scholarly journals Free Fatty Acids and Cytokines Induce Pancreatic β-Cell Apoptosis by Different Mechanisms: Role of Nuclear Factor-κB and Endoplasmic Reticulum Stress

Endocrinology ◽  
2004 ◽  
Vol 145 (11) ◽  
pp. 5087-5096 ◽  
Author(s):  
Ilham Kharroubi ◽  
Laurence Ladrière ◽  
Alessandra K. Cardozo ◽  
Zeynep Dogusan ◽  
Miriam Cnop ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Fatty Acids ◽  
Cell Death ◽  
Er Stress ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Β Cells ◽  
Β Cell ◽  
Er Stress Response ◽  
Activating Transcription Factor

Abstract Apoptosis is probably the main form of β-cell death in both type 1 diabetes mellitus (T1DM) and T2DM. In T1DM, cytokines contribute to β-cell destruction through nuclear factor-κB (NF-κB) activation. Previous studies suggested that in T2DM high glucose and free fatty acids (FFAs) are β-cell toxic also via NF-κB activation. The aims of this study were to clarify whether common mechanisms are involved in FFA- and cytokine-induced β-cell apoptosis and determine whether TNFα, an adipocyte-derived cytokine, potentiates FFA toxicity through enhanced NF-κB activation. Apoptosis was induced in insulinoma (INS)-1E cells, rat islets, and fluorescence-activated cell sorting-purified β-cells by oleate, palmitate, and/or cytokines (IL-1β, interferon-γ, TNFα). Palmitate and IL-1β induced a similar percentage of apoptosis in INS-1E cells, whereas oleate was less toxic. TNFα did not potentiate FFA toxicity in primary β-cells. The NF-κB-dependent genes inducible nitric oxide synthase and monocyte chemoattractant protein-1 were induced by IL-1β but not by FFAs. Cytokines activated NF-κB in INS-1E and β-cells, but FFAs did not. Moreover, FFAs did not enhance NF-κB activation by TNFα. Palmitate and oleate induced C/EBP homologous protein, activating transcription factor-4, and immunoglobulin heavy chain binding protein mRNAs, X-box binding protein-1 alternative splicing, and activation of the activating transcription factor-6 promoter in INS-1E cells, suggesting that FFAs trigger an endoplasmic reticulum (ER) stress response. We conclude that apoptosis is the main mode of FFA- and cytokine-induced β-cell death but the mechanisms involved are different. Whereas cytokines induce NF-κB activation and ER stress (secondary to nitric oxide formation), FFAs activate an ER stress response via an NF-κB- and nitric oxide-independent mechanism. Our results argue against a unifying hypothesis for the mechanisms of β-cell death in T1DM and T2DM.

scholarly journals Inhibition of Nuclear Factor-κB or Bax Prevents Endoplasmic Reticulum Stress- But Not Nitric Oxide-Mediated Apoptosis in INS-1E Cells

Endocrinology ◽  
2009 ◽  
Vol 150 (9) ◽  
pp. 4094-4103 ◽  
Author(s):  
Morten F. Tonnesen ◽  
Lars G. Grunnet ◽  
Josefine Friberg ◽  
Alessandra K. Cardozo ◽  
Nils Billestrup ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Transcription Factor ◽  
Er Stress ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Β Cell ◽  
No Donor ◽  
Homologous Protein ◽  
Enhancer Binding Protein

Abstract Accumulating evidence suggests that endoplasmic reticulum (ER) stress by mechanisms that include ER Ca2+ depletion via NO-dependent down-regulation of sarcoendoplasmic reticulum Ca2+ ATPase 2b (SERCA2b) contributes to β-cell death in type 1 diabetes. To clarify whether the molecular pathways elicited by NO and ER Ca2+ depletion differ, we here compare the direct effects of NO, in the form of the NO donor S-nitroso-N-acetyl-d,l-penicillamine (SNAP), with the effects of SERCA2 inhibitor thapsigargin (TG) on MAPK, nuclear factor κB (NFκB), Bcl-2 proteins, ER stress, and apoptosis. Exposure of INS-1E cells to TG or SNAP caused caspase-3 cleavage and apoptosis. Both TG and SNAP induced activation of the proapoptotic transcription factor CCAAT/enhancer-binding protein homologous protein (CHOP). However, other classical ER stress-induced markers such as up-regulation of ER chaperone Bip and alternative splicing of the transcription factor Xbp-1 were exclusively activated by TG. TG exposure caused NFκB activation, as assessed by IκB degradation and NFκB DNA binding. Inhibition of NFκB or the Bcl-2 family member Bax pathways protected β-cells against TG- but not SNAP-induced β-cell death. These data suggest that NO generation and direct SERCA2 inhibition cause two quantitative and qualitative different forms of ER stress. In contrast to NO, direct ER stress induced by SERCA inhibition causes activation of ER stress signaling pathways and elicit proapoptotic signaling via NFκB and Bax.

Use of a systems biology approach to understand pancreatic β-cell death in Type 1 diabetes

2008 ◽  
Vol 36 (3) ◽  
pp. 321-327 ◽  
Author(s):  
Decio L. Eizirik ◽  
Fabrice Moore ◽  
Daisy Flamez ◽  
Fernanda Ortis
Keyword(s):  
Cell Death ◽  
Type 1 Diabetes ◽  
Systems Biology ◽  
Gene Networks ◽  
Nuclear Factor Κb ◽  
Signal Transducer ◽  
Trial And Error ◽  
Β Cells ◽  
Β Cell

Accumulating evidence indicates that β-cells die by apoptosis in T1DM (Type 1 diabetes mellitus). Apoptosis is an active gene-directed process, and recent observations suggest that β-cell apoptosis depends on the parallel and/or sequential up- and down-regulation of hundreds of genes controlled by key transcription factors such as NF-κB (nuclear factor κB) and STAT-1 (signal transducer and activator of transcription 1). Understanding the regulation of these gene networks, and how they modulate β-cell death and the ‘dialogue’ between β-cells and the immune system, will require a systems biology approach to the problem. This will hopefully allow the search for a cure for T1DM to move from a ‘trial-and-error’ approach to one that is really mechanistically driven.

Role of NF-κB in β-cell death

2008 ◽  
Vol 36 (3) ◽  
pp. 334-339 ◽  
Author(s):  
Danielle Melloul
Keyword(s):  
Cell Death ◽  
Lymphocytic Infiltration ◽  
Nuclear Factor Κb ◽  
Interferon Γ ◽  
Cell Protection ◽  
Β Cells ◽  
Β Cell ◽  
Ifn Γ ◽  
Induced Apoptosis

Apoptotic β-cell death appears to be central to the pathogenesis of Type 1 diabetes mellitus and in islet graft rejection. The β-cell destruction is partially mediated by cytokines, such as IL-1β (interleukin 1β), TNFα (tumour necrosis factor α) and IFN-γ (interferon γ). IL-1β and TNFα mediate activation of the transcription factor NF-κB (nuclear factor κB) pathway. Use of a degradation-resistant NF-κB protein inhibitor (ΔNIκBα), specifically expressed in β-cells, significantly reduced IL-1β+IFN-γ-induced apoptosis. Moreover, in vivo, it protected against multiple low-dose streptozocin-induced diabetes, with reduced intra-islet lymphocytic infiltration. Thus β-cell-specific activation of NF-κB is a key event in the progressive loss of β-cells in diabetes. Inhibition of this process could be a potential effective strategy for β-cell protection.

scholarly journals Diazoxide-induced β-cell rest reduces endoplasmic reticulum stress in lipotoxic β-cells

2008 ◽  
Vol 199 (1) ◽  
pp. 41-50 ◽  
Author(s):  
Ernest Sargsyan ◽  
Henrik Ortsäter ◽  
Kristofer Thorn ◽  
Peter Bergsten
Keyword(s):  
Endoplasmic Reticulum ◽  
Insulin Secretion ◽  
Er Stress ◽  
Cell Function ◽  
Β Cells ◽  
Β Cell ◽  
Eukaryotic Translation ◽  
Β Cell Function ◽  
Activating Transcription Factor ◽  
The Unfolded Protein Response

Elevated levels of glucose and lipids are characteristics of individuals with type 2 diabetes mellitus (T2DM). The enhanced nutrient levels have been connected with deterioration of β-cell function and impaired insulin secretion observed in these individuals. A strategy to improve β-cell function in individuals with T2DM has been intermittent administration of KATP channel openers. After such treatment, both the magnitude and kinetics of insulin secretion are markedly improved. In an attempt to further delineate mechanisms of how openers of KATP channels improve β-cell function, the effects of diazoxide on markers of endoplasmic reticulum (ER) stress was determined in β-cells exposed to the fatty acid palmitate. The eukaryotic translation factor 2-alpha kinase 3 (EIF2AK3; also known as PERK) and endoplasmic reticulum to nucleus signaling 1 (ERN1; also known as IRE1) pathways, but not the activating transcription factor (ATF6) pathway of the unfolded protein response, are activated in such lipotoxic β-cells. Inclusion of diazoxide during culture attenuated activation of the EIF2AK3 pathway but not the ERN1 pathway. This attenuation was associated with reduced levels of DNA-damage inducible transcript 3 (DDIT3; also known as CHOP) and β-cell apoptosis was decreased. It is concluded that reduction of ER stress may be a mechanism by which diazoxide improves β-cell function.

scholarly journals Glycated Albumin Causes Pancreatic β-Cells Dysfunction Through Autophagy Dysfunction

Endocrinology ◽  
2013 ◽  
Vol 154 (8) ◽  
pp. 2626-2639 ◽  
Author(s):  
Young Mi Song ◽  
Sun Ok Song ◽  
Young-Hye You ◽  
Kun-Ho Yoon ◽  
Eun Seok Kang ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Glycated Albumin ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Bafilomycin A1 ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Autophagy Induction ◽  
Interfering Rna

Abstract Growing evidence suggests that advanced glycation end-products (AGEs) are cytotoxic to pancreatic β-cells. The aims of this study were to investigate whether glycated albumin (GA), an early precursor of AGEs, would induce dysfunction in pancreatic β-cells and to determine which kinds of cellular mechanisms are activated in GA-induced β-cell apoptosis. Decreased viability and increased apoptosis were induced in INS-1 cells treated with 2.5 mg/mL GA under 16.7mM high-glucose conditions. Insulin content and glucose-stimulated secretion from isolated rat islets were reduced in 2.5 mg/mL GA-treated cells. In response to 2.5 mg/mL GA in INS-1 cells, autophagy induction and flux decreased as assessed by green fluorescent protein–microtubule-associated protein 1 light chain 3 dots, microtubule-associated protein 1 light chain 3-II conversion, and SQSTM1/p62 in the presence and absence of bafilomycin A1. Accumulated SQSTM1/p62 through deficient autophagy activated the nuclear factor-κB (p65)-inducible nitric oxide synthase-caspase-3 cascade, which was restored by treatment with small interfering RNA against p62. Small interfering RNA treatment against autophagy-related protein 5 significantly inhibited the autophagy machinery resulting in a significant increase in iNOS-cleaved caspase-3 expression. Treatment with 500μM 4-phenyl butyric acid significantly alleviated the expression of endoplasmic reticulum stress markers and iNOS in parallel with upregulated autophagy induction. However, in the presence of bafilomycin A1, the decreased viability of INS-1 cells was not recovered. Glycated albumin, an early precursor of AGE, caused pancreatic β-cell death by inhibiting autophagy induction and flux, resulting in nuclear factor-κB (p65)-iNOS-caspase-3 cascade activation as well as by increasing susceptibility to endoplasmic reticulum stress and oxidative stress.

scholarly journals Protection of pancreatic β-cells by exendin-4 may involve the reduction of endoplasmic reticulum stress; in vivo and in vitro studies

2007 ◽  
Vol 193 (1) ◽  
pp. 65-74 ◽  
Author(s):  
Shin Tsunekawa ◽  
Naoki Yamamoto ◽  
Katsura Tsukamoto ◽  
Yuji Itoh ◽  
Yukiko Kaneko ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Islet Cells ◽  
Binding Protein ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells

The aim of this study was to investigate the in vivo and in vitro effects of exendin-4, a potent glucagon-like peptide 1 agonist, on the protection of the pancreatic β-cells against their cell death. In in vivo experiments, we used β-cell-specific calmodulin-overexpressing mice where massive apoptosis takes place in their β-cells, and we examined the effects of chronic treatment with exendin-4. Chronic and s.c. administration of exendin-4 reduced hyperglycemia. The treatment caused significant increases of the insulin contents of the pancreas and islets, and retained the insulin-positive area. Dispersed transgenic islet cells lived only shortly, and several endoplasmic reticulum (ER) stress-related molecules such as immunoglobulin-binding protein (Bip), inositol-requiring enzyme-1α, X-box-binding protein-1 (XBP-1), RNA-activated protein kinase-like endoplasmic reticulum kinase, activating transcription factor-4, and C/EBP-homologous protein (CHOP) were more expressed in the transgenic islets. We also found that the spliced form of XBP-1, a marker of ER stress, was also increased in β-cell-specific calmodulin-overexpressing transgenic islets. In the quantitative real-time PCR analyses, the expression levels of Bip and CHOP were reduced in the islets from the transgenic mice treated with exendin-4. These findings suggest that excess of ER stress occurs in the transgenic β-cells, and the suppression of ER stress and resultant protection against cell death may be involved in the anti-diabetic effects of exendin-4.

scholarly journals Mitogen-Inducible Gene 6 Triggers Apoptosis and Exacerbates ER Stress-Induced β-Cell Death

2013 ◽  
Vol 27 (1) ◽  
pp. 162-171 ◽  
Author(s):  
Yi-Chun Chen ◽  
E. Scott Colvin ◽  
Bernhard F. Maier ◽  
Raghavendra G. Mirmira ◽  
Patrick T. Fueger
Keyword(s):  
Cell Death ◽  
Er Stress ◽  
Caspase 3 ◽  
Cell Mass ◽  
Growth Factor Receptor ◽  
Protein Translation ◽  
Β Cells ◽  
Β Cell ◽  
Inducible Gene

The increased insulin secretory burden placed on pancreatic β-cells during obesity and insulin resistance can ultimately lead to β-cell dysfunction and death and the development of type 2 diabetes. Mitogen-inducible gene 6 (Mig6) is a cellular stress-responsive protein that can negatively regulate the duration and intensity of epidermal growth factor receptor signaling and has been classically viewed as a molecular brake for proliferation. In this study, we used Mig6 heterozygous knockout mice (Mig6+/−) to study the role of Mig6 in regulating β-cell proliferation and survival. Surprisingly, the proliferation rate of Mig6+/− pancreatic islets was lower than wild-type islets despite having comparable β-cell mass and glucose tolerance. We thus speculated that Mig6 regulates cellular death. Using adenoviral vectors to overexpress or knockdown Mig6, we found that caspase 3 activation during apoptosis was dependent on the level of Mig6. Interestingly, Mig6 expression was induced during endoplasmic reticulum (ER) stress, and its protein levels were maintained throughout ER stress. Using polyribosomal profiling, we identified that Mig6 protein translation was maintained, whereas the global protein translation was inhibited during ER stress. In addition, Mig6 overexpression exacerbated ER stress-induced caspase 3 activation in vitro. In conclusion, Mig6 is transcriptionally up-regulated and resistant to global translational inhibition during stressed conditions in β-cells and mediates apoptosis in the form of caspase 3 activation. The sustained production of Mig6 protein exacerbates ER stress-induced β-cell death. Thus, preventing the induction, translation, and/or function of Mig6 is warranted for increasing β-cell survival.

scholarly journals Role for Activating Transcription Factor 3 in Stress-Induced β-Cell Apoptosis

2004 ◽  
Vol 24 (13) ◽  
pp. 5721-5732 ◽  
Author(s):  
Matthew G. Hartman ◽  
Dan Lu ◽  
Mi-Lyang Kim ◽  
Gary J. Kociba ◽  
Tala Shukri ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Type 2 Diabetes ◽  
Transcription Factor ◽  
Cell Apoptosis ◽  
Activating Transcription Factor 3 ◽  
Β Cells ◽  
Β Cell ◽  
Activating Transcription Factor

ABSTRACT Activating transcription factor 3 (ATF3) is a stress-inducible gene and encodes a member of the ATF/CREB family of transcription factors. However, the physiological significance of ATF3 induction by stress signals is not clear. In this report, we describe several lines of evidence supporting a role of ATF3 in stress-induced β-cell apoptosis. First, ATF3 is induced in β cells by signals relevant to β-cell destruction: proinflammatory cytokines, nitric oxide, and high concentrations of glucose and palmitate. Second, induction of ATF3 is mediated in part by the NF-κB and Jun N-terminal kinase/stress-activated protein kinase signaling pathways, two stress-induced pathways implicated in both type 1 and type 2 diabetes. Third, transgenic mice expressing ATF3 in β cells develop abnormal islets and defects secondary to β-cell deficiency. Fourth, ATF3 knockout islets are partially protected from cytokine- or nitric oxide-induced apoptosis. Fifth, ATF3 is expressed in the islets of patients with type 1 or type 2 diabetes, and in the islets of nonobese diabetic mice that have developed insulitis or diabetes. Taken together, our results suggest ATF3 to be a novel regulator of stress-induced β-cell apoptosis.

scholarly journals Molecular Mechanisms of Apoptosis Induction and Its Regulation by Fatty Acids in Pancreatic β-Cells

2021 ◽  
Vol 22 (8) ◽  
pp. 4285
Author(s):  
Jan Šrámek ◽  
Vlasta Němcová-Fürstová ◽  
Jan Kovář
Keyword(s):  
Fatty Acids ◽  
Er Stress ◽  
Membrane Fluidity ◽  
Molecular Mechanisms ◽  
Mitochondrial Pathway ◽  
Signalling Pathways ◽  
Apoptosis Induction ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells

Pancreatic β-cell failure and death contribute significantly to the pathogenesis of type 2 diabetes. One of the main factors responsible for β-cell dysfunction and subsequent cell death is chronic exposure to increased concentrations of FAs (fatty acids). The effect of FAs seems to depend particularly on the degree of their saturation. Saturated FAs induce apoptosis in pancreatic β-cells, whereas unsaturated FAs are well tolerated and are even capable of inhibiting the pro-apoptotic effect of saturated FAs. Molecular mechanisms of apoptosis induction by saturated FAs in β-cells are not completely elucidated. Saturated FAs induce ER stress, which in turn leads to activation of all ER stress pathways. When ER stress is severe or prolonged, apoptosis is induced. The main mediator seems to be the CHOP transcription factor. Via regulation of expression/activity of pro- and anti-apoptotic Bcl-2 family members, and potentially also through the increase in ROS production, CHOP switches on the mitochondrial pathway of apoptosis induction. ER stress signalling also possibly leads to autophagy signalling, which may activate caspase-8. Saturated FAs activate or inhibit various signalling pathways, i.e., p38 MAPK signalling, ERK signalling, ceramide signalling, Akt signalling and PKCδ signalling. This may lead to the activation of the mitochondrial pathway of apoptosis, as well. Particularly, the inhibition of the pro-survival Akt signalling seems to play an important role. This inhibition may be mediated by multiple pathways (e.g., ER stress signalling, PKCδ and ceramide) and could also consequence in autophagy signalling. Experimental evidence indicates the involvement of certain miRNAs in mechanisms of FA-induced β-cell apoptosis, as well. In the rather rare situations when unsaturated FAs are also shown to be pro-apoptotic, the mechanisms mediating this effect in β-cells seem to be the same as for saturated FAs. To conclude, FA-induced apoptosis rather appears to be preceded by complex cross talks of multiple signalling pathways. Some of these pathways may be regulated by decreased membrane fluidity due to saturated FA incorporation. Few data are available concerning molecular mechanisms mediating the protective effect of unsaturated FAs on the effect of saturated FAs. It seems that the main possible mechanism represents a rather inhibitory intervention into saturated FA-induced pro-apoptotic signalling than activation of some pro-survival signalling pathway(s) or metabolic interference in β-cells. This inhibitory intervention may be due to an increase of membrane fluidity.

scholarly journals Lactogens reduce endoplasmic reticulum stress-induced rodent and human β-cell death and diabetes incidence in Akita mice

2020 ◽  
Author(s):  
Ada Admin ◽  
Rosemary Li ◽  
Nagesha Guthalu Kondegowda ◽  
Joanna Filipowska ◽  
Rollie F. Hampton ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Placental Lactogen ◽  
Diabetes Incidence ◽  
Β Cells ◽  
Β Cell ◽  
Akita Mice ◽  
Stress Pathway

Diabetes occurs due to a loss of functional β-cells, resulting from β-cell death and dysfunction. Lactogens protect rodent and human β-cells <i>in vitro</i> and<i> in vivo</i> against triggers of β-cell cytotoxicity relevant to diabetes, many of which converge onto a common pathway, endoplasmic reticulum (ER) stress. However, whether lactogens modulate the ER stress pathway is unknown. This study examines if lactogens can protect β-cells against ER stress and mitigate diabetes incidence in Akita mice, a rodent model of ER stress-induced diabetes, akin to neonatal diabetes in humans. We show that lactogens protect INS1 cells, primary rodent and human β-cells <i>in vitro</i> against two distinct ER stressors, tunicamycin and thapsigargin, through activation of the JAK2/STAT5 pathway. Lactogens mitigate expression of pro-apoptotic molecules in the ER stress pathway that are induced by chronic ER stress in INS1 cells and rodent islets. Transgenic expression of placental lactogen in β-cells of Akita mice drastically reduces the severe hyperglycemia, diabetes incidence, hypoinsulinemia, β-cell death, and loss of β-cell mass observed in Akita littermates. These are the first studies in any cell type demonstrating lactogens modulate the ER stress pathway, causing enhanced β-cell survival and reduced diabetes incidence in the face of chronic ER stress.

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