scholarly journals Nodal induces apoptosis through activation of the ALK7 signaling pathway in pancreatic INS-1 β-cells

2012 ◽  
Vol 303 (1) ◽  
pp. E132-E143 ◽  
Author(s):  
Fang Zhao ◽  
Fengjie Huang ◽  
Mengxiong Tang ◽  
Xiaoming Li ◽  
Nina Zhang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Cell Apoptosis ◽  
Caspase 3 ◽  
Biological Effects ◽  
Cell Mass ◽  
Type I ◽  
Β Cells ◽  
Β Cell ◽  
Akt Phosphorylation ◽  
Induced Apoptosis

We demonstrated previously that the activation of ALK7 (activin receptor-like kinase-7), a member of the type I receptor serine/threonine kinases of the TGF-β superfamily, resulted in increased apoptosis and reduced proliferation through suppression of Akt signaling and the activation of Smad2-dependent signaling pathway in pancreatic β-cells. Here, we show that Nodal activates ALK7 signaling and regulates β-cell apoptosis. We detected Nodal expression in the clonal β-cell lines and rodent islet β-cells. Induction of β-cell apoptosis by treatment with high glucose, palmitate, or cytokines significantly increased Nodal expression in clonal INS-1 β-cells and isolated rat islets. The stimuli induced upregulation of Nodal expression levels were associated with elevation of ALK7 protein and enhanced phosphorylated Smad3 protein. Nodal treatment or overexpression of Nodal dose- or time-dependently increased active caspase-3 levels in INS-1 cells. Nodal-induced apoptosis was associated with decreased Akt phosphorylation and reduced expression level of X-linked inhibitor of apoptosis (XIAP). Remarkably, overexpression of XIAP or constitutively active Akt, or ablation of Smad2/3 activity partially blocked Nodal-induced apoptosis. Furthermore, siRNA-mediated ALK7 knockdown significantly attenuated Nodal-induced apoptosis of INS-1 cells. We suggest that Nodal-induced apoptosis in β-cells is mediated through ALK7 signaling involving the activation of Smad2/3-caspase-3 and the suppression of Akt and XIAP pathways and that Nodal may exert its biological effects on the modulation of β-cell survival and β-cell mass in an autocrine fashion.

Delphinidin-induced autophagy protects pancreatic β cells against apoptosis resulting from high-glucose stress via AMPK signaling pathway

2019 ◽  
Vol 51 (12) ◽  
pp. 1242-1249 ◽  
Author(s):  
Dengni Lai ◽  
Mingyong Huang ◽  
Lingyan Zhao ◽  
Yan Tian ◽  
Yong Li ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
High Glucose ◽  
Cell Mass ◽  
Protective Role ◽  
Common Disease ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Ampk Signaling ◽  
Compound C ◽  
Induced Apoptosis

Abstract Hyperglycemia, a diagnostic characteristic of diabetes mellitus, is detrimental to pancreatic β cells. Delphinidin, a member of the anthocyanin family, inhibits glucose absorption, increases glucagon-like peptide-1 (GLP-1) secretion, and improves insulin secretion in diabetes. However, whether delphinidin plays a protective role in pancreatic β-cell mass and function is not clear. In this study, delphinidin was found to decrease the high-glucose-induced apoptosis of RIN-m5F pancreatic β cells. In addition, delphinidin induced autophagy in RIN-m5F cells under the normal and high-glucose conditions, while 3-methyladenine (3-MA) inhibition of autophagy significantly diminished the protective role of delphinidin against high-glucose-induced apoptosis of pancreatic β cells. Delphinidin also decreased the level of cleaved caspase 3 and increased the phosphorylation level of AMP-activated protein kinase α (AMPKα) Thr172. Compound C, an AMPK inhibitor, was found to decrease the ratio of LC3-II/LC3-I, and the apoptotic rate of high-glucose-injured cells was increased after treatment with delphinidin, indicating that delphinidin attenuated the negative effects of high-glucose stress to cells. In conclusion, our data demonstrate that delphinidin protects pancreatic β cells against high-glucose-induced injury by autophagy regulation via the AMPK signaling pathway. These findings might shed light on the underlying mechanisms of diabetes and help improve the prevention and therapy of this common disease.

scholarly journals A Sustained Activation of Pancreatic NMDARs Is a Novel Factor of β-Cell Apoptosis and Dysfunction

Endocrinology ◽  
2017 ◽  
Vol 158 (11) ◽  
pp. 3900-3913 ◽  
Author(s):  
Xiao-Ting Huang ◽  
Shao-Jie Yue ◽  
Chen Li ◽  
Yan-Hong Huang ◽  
Qing-Mei Cheng ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cell Apoptosis ◽  
Cell Function ◽  
Cell Mass ◽  
Nuclear Factor Κb ◽  
Β Cells ◽  
Β Cell ◽  
Stimulation Of ◽  
Sustained Activation

Abstract Type 2 diabetes, which features β-cell failure, is caused by the decrease of β-cell mass and insulin secretory function. Current treatments fail to halt the decrease of functional β-cell mass. Strategies to prevent β-cell apoptosis and dysfunction are highly desirable. Recently, our group and others have reported that blockade of N-methyl-d-aspartate receptors (NMDARs) in the islets has been proposed to prevent the progress of type 2 diabetes through improving β-cell function. It suggests that a sustained activation of the NMDARs may exhibit deleterious effect on β-cells. However, the exact functional impact and mechanism of the sustained NMDAR stimulation on islet β-cells remains unclear. Here, we identify a sustained activation of pancreatic NMDARs as a novel factor of apoptotic β-cell death and function. The sustained treatment with NMDA results in an increase of intracellular [Ca2+] and reactive oxygen species, subsequently induces mitochondrial membrane potential depolarization and a decrease of oxidative phosphorylation expression, and then impairs the mitochondrial function of β-cells. NMDA specifically induces the mitochondrial-dependent pathway of apoptosis in β-cells through upregulation of the proapoptotic Bim and Bax, and downregulation of antiapoptotic Bcl-2. Furthermore, a sustained stimulation of NMDARs impairs β-cell insulin secretion through decrease of pancreatic duodenal homeobox-1 (Pdx-1) and adenosine triphosphate synthesis. The activation of nuclear factor–κB partly contributes to the reduction of Pdx-1 expression induced by overstimulation of NMDARs. In conclusion, we show that the sustained stimulation of NMDARs is a novel mediator of apoptotic signaling and β-cell dysfunction, providing a mechanistic insight into the pathological role of NMDARs activation in diabetes.

scholarly journals VMP1-related autophagy induced by a fructose-rich diet in β-cells: its prevention by incretins

2017 ◽  
Vol 131 (8) ◽  
pp. 673-687 ◽  
Author(s):  
Bárbara Maiztegui ◽  
Verónica Boggio ◽  
Carolina L. Román ◽  
Luis E. Flores ◽  
Héctor Del Zotto ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Cell Function ◽  
Cell Damage ◽  
Cell Mass ◽  
Ultrastructural Changes ◽  
Mrna Levels ◽  
Model Assessment ◽  
Β Cells ◽  
Β Cell ◽  
Insulin Mrna

The aim of the present study was to demonstrate the role of autophagy and incretins in the fructose-induced alteration of β-cell mass and function. Normal Wistar rats were fed (3 weeks) with a commercial diet without (C) or with 10% fructose in drinking water (F) alone or plus sitagliptin (CS and FS) or exendin-4 (CE and FE). Serum levels of metabolic/endocrine parameters, β-cell mass, morphology/ultrastructure and apoptosis, vacuole membrane protein 1 (VMP1) expression and glucose-stimulated insulin secretion (GSIS) were studied. Complementary to this, islets isolated from normal rats were cultured (3 days) without (C) or with F and F + exendin-4 or chloroquine. Expression of autophagy-related proteins [VMP1 and microtubule-associated protein light chain 3 (LC3)], apoptotic/antiapoptotic markers (caspase-3 and Bcl-2), GSIS and insulin mRNA levels were measured. F rats developed impaired glucose tolerance (IGT) and a significant increase in plasma triacylglycerols, thiobarbituric acid-reactive substances, insulin levels, homoeostasis model assessment (HOMA) for insulin resistance (HOMA-IR) and β-cell function (HOMA-β) indices. A significant reduction in β-cell mass was associated with an increased apoptotic rate and morphological/ultrastructural changes indicative of autophagic activity. All these changes were prevented by either sitagliptin or exendin-4. In cultured islets, F significantly enhanced insulin mRNA and GSIS, decreased Bcl-2 mRNA levels and increased caspase-3 expression. Chloroquine reduced these changes, suggesting the participation of autophagy in this process. Indeed, F induced the increase of both VMP1 expression and LC3-II, suggesting that VMP1-related autophagy is activated in injured β-cells. Exendin-4 prevented islet-cell damage and autophagy development. VMP1-related autophagy is a reactive process against F-induced islet dysfunction, being prevented by exendin-4 treatment. This knowledge could help in the use of autophagy as a potential target for preventing progression from IGT to type 2 diabetes mellitus.

scholarly journals High sensitivity of β-cell replication to the inhibitory effects of interleukin-1β: modulation by adenoviral overexpression of IGF2 in rat islets

2009 ◽  
Vol 203 (1) ◽  
pp. 55-63 ◽  
Author(s):  
Elisabet Estil.les ◽  
Noèlia Téllez ◽  
Joan Soler ◽  
Eduard Montanya
Keyword(s):  
Cell Proliferation ◽  
Cell Apoptosis ◽  
Interleukin 1Β ◽  
Complete Suppression ◽  
Cell Replication ◽  
Inhibitory Effects ◽  
Β Cells ◽  
Β Cell ◽  
Rat Islets ◽  
Induced Apoptosis

Interleukin-1β (IL1B) is an important contributor to the autoimmune destruction of β-cells in type 1 diabetes, and it has been recently related to the development of type 2 diabetes. IGF2 stimulates β-cell proliferation and survival. We have determined the effect of IL1B on β-cell replication, and the potential modulation by IGF2 and glucose. Control-uninfected and adenovirus encoding for IGF2 (Ad-IGF2)-infected rat islets were cultured at 5.5 or 22.2 mmol/l glucose with or without 1, 10, 30, and 50 U/ml of IL1B. β-Cell replication was markedly reduced by 10 U/ml of IL1B and was almost nullified with 30 or 50 U/ml of IL1B. Higher concentrations of IL1B were required to increase β-cell apoptosis. Although IGF2 overexpression had a strong mitogenic effect on β-cells, IGF2 could preserve β-cell proliferation only in islets cultured with 10 U/ml IL1B, and had no effect with 30 and 50 U/ml of IL1B. In contrast, IGF2 overexpression induced a clear protection against IL1B-induced apoptosis, and higher concentrations of the cytokine were needed to increase β-cell apoptosis in Ad-IGF2-infected islets. These results indicate that β-cell replication is highly sensitive to the deleterious effects of the IL1B as shown by the inhibition of replication by relatively low IL1B concentrations, and the almost complete suppression of β-cell replication with high IL1B concentrations. Likewise, the inhibitory effects of IL-β on β-cell replication were not modified by glucose, and were only modestly prevented by IGF2 overexpression, in contrast with the higher protection against IL1B-induced apoptosis afforded by glucose and by IGF2 overexpression.

scholarly journals Imeglimin Ameliorates β-cell Apoptosis by Modulating the Endoplasmic Reticulum Homeostasis Pathway

2021 ◽  
Author(s):  
Jinghe Li ◽  
Ryota Inoue ◽  
Yu Togashi ◽  
Tomoko Okuyama ◽  
Aoi Satoh ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Cell Survival ◽  
Cell Apoptosis ◽  
Cell Function ◽  
Cell Mass ◽  
Β Cells ◽  
Β Cell ◽  
Akita Mice ◽  
The Impact

The effects of imeglimin, a novel anti-diabetes agent, on β-cell function remain unclear. Here, we unveiled the impact of imeglimin on β-cell survival. Treatment with imeglimin augmented mitochondrial function, enhanced insulin secretion, promoted β-cell proliferation, and improved β-cell survival in mouse islets. Imeglimin upregulated the expression of endoplasmic reticulum (ER)-related molecules including <i>Chop (Ddit3),</i> <i>Gadd34</i> (<i>Ppp1r15a</i>), <i>Atf3</i>, and <i>Sdf2l1</i>, and decreased eIF2α phosphorylation, after treatment with thapsigargin, and restored global protein synthesis in β-cells under ER stress. Imeglimin failed to protect ER stress-induced β-cell apoptosis in CHOP-deficient islets or in the presence of GADD34 inhibitor. Treatment with imeglimin showed a significant decrease in the number of apoptotic β-cells and increased β-cell mass in Akita mice. Imeglimin also protected against β-cell apoptosis in both human islets and human pluripotent stem cell (<a>hPSC)-derived β-like cells</a>. <a>Taken together, imeglimin modulates ER homeostasis pathway, which results in the prevention of β-cell apoptosis both <i>in vitro</i> and <i>in vivo</i>.</a>

scholarly journals Banxia Xiexin Decoction Ameliorates t-BHP-Induced Apoptosis in Pancreatic Beta Cells by Activating the PI3K/AKT/FOXO1 Signaling Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Li-juan Du ◽  
Bing Pang ◽  
Yu-meng Tan ◽  
Ya-nan Yang ◽  
Mei-zhen Zhang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Cell Apoptosis ◽  
Pancreatic Beta Cells ◽  
Caspase 3 ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Signal Molecules ◽  
Protective Effects ◽  
Min6 Cells ◽  
Banxia Xiexin Decoction ◽  
Induced Apoptosis

Background. Banxia Xiexin Decoction (BXXD) reportedly regulates glycolipid metabolism and inhibits pancreatic β-cell apoptosis. This study is aimed at investigating the protective effect of BXXD on tert-butyl hydroperoxide- (t-BHP-) induced apoptosis in MIN6 cells and the underlying mechanisms. Methods. MIN6 cells were preincubated with BXXD or liraglutide (Li) with or without PI3K inhibitor LY294002 (LY) for 12 h, following which t-BHP was added to induce MIN6 cell apoptosis. The protective effects of BXXD on MIN6 cells were evaluated by detecting cell viability and proliferation and glucose-stimulated insulin secretion (GSIS). The antiapoptotic effects were evaluated by Hoechst 33342 staining and terminal deoxynucleotidyl transferase dUTP nick end labeling assay (TUNEL). Malondialdehyde and glutathione peroxidase content and superoxide dismutase activity were measured using commercial kits. The expression of PI3K/AKT/FOXO1 signaling pathway-related signal molecules, and that of apoptotic indicators Bax, P27, and Caspase-3, was quantified using western blotting. Results. Preincubation with BXXD significantly improved t-BHP-induced proliferation inhibition and apoptosis and enhanced GSIS. t-BHP induced the generation of reactive oxygen species and inhibited the activities of antioxidant enzymes, which could be neutralized by pretreatment with BXXD. BXXD promoted the phosphorylation of AKT and FOXO1 in t-BHP-induced MIN6 cells. Moreover, BXXD attenuated the expression of related apoptotic indicators Bax, P27, and Caspase-3. LY abolished these effects of BXXD. Conclusion. BXXD protected MIN6 cells against t-BHP-induced apoptosis and improved insulin secretory function through modulation of the PI3K/AKT pathway and the downstream FOXO1, thus suggesting a novel therapeutic approach for type 2 diabetes mellitus (T2DM).

scholarly journals Role of calcium-independent phospholipase A2β in human pancreatic islet β-cell apoptosis

2012 ◽  
Vol 303 (11) ◽  
pp. E1386-E1395 ◽  
Author(s):  
Xiaoyong Lei ◽  
Sheng Zhang ◽  
Alan Bohrer ◽  
Suzanne E. Barbour ◽  
Sasanka Ramanadham
Keyword(s):  
Er Stress ◽  
Cell Apoptosis ◽  
Caspase 3 ◽  
Apoptotic Cell ◽  
Human Islet ◽  
Β Cells ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Β Protein ◽  
Insulinoma Cells

Death of β-cells due to apoptosis is an important contributor to β-cell dysfunction in both type 1 and type 2 diabetes mellitus. Previously, we described participation of the Group VIA Ca2+-independent phospholipase A2 (iPLA2β) in apoptosis of insulinoma cells due to ER stress. To examine whether islet β-cells are similarly susceptible to ER stress and undergo iPLA2β-mediated apoptosis, we assessed the ER stress response in human pancreatic islets. Here, we report that the iPLA2β protein is expressed predominantly in the β-cells of human islets and that thapsigargin-induced ER stress promotes β-cell apoptosis, as reflected by increases in activated caspase-3 in the β-cells. Furthermore, we demonstrate that ER stress is associated with increases in islet iPLA2β message, protein, and activity, iPLA2β-dependent induction of neutral sphingomyelinase and ceramide accumulation, and subsequent loss of mitochondrial membrane potential. We also observe that basal activated caspase-3 increases with age, raising the possibility that β-cells in older human subjects have a greater susceptibility to undergo apoptotic cell death. These findings reveal for the first time expression of iPLA2β protein in human islet β-cells and that induction of iPLA2β during ER stress contributes to human islet β-cell apoptosis. We hypothesize that modulation of iPLA2β activity might reduce β-cell apoptosis and this would be beneficial in delaying or preventing β-cell dysfunction associated with diabetes.

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 Protein Kinase B/Akt Prevents Fatty Acid-induced Apoptosis in Pancreatic β-Cells (INS-1)

2002 ◽  
Vol 277 (51) ◽  
pp. 49676-49684 ◽  
Author(s):  
Christian E. Wrede ◽  
Lorna M. Dickson ◽  
Melissa K. Lingohr ◽  
Isabelle Briaud ◽  
Christopher J. Rhodes
Keyword(s):  
Growth Factor ◽  
Protein Kinase ◽  
Cell Apoptosis ◽  
Glycogen Synthase ◽  
Protein Kinase B ◽  
Glycogen Synthase Kinase ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Induced Apoptosis

Free fatty acids (FFA) have been reported to reduce pancreatic β-cell mitogenesis and to increase apoptosis. Here we show that the FFA, oleic acid, increased apoptosis 16-fold in the pancreatic β-cell line, INS-1, over a 18-h period as assessed by Hoechst 33342/propidium iodide staining and caspase-3 and -9 activation, with negligible necrosis. A parallel analysis of the phosphorylation activation of protein kinase B (PKB) showed this was reduced in the presence of FFA that correlated with the incidence of apoptosis. At stimulatory 15 mmglucose and/or in the added presence of insulin-like growth factor 1, FFA-induced β-cell apoptosis was lessened compared with that at a basal 5 mmglucose. However, most strikingly, adenoviral mediated expression of a constitutively active PKB, but not a “kinase-dead” PKB variant, essentially prevented FFA-induced β-cell apoptosis under all glucose/insulin-like growth factor 1 conditions. Further analysis of pro-apoptotic downstream targets of PKB, implicated a role for PKB-mediated phosphorylation inhibition of glycogen synthase kinase-3α/β and the forkhead transcription factor, FoxO1, in protection of FFA-induced β-cell apoptosis. In addition, down-regulation of the pro-apoptotic tumor suppresser protein, p53, via PKB-mediated phosphorylation of MDM2 might also play a role in partially protecting β-cells from FFA-induced apoptosis. Adenoviral mediated expression of wild type p53 potentiated FFA-induced β-cell apoptosis, whereas expression of a dominant negative p53 partly inhibited β-cell apoptosis by ∼50%. Hence, these data demonstrate that PKB activation plays an important role in promoting pancreatic β-cell survival in part via inhibition of the pro-apoptotic proteins glycogen synthase kinase-3α/β, FoxO1, and p53. This, in turn, provides novel insight into the mechanisms involved in FFA-induced β-cell apoptosis.

scholarly journals The Hippo kinase LATS2 impairs pancreatic β-cell survival in diabetes through the mTORC1-autophagy axis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ting Yuan ◽  
Karthika Annamalai ◽  
Shruti Naik ◽  
Blaz Lupse ◽  
Shirin Geravandi ◽  
...  
Keyword(s):  
Cell Survival ◽  
Cell Apoptosis ◽  
Molecular Mechanisms ◽  
Cell Mass ◽  
Human Islets ◽  
Hippo Signaling ◽  
Pancreatic Β Cell ◽  
Β Cells ◽  
Β Cell ◽  
Large Tumor

AbstractDiabetes results from a decline in functional pancreatic β-cells, but the molecular mechanisms underlying the pathological β-cell failure are poorly understood. Here we report that large-tumor suppressor 2 (LATS2), a core component of the Hippo signaling pathway, is activated under diabetic conditions and induces β-cell apoptosis and impaired function. LATS2 deficiency in β-cells and primary isolated human islets as well as β-cell specific LATS2 ablation in mice improves β-cell viability, insulin secretion and β-cell mass and ameliorates diabetes development. LATS2 activates mechanistic target of rapamycin complex 1 (mTORC1), a physiological suppressor of autophagy, in β-cells and genetic and pharmacological inhibition of mTORC1 counteracts the pro-apoptotic action of activated LATS2. We further show a direct interplay between Hippo and autophagy, in which LATS2 is an autophagy substrate. On the other hand, LATS2 regulates β-cell apoptosis triggered by impaired autophagy suggesting an existence of a stress-sensitive multicomponent cellular loop coordinating β-cell compensation and survival. Our data reveal an important role for LATS2 in pancreatic β-cell turnover and suggest LATS2 as a potential therapeutic target to improve pancreatic β-cell survival and function in diabetes.

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