◽  
pp. E690-E701 ◽  
Author(s):  
Kamila S. Gwiazda ◽  
Ting-Lin B. Yang ◽  
Yalin Lin ◽  
James D. Johnson
Keyword(s):  
Type 2 Diabetes ◽  
Fatty Acids ◽  
Fatty Acid ◽  
Free Fatty Acids ◽  
Cell Function ◽  
Fluorescent Protein ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function

There are strong links between obesity, elevated free fatty acids, and type 2 diabetes. Specifically, the saturated fatty acid palmitate has pleiotropic effects on β-cell function and survival. In the present study, we sought to determine the mechanism by which palmitate affects intracellular Ca2+, and in particular the role of the endoplasmic reticulum (ER). In human β-cells and MIN6 cells, palmitate rapidly increased cytosolic Ca2+ through a combination of Ca2+ store release and extracellular Ca2+ influx. Palmitate caused a reversible lowering of ER Ca2+, measured directly with the fluorescent protein-based ER Ca2+ sensor D1ER. Using another genetically encoded indicator, we observed long-lasting oscillations of cytosolic Ca2+ in palmitate-treated cells. In keeping with this observed ER Ca2+ depletion, palmitate induced rapid phosphorylation of the ER Ca2+ sensor protein kinase R-like ER kinase (PERK) and subsequently ER stress and β-cell death. We detected little palmitate-induced insulin secretion, suggesting that these Ca2+ signals are poorly coupled to exocytosis. In summary, we have characterized Ca2+-dependent mechanisms involved in altered β-cell function and survival induced by the free fatty acid palmitate. We present the first direct evidence that free fatty acids reduce ER Ca2+ and shed light on pathways involved in lipotoxicity and the pathogenesis of type 2 diabetes.

Effects of adipocytokines and free fatty acids on viability and apoptosis of rat INS-1E β-cells

2011 ◽  
Vol 6 (S 01) ◽  
Author(s):  
R Spinnler ◽  
T Gorski ◽  
S Schuster ◽  
A Garten ◽  
S Laue ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Free Fatty Acids ◽  
Β Cells

scholarly journals Acute Insulin Signaling in Pancreatic Beta-Cells Is Mediated by Multiple Raf-1 Dependent Pathways

Endocrinology ◽  
2010 ◽  
Vol 151 (2) ◽  
pp. 502-512 ◽  
Author(s):  
Emilyn U. Alejandro ◽  
Tatyana B. Kalynyak ◽  
Farnaz Taghizadeh ◽  
Kamila S. Gwiazda ◽  
Erin K. Rawstron ◽  
...  
Keyword(s):  
Cell Death ◽  
Nicotinic Acid ◽  
Insulin Signaling ◽  
Pancreatic Beta Cells ◽  
Human Islets ◽  
Dominant Negative ◽  
Fluorescent Imaging ◽  
Β Cells ◽  
Erk Phosphorylation ◽  
Mouse Islets

Insulin enhances the proliferation and survival of pancreatic β-cells, but its mechanisms remain unclear. We hypothesized that Raf-1, a kinase upstream of both ERK and Bad, might be a critical target of insulin in β-cells. To test this hypothesis, we treated human and mouse islets as well as MIN6 β-cells with multiple insulin concentrations and examined putative downstream targets using immunoblotting, immunoprecipitation, quantitative fluorescent imaging, and cell death assays. Low doses of insulin rapidly activated Raf-1 by dephosphorylating serine 259 and phosphorylating serine 338 in human islets, mouse islets, and MIN6 cells. The phosphorylation of ERK by insulin was eliminated by exposure to a Raf inhibitor (GW5074) or transfection with a dominant-negative Raf-1 mutant. Insulin also enhanced the interaction between mitochondrial Raf-1 and Bcl-2 agonist of cell death (Bad), promoting Bad inactivation via its phosphorylation on serine 112. Insulin-stimulated ERK phosphorylation was abrogated by calcium chelation, calcineurin and calmodulin-dependent protein kinase II inhibitors, and Ned-19, a nicotinic acid adenine dinucleotide phosphate receptor (NAADPR) antagonist. Blocking Raf-1 and Ca2+ signaling resulted in nonadditive β-cell death. Autocrine insulin signaling partly accounted for the effects of glucose on ERK phosphorylation. Our results demonstrate that Raf-1 is a critical target of insulin in primary β-cells. Activation of Raf-1 leads to both an ERK-dependent pathway that involves nicotinic acid adenine dinucleotide phosphate-sensitive Ca2+ stores and Ca2+-dependent phosphorylation events, and an ERK-independent pathway that involves Bad inactivation at the mitochondria. Together our findings identify a novel insulin signaling pathway in β-cells and shed light on insulin’s antiapoptotic and mitogenic mechanisms.

scholarly journals Proteomic and Transcriptional Profiles of Human Stem Cell-Derived β Cells Following Enteroviral Challenge

2020 ◽  
Vol 8 (2) ◽  
pp. 295 ◽  
Author(s):  
Julius O. Nyalwidhe ◽  
Agata Jurczyk ◽  
Basanthi Satish ◽  
Sambra Redick ◽  
Natasha Qaisar ◽  
...  
Keyword(s):  
Stem Cell ◽  
Ex Vivo ◽  
Human Islets ◽  
Islet Autoimmunity ◽  
Type I ◽  
Human Stem Cell ◽  
Β Cells ◽  
Enteroviral Infection ◽  
Insulin Gene Expression ◽  
New Treatments

Enteroviral infections are implicated in islet autoimmunity and type 1 diabetes (T1D) pathogenesis. Significant β-cell stress and damage occur with viral infection, leading to cells that are dysfunctional and vulnerable to destruction. Human stem cell-derived β (SC-β) cells are insulin-producing cell clusters that closely resemble native β cells. To better understand the events precipitated by enteroviral infection of β cells, we investigated transcriptional and proteomic changes in SC-β cells challenged with coxsackie B virus (CVB). We confirmed infection by demonstrating that viral protein colocalized with insulin-positive SC-β cells by immunostaining. Transcriptome analysis showed a decrease in insulin gene expression following infection, and combined transcriptional and proteomic analysis revealed activation of innate immune pathways, including type I interferon (IFN), IFN-stimulated genes, nuclear factor-kappa B (NF-κB) and downstream inflammatory cytokines, and major histocompatibility complex (MHC) class I. Finally, insulin release by CVB4-infected SC-β cells was impaired. These transcriptional, proteomic, and functional findings are in agreement with responses in primary human islets infected with CVB ex vivo. Human SC-β cells may serve as a surrogate for primary human islets in virus-induced diabetes models. Because human SC-β cells are more genetically tractable and accessible than primary islets, they may provide a preferred platform for investigating T1D pathogenesis and developing new treatments.

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