Stress-Associated Endoplasmic Reticulum Protein 1 Protected High Glucose-Induced Islet β Cells from Apoptosis by Attenuating Endoplasmic Reticulum Stress

2019 ◽  
Vol 9 (12) ◽  
pp. 1731-1738
Author(s):  
Shulong Guo ◽  
Shaoya Wang ◽  
Youxiao Zeng ◽  
Qiaosheng Hu
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Western Blotting ◽  
High Glucose ◽  
Islet Cell ◽  
Β Cells ◽  
Β Cell ◽  
Tnf Α ◽  
Endoplasmic Reticulum Protein ◽  
Related Proteins

The incidence of type II diabetes caused by islet cell injury is increasing in recent years. Endoplasmic reticulum stress is one of the crucial causes of islet β cell damage, and stress-associated endoplasmic reticulum protein 1 (SERP1) could inhibit the occurrence and development of endoplasmic reticulum stress. But whether SERP1 could inhibit the damage of islet β cell caused by endoplasmic reticulum stress is unclear. In this study, we detected the levels of SERP1 and endoplasmic reticulum stress related proteins (p-PERK, p-Eif2 α, ATF-4 and CHOP) by western blotting. Next the lentivirus was used to construct the islet cell line which was stable overexpressed SERP1. Then the expression of endoplasmic reticulum stress related proteins and inflammatory factors was determined with western blotting. At last the apoptosis rates of islet β cells were detected by flow cytometry. We found that high glucose medium promoted the expression of p-PERK, p-Eif2 α, ATF-4 and CHOP while downregulated the levels of SERP1 in isletβ cells. Moreover, overexpression of SERP1 induced the downregulation of levels of p-PERK, p-Eif2 α, ATF-4, CHOP, TNF-α , IL-1β and IL-6 and alleviated the apoptosis of islet cells. At last, the overexpression of CHOP rescued the apoptosis rates and the expression of TNF-α, IL-1β and IL-6. These results indicated SERP1 relieved the inflammation response and apoptosis of islet β cells by inhibiting the expression of CHOP and alleviating the endoplasmic reticulum stress induced damage.

scholarly journals Endoplasmic Reticulum Stress Induced Proliferation Remains Intact in Aging Mouse β-Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Jarin T. Snyder ◽  
Christine Darko ◽  
Rohit B. Sharma ◽  
Laura C. Alonso
Keyword(s):  
Cell Proliferation ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
High Glucose ◽  
Low Dose ◽  
Target Genes ◽  
Brdu Incorporation ◽  
Older Individuals ◽  
Β Cells ◽  
Β Cell

Aging is associated with loss of proliferation of the insulin-secreting β-cell, a possible contributing factor to the increased prevalence of type 2 diabetes in the elderly. Our group previously discovered that moderate endoplasmic reticulum (ER) stress occurring during glucose exposure increases the adaptive β-cell proliferation response. Specifically, the ATF6α arm of the tripartite Unfolded Protein Response (UPR) promotes β-cell replication in glucose excess conditions. We hypothesized that β-cells from older mice have reduced proliferation due to aberrant UPR signaling or an impaired proliferative response to ER stress or ATF6α activation. To investigate, young and old mouse islet cells were exposed to high glucose with low-dose thapsigargin or activation of overexpressed ATF6α, and β-cell proliferation was quantified by BrdU incorporation. UPR pathway activation was compared by qPCR of target genes and semi-quantitative Xbp1 splicing assay. Intriguingly, although old β-cells had reduced proliferation in high glucose compared to young β-cells, UPR activation and induction of proliferation in response to low-dose thapsigargin or ATF6α activation in high glucose were largely similar between young and old. These results suggest that loss of UPR-led adaptive proliferation does not explain the reduced cell cycle entry in old β-cells, and raise the exciting possibility that future therapies that engage adaptive UPR could increase β-cell number through proliferation even in older individuals.

scholarly journals Activation of Nicotinic Acetylcholine Receptors Decreases Apoptosis in Human and Female Murine Pancreatic Islets

Endocrinology ◽  
2016 ◽  
Vol 157 (10) ◽  
pp. 3800-3808 ◽  
Author(s):  
Philippe Klee ◽  
Domenico Bosco ◽  
Audrey Guérardel ◽  
Emmanuel Somm ◽  
Audrey Toulotte ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Endoplasmic Reticulum Stress ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
B Cell Lymphoma ◽  
Β Cells ◽  
Β Cell ◽  
Nicotinic Acetylcholine ◽  
Mitochondrial Outer Membrane Permeabilization

Type 1 diabetes (T1DM) results from destruction of most insulin-secreting pancreatic β-cells. The persistence of β-cells decades after the onset of the disease indicates that the resistance of individual cells to the autoimmune insult is heterogeneous and might depend on the metabolic status of a cell at a given moment. The aim of this study is to investigate whether activation of nicotinic acetylcholine receptors (nACh-Rs) could increase β-cell resistance against the adverse environment prevailing at the onset of T1DM. Here, we show that nACh-R activation by nicotine and choline, 2 agonists of the receptor, decreases murine and human β-cell apoptosis induced by proinflammatory cytokines known to be present in the islet environment at the onset of T1DM. The protective mechanism activated by nicotine and choline involves attenuation of mitochondrial outer membrane permeabilization via modulation of endoplasmic reticulum stress, of the activity of B-cell lymphoma 2 family proteins and cytoplasmic calcium levels. Local inflammation and endoplasmic reticulum stress being key determinants of β-cell death in T1DM, we conclude that pharmacological activation of nACh-R could represent a valuable therapeutic option in the modulation of β-cell death in T1DM.

scholarly journals Emulsified isoflurane alleviates rat islet beta cell RIN-m5F apoptosis induced by glucose via inhibiting endoplasmic reticulum stress

2019 ◽  
Author(s):  
Wenyan Dong ◽  
Zhenkun Yang ◽  
Jingjing Zhao ◽  
Jie Sun ◽  
Min Yao ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Beta Cell ◽  
Beta Cells ◽  
Western Blotting ◽  
High Glucose ◽  
Caspase 3 ◽  
Control Group ◽  
Group Culture ◽  
Islet Beta Cell

Abstract Background Diabetes mellitus (DM) is a critical disease that considered a detriment to the health of people all over the world. Endoplasmic reticulum stress (ERS) is the response cause by endoplasmic reticulum misfolded and unfolded protein aggregation, which induces cell apoptosis. Our previous work showed that EIso could alleviate ERS in lung reperfusion injury. This study aimed to elucidate whether Emulsified isoflurane (EIso) could alleviate apoptosis induced by glucose in rat islet beta cell RIN-m5F via inhibiting ERS. Methods RIN-m5F cells were divided into five groups: Control group, cultured in 0.1M glucose for 24h (0.1G group), culture in 0.3M glucose for 24h (0.3G group), culture in 0.3M glucose with 57uM EIso for 24h (0.3G+57E group), and culture in 0.3M glucose with 76uM EIso for 24h (0.3G+76E group). First, the cellular proliferation was measured by MTT assay, and the level of insulin secretion was measured with ELISA kit. Second, the expression of Bax and Bcl-2 were detected by Western blotting. The level of caspase-3 activity was assessed by colorimetric method. Finally, the CHOP and GRP78 expression were detected by Western blotting. The level of ATF6, Xbp1 and eIF2α mRNA were assessed by qRT-PCR after treated with EIso for 24h. Results High glucose induced significant loss of RIN-m5F cell viability, and stimulated the secretion of insulin; EIso improved the survival and protected the function of RIN-m5F. Compare to 0.3G group, treatment with EIso inhibited the activity of caspase-3, decreased the expression of Bax and increased the expression of Bcl-2. The expression of CHOP and GRP78 were inhibited by EIso at 24 h after treatment, and decrement of CHOP and GRP78 expression were correlated with EIso concentration. The level of ATF6, Xbp1 and eIF2α mRNA of RIN-m5F were enhanced culture with high glucose, but only eIF2α mRNA was decreased by EIso treatment. Conclusion High glucose induces rat islet beta cell RIN-m5F apoptosis and aggravates the function of beta cells. EIso protects beta cells from glucose-induced apoptosis, and anti-apoptosis is mediated, at least in part, by inhibiting ERS.

scholarly journals Mild Endoplasmic Reticulum Stress Augments the Proinflammatory Effect of IL-1β in Pancreatic Rat β-Cells via the IRE1α/XBP1s Pathway

Endocrinology ◽  
2012 ◽  
Vol 153 (7) ◽  
pp. 3017-3028 ◽  
Author(s):  
Michela Miani ◽  
Maikel L. Colli ◽  
Laurence Ladrière ◽  
Miriam Cnop ◽  
Decio L. Eizirik
Keyword(s):  
Fatty Acids ◽  
Endoplasmic Reticulum ◽  
Type 1 Diabetes ◽  
Inflammatory Response ◽  
Er Stress ◽  
Low Dose ◽  
Β Cells ◽  
Β Cell ◽  
Tnf Α

The prevalence of obesity and type 1 diabetes in children is increasing worldwide. Insulin resistance and augmented circulating free fatty acids associated with obesity may cause pancreatic β-cell endoplasmic reticulum (ER) stress. We tested the hypothesis that mild ER stress predisposes β-cells to an exacerbated inflammatory response when exposed to IL-1β or TNF-α, cytokines that contribute to the pathogenesis of type 1 diabetes. INS-1E cells or primary rat β-cells were exposed to a low dose of the ER stressor cyclopiazonic acid (CPA) or free fatty acids, followed by low-dose IL-1β or TNF-α. ER stress signaling was inhibited by small interfering RNA. Cells were evaluated for proinflammatory gene expression by RT-PCR and ELISA, gene reporter activity, p65 activation by immunofluorescence, and apoptosis. CPA pretreatment enhanced IL-1β- induced, but not TNF-α-induced, expression of chemokine (C-C motif) ligand 2, chemokine (C-X-C motif) ligand 1, inducible nitric oxide synthase, and Fas via augmented nuclear factor κB (NF-κB) activation. X-box binding protein 1 (XBP1) and inositol-requiring enzyme 1, but not CCAAT/enhancer binding protein homologous protein, knockdown prevented the CPA-induced exacerbation of NF-κB-dependent genes and decreased IL-1β-induced NF-κB promoter activity. XBP1 modulated NF-κB activity via forkhead box O1 inhibition. In conclusion, rat β-cells facing mild ER stress are sensitized to IL-1β, generating a more intense and protracted inflammatory response through inositol-requiring enzyme 1/XBP1 activation. These observations link β-cell ER stress to the triggering of exacerbated local inflammation.

scholarly journals TCONS_00230836 silencing restores stearic acid-induced β cell dysfunction through alleviating endoplasmic reticulum stress rather than apoptosis

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Rui Guo ◽  
Yunjin Zhang ◽  
Yue Yu ◽  
Shenghan Su ◽  
Qingrui Zhao ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Insulin Secretion ◽  
Endoplasmic Reticulum Stress ◽  
Stearic Acid ◽  
Β Cells ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Acid Diet ◽  
High Stearic Acid ◽  
Mouse Islets

Abstract Background Chronic exposure of pancreatic β cells to high levels of stearic acid (C18:0) leads to impaired insulin secretion, which accelerates the progression of type 2 diabetes mellitus (T2DM). Recently, long noncoding RNAs (lncRNAs) were found to participate in saturated fatty acid-induced metabolism dysfunction. However, their contribution to stearic acid-induced β-cell dysfunction remains largely unknown. This study evaluated the possible role of the lncRNA TCONS_00230836 in stearic acid-stimulated lipotoxicity to β cells. Method Using high-throughput RNA-sequencing, TCONS_00230836 was screened out as being exclusively differentially expressed in stearic acid-treated mouse β-TC6 cells. Co-expression network was constructed to reveal the potential mRNAs targeted for lncRNA TCONS_00230836. Changes in this lncRNA’s and candidate mRNAs’ levels were further assessed by real-time PCR in stearic acid-treated β-TC6 cells and islets of mice fed a high-stearic-acid diet (HSD). The localization of TCONS_00230836 was detected by fluorescent in situ hybridization. The endogenous lncRNA TCONS_00230836 in β-TC6 cells was abrogated by its Smart Silencer. Results TCONS_00230836 was enriched in mouse islets and mainly localized in the cytoplasm. Its expression was significantly increased in stearic acid-treated β-TC6 cells and HSD-fed mouse islets. Knockdown of TCONS_00230836 significantly restored stearic acid-impaired glucose-stimulated insulin secretion through alleviating endoplasmic reticulum stress. However, stearic acid-induced β cell apoptosis was not obviously recovered. Conclusion Our findings suggest the involvement of TCONS_00230836 in stearic acid-induced β-cell dysfunction, which provides novel insight into stearic acid-induced lipotoxicity to β cells. Anti-lncRNA TCONS_00230836 might be a new therapeutic strategy for alleviating stearic acid-induced β-cell dysfunction in the progression of T2DM.

Effects of fructosamine-3-kinase deficiency on function and survival of mouse pancreatic islets after prolonged culture in high glucose or ribose concentrations

2010 ◽  
Vol 298 (3) ◽  
pp. E586-E596 ◽  
Author(s):  
S. M. A. Pascal ◽  
M. Veiga-da-Cunha ◽  
P. Gilon ◽  
E. Van Schaftingen ◽  
J. C. Jonas
Keyword(s):  
Cell Survival ◽  
High Glucose ◽  
Islet Cell ◽  
Protein Glycation ◽  
Intracellular Protein ◽  
Β Cells ◽  
Β Cell ◽  
And Function ◽  
Glucose Responsiveness ◽  
Cell Glucose

Due to their high glucose permeability, insulin-secreting pancreatic β-cells likely undergo strong intracellular protein glycation at high glucose concentrations. They may, however, be partly protected from the glucotoxic alterations of their survival and function by fructosamine-3-kinase (FN3K), a ubiquitous enzyme that initiates deglycation of intracellular proteins. To test that hypothesis, we cultured pancreatic islets from Fn3k-knockout ( Fn3k−/−) mice and their wild-type (WT) littermates for 1–3 wk in the presence of 10 or 30 mmol/l glucose (G10 or G30, respectively) and measured protein glycation, apoptosis, preproinsulin gene expression, and Ca2+ and insulin secretory responses to acute glucose stimulation. The more potent glycating agent d-ribose (25 mmol/l) was used as positive control for protein glycation. In WT islets, a 1-wk culture in G30 significantly increased the amount of soluble intracellular protein-bound fructose-ε-lysines and the glucose sensitivity of β-cells for changes in Ca2+ and insulin secretion, whereas it decreased the islet insulin content. After 3 wk, culture in G30 also strongly decreased β-cell glucose responsiveness and preproinsulin mRNA levels, whereas it increased islet cell apoptosis. Although protein-bound fructose-ε-lysines were more abundant in Fn3k−/− vs. WT islets, islet cell survival and function and their glucotoxic alterations were almost identical in both types of islets, except for a lower level of apoptosis in Fn3k−/− islets cultured for 3 wk in G30. In comparison, d-ribose (1 wk) similarly decreased preproinsulin expression and β-cell glucose responsiveness in both types of islets, whereas it increased apoptosis to a larger extent in Fn3k−/− vs. WT islets. We conclude that, despite its ability to reduce the glycation of intracellular islet proteins, FN3K is neither required for the maintenance of β-cell survival and function under control conditions nor involved in protection against β-cell glucotoxicity. The latter, therefore, occurs independently from the associated increase in the level of intracellular fructose-ε-lysines.

scholarly journals TCONS_00230836 silencing restores stearic acid-induced β-cell dysfunction through alleviating endoplasmic reticulum stress via a PERK/eIF2α-dependent pathway rather than apoptosis

2020 ◽  
Author(s):  
Rui Guo ◽  
Yunjin Zhang ◽  
Yue Yu ◽  
Shenghan Su ◽  
Qingrui Zhao ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Stearic Acid ◽  
Β Cells ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Acid Diet ◽  
High Stearic Acid ◽  
Mouse Islets ◽  
Dependent Pathway

Abstract Background: Chronic exposure of pancreatic β cells to high levels of stearic acid (C18:0) leads to impaired insulin secretion, which accelerates the progression of type 2 diabetes mellitus (T2DM). Recently, long noncoding RNAs (lncRNAs) were found to participate in saturated fatty acid-induced metabolism dysfunction. However, their contribution to stearic acid-induced β-cell dysfunction remains largely unknown. This study evaluated the possible role of the lncRNA TCONS_00230836 in stearic acid-stimulated lipotoxicity to β cells. Method: Using high-throughput RNA-sequencing, TCONS_00230836 was screened out as being exclusively differentially expressed in stearic acid-treated mouse β-TC6 cells. Co-expression network was constructed to reveal the potential mRNAs targeted for lncRNA TCONS_00230836. Changes in this lncRNA’s and candidate mRNAs’levels were further assessed by real-time PCR in stearic acid-treated β-TC6 cells and islets of mice fed a high-stearic-acid diet (HSD). The localization of TCONS_00230836 was detected by fluorescent in situ hybridization. The endogenous lncRNA TCONS_00230836 in β-TC6 cells was abrogated by its Smart Silencer. Results: The lncRNA TCONS_00230836 was enriched in mouse islets and mainly localized in the cytoplasm. Its expression was significantly increased in stearic acid-treated β-TC6 cells and HSD-fed mouse islets. Knockdown of TCONS_00230836 apparently restored stearic acid-impaired GSIS through alleviating endoplasmic reticulum stress via a PERK/eIF2α-dependent pathway. However, stearic acid-induced β-cell apoptosis was not obviously recovered. Conclusion: Our findings suggest the involvement of the lncRNA TCONS_00230836 in stearic acid-induced β-cell dysfunction, which provides novel insight into stearic acid-induced lipotoxicity to β cells. Anti-lncRNA TCONS_00230836 might be a new therapeutic strategy for alleviating stearic acid-induced β-cell dysfunction in the progression of T2DM.

scholarly journals DNAJC3 deficiency induces β-cell mitochondrial apoptosis and causes syndromic young-onset diabetes

2021 ◽  
Vol 184 (3) ◽  
pp. 459-472
Author(s):  
Maria Lytrivi ◽  
Valérie Senée ◽  
Paraskevi Salpea ◽  
Federica Fantuzzi ◽  
Anne Philippi ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Early Onset ◽  
Cell Loss ◽  
Endoplasmic Reticulum Stress Response ◽  
Mitochondrial Apoptosis ◽  
Loss Of Function ◽  
Β Cells ◽  
Β Cell ◽  
Onset Diabetes

Objective DNAJC3, also known as P58IPK, is an Hsp40 family member that interacts with and inhibits PKR-like ER-localized eIF2α kinase (PERK). Dnajc3 deficiency in mice causes pancreatic β-cell loss and diabetes. Loss-of-function mutations in DNAJC3 cause early-onset diabetes and multisystemic neurodegeneration. The aim of our study was to investigate the genetic cause of early-onset syndromic diabetes in two unrelated patients, and elucidate the mechanisms of β-cell failure in this syndrome. Methods Whole exome sequencing was performed and identified variants were confirmed by Sanger sequencing. DNAJC3 was silenced by RNAi in INS-1E cells, primary rat β-cells, human islets, and induced pluripotent stem cell-derived β-cells. β-cell function and apoptosis were assessed, and potential mediators of apoptosis examined. Results The two patients presented with juvenile-onset diabetes, short stature, hypothyroidism, neurodegeneration, facial dysmorphism, hypoacusis, microcephaly and skeletal bone deformities. They were heterozygous compound and homozygous for novel loss-of-function mutations in DNAJC3. DNAJC3 silencing did not impair insulin content or secretion. Instead, the knockdown induced rat and human β-cell apoptosis and further sensitized cells to endoplasmic reticulum stress, triggering mitochondrial apoptosis via the pro-apoptototic Bcl-2 proteins BIM and PUMA. Conclusions This report confirms previously described features and expands the clinical spectrum of syndromic DNAJC3 diabetes, one of the five monogenic forms of diabetes pertaining to the PERK pathway of the endoplasmic reticulum stress response. DNAJC3 deficiency may lead to β-cell loss through BIM- and PUMA-dependent activation of the mitochondrial pathway of apoptosis.

Testicular Injury Attenuated by Rapamycin Through Induction of Autophagy and Inhibition of Endoplasmic Reticulum Stress in Streptozotocin- Induced Diabetic Rats

2019 ◽  
Vol 19 (5) ◽  
pp. 665-675 ◽  
Author(s):  
Wenjiao Shi ◽  
Zhixin Guo ◽  
Ruixia Yuan
Keyword(s):  
Oxidative Stress ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Protective Effect ◽  
Er Stress ◽  
B Cell Lymphoma ◽  
Diabetic Rats ◽  
Pathological Changes ◽  
Rapamycin Treatment ◽  
Related Proteins

Background and Objective: This study investigated whether rapamycin has a protective effect on the testis of diabetic rats by regulating autophagy, endoplasmic reticulum stress, and oxidative stress. Methods: Thirty male Sprague-Dawley rats were randomly divided into three groups: control, diabetic, and diabetic treated with rapamycin, which received gavage of rapamycin (2mg.kg-1.d-1) after induction of diabetes. Diabetic rats were induced by intraperitoneal injection of streptozotocin (STZ, 65mg.Kg-1). All rats were sacrificed at the termination after 8 weeks of rapamycin treatment. The testicular pathological changes were determined by hematoxylin and eosin staining. The protein or mRNA expression of autophagy-related proteins (Beclin1, microtubule-associated protein light chain 3 (LC3), p62), ER stress marked proteins (CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP), caspase-12), oxidative stress-related proteins (p22phox, nuclear factor erythroid2-related factor 2 (Nrf2)) and apoptosis-related proteins (Bax, B cell lymphoma-2 (Bcl-2)) were assayed by western blot or real-time fluorescence quantitative PCR. Results: There were significant pathological changes in the testes of diabetic rats. The expression of Beclin1, LC3, Nrf2, Bcl-2 were significantly decreased and p62, CHOP, caspase12, p22phox, and Bax were notably increased in the testis of diabetic rats (P <0.05). However, rapamycin treatment for 8 weeks significantly reversed the above changes in the testis of diabetic rats (P <0.05). Conclusion: Rapamycin appears to produce a protective effect on the testes of diabetic rats by inducing the expression of autophagy and inhibiting the expression of ER-stress, oxidative stress, and apoptosis.

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