scholarly journals MicroRNA-181c Inhibits Interleukin-6-mediated Beta Cell Apoptosis by Targeting TNF-α Expression

Molecules ◽  
2019 ◽  
Vol 24 (7) ◽  
pp. 1410 ◽  
Author(s):  
Yoon Sin Oh ◽  
Gong Deuk Bae ◽  
Eun-Young Park ◽  
Hee-Sook Jun
Keyword(s):  
Beta Cell ◽  
Mrna Expression ◽  
Beta Cells ◽  
Interleukin 6 ◽  
Cell Apoptosis ◽  
Neutralizing Antibodies ◽  
Annexin V ◽  
Beta Cell Apoptosis ◽  
Tnf Α ◽  
Long Term Treatment

We have previously reported that long-term treatment of beta cells with interleukin-6 (IL-6) is pro-apoptotic. However, little is known about the regulatory mechanisms that are involved. Therefore, we investigated pro-apoptotic changes in mRNA expression in beta cells in response to IL-6 treatment. We analyzed a microarray with RNA from INS-1 beta cells treated with IL-6, and found that TNF-α mRNA was significantly upregulated. Inhibition of TNF-α expression by neutralizing antibodies significantly decreased annexin V staining in cells compared with those treated with a control antibody. We identified three microRNAs that were differentially expressed in INS-1 cells incubated with IL-6. In particular, miR-181c was significantly downregulated in IL-6-treated cells compared with control cells and the decrease of miR-181c was attenuated by STAT-3 signaling inhibition. TNF-α mRNA was a direct target of miR-181c and upregulation of miR-181c by mimics, inhibited IL-6-induced increase in TNF-α mRNA expression. Consequently, reduction of TNF-α mRNA caused by miR-181c mimics enhanced cell viability in IL-6 treated INS-1 cells. These results demonstrated that miR-181c regulation of TNF-α expression plays a role in IL-6-induced beta cell apoptosis.

scholarly journals Bergenin protects pancreatic beta cells against cytokine-induced apoptosis in INS-1E cells

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0241349
Author(s):  
Sajid Ali Rajput ◽  
Munazza Raza Mirza ◽  
M. Iqbal Choudhary
Keyword(s):  
Insulin Secretion ◽  
Beta Cell ◽  
Beta Cells ◽  
Proinflammatory Cytokines ◽  
Cell Apoptosis ◽  
Pancreatic Beta Cells ◽  
Cell Function ◽  
Beta Cell Apoptosis ◽  
Atp Levels ◽  
Induced Apoptosis

Beta cell apoptosis induced by proinflammatory cytokines is one of the hallmarks of diabetes. Small molecules which can inhibit the cytokine-induced apoptosis could lead to new drug candidates that can be used in combination with existing therapeutic interventions against diabetes. The current study evaluated several effects of bergenin, an isocoumarin derivative, in beta cells in the presence of cytokines. These included (i) increase in beta cell viability (by measuring cellular ATP levels) (ii) suppression of beta cell apoptosis (by measuring caspase activity), (iii) improvement in beta cell function (by measuring glucose-stimulated insulin secretion), and (iv) improvement of beta cells mitochondrial physiological functions. The experiments were carried out using rat beta INS-1E cell line in the presence or absence of bergenin and a cocktail of proinflammatory cytokines (interleukin-1beta, tumor necrosis factor-alpha, and interferon- gamma) for 48 hr. Bergenin significantly inhibited beta cell apoptosis, as inferred from the reduction in the caspase-3 activity (IC50 = 7.29 ± 2.45 μM), and concurrently increased cellular ATP Levels (EC50 = 1.97 ± 0.47 μM). Bergenin also significantly enhanced insulin secretion (EC50 = 6.73 ± 2.15 μM) in INS-1E cells, presumably because of the decreased nitric oxide production (IC50 = 6.82 ± 2.83 μM). Bergenin restored mitochondrial membrane potential (EC50 = 2.27 ± 0.83 μM), decreased ROS production (IC50 = 14.63 ± 3.18 μM), and improved mitochondrial dehydrogenase activity (EC50 = 1.39 ± 0.62 μM). This study shows for the first time that bergenin protected beta cells from cytokine-induced apoptosis and restored insulin secretory function by virtue of its anti-inflammatory, antioxidant and anti-apoptotic properties. To sum up, the above mentioned data highlight bergenin as a promising anti-apoptotic agent in the context of diabetes.

scholarly journals Glucagon-like peptide-1 prevents methylglyoxal-induced apoptosis of beta cells through improving mitochondrial function and suppressing prolonged AMPK activation

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Tien-Jyun Chang ◽  
Hsing-Chi Tseng ◽  
Meng-Wei Liu ◽  
Yi-Cheng Chang ◽  
Meng-Lun Hsieh ◽  
...  
Keyword(s):  
Beta Cell ◽  
Beta Cells ◽  
Mitochondrial Function ◽  
Cell Apoptosis ◽  
Beta Cell Apoptosis ◽  
Ampk Activation ◽  
Apoptotic Effect ◽  
Glucagon Like Peptide 1 ◽  
Induced Apoptosis ◽  
Apoptotic Effects

Abstract Accumulation of methylglyoxal (MG) contributes to glucotoxicity and mediates beta cell apoptosis. The molecular mechanism by which GLP-1 protects MG-induced beta cell apoptosis remains unclear. Metformin is a first-line drug for treating type 2 diabetes associated with AMPK activation. However, whether metformin prevents MG-induced beta cell apoptosis is controversial. Here, we explored the signaling pathway involved in the anti-apoptotic effect of GLP-1, and investigated whether metformin had an anti-apoptotic effect on beta cells. MG treatment induced apoptosis of beta cells, impaired mitochondrial function, and prolonged activation of AMP-dependent protein kinase (AMPK). The MG-induced pro-apoptotic effects were abolished by an AMPK inhibitor. Pretreatment of GLP-1 reversed MG-induced apoptosis, and mitochondrial dysfunction, and suppressed prolonged AMPK activation. Pretreatment of GLP-1 reversed AMPK activator 5-aminoimidazole-4-carboxamide riboside (AICAR)-induced apoptosis, and suppressed prolonged AMPK activation. However, metformin neither leads to beta cell apoptosis nor ameliorates MG-induced beta cell apoptosis. In parallel, GLP-1 also prevents MG-induced beta cell apoptosis through PKA and PI3K-dependent pathway. In conclusion, these data indicates GLP-1 but not metformin protects MG-induced beta cell apoptosis through improving mitochondrial function, and alleviating the prolonged AMPK activation. Whether adding GLP-1 to metformin provides better beta cell survival and delays disease progression remains to be validated.

scholarly journals The adaptor protein NumbL is involved in the control of glucolipotoxicity-induced pancreatic beta cell apoptosis

2020 ◽  
Author(s):  
Halesha D. Basavarajappa ◽  
Jose M. Irimia ◽  
Patrick T. Fueger
Keyword(s):  
Cell Death ◽  
Beta Cell ◽  
Beta Cells ◽  
Cell Apoptosis ◽  
Molecular Mechanisms ◽  
Pancreatic Beta Cell ◽  
Adaptor Protein ◽  
Beta Cell Apoptosis ◽  
Beta Cell Death ◽  
Egf Signaling

AbstractAvoiding loss of functional beta cell mass is critical for preventing or treating diabetes. Currently, the molecular mechanisms underlying beta cell death are partially understood, and there is a need to identify new targets for developing novel therapeutics to treat diabetes. Previously, our group established that Mig6, an inhibitor of EGF signaling, mediates beta cell death under diabetogenic conditions. The objective of this study was to clarify the mechanisms linking diabetogenic stimuli to beta cell death by investigating Mig6-interacting proteins. Using co-immunoprecipitation and mass spectrometry, we evaluated the binding partners of Mig6 under both normal glucose (NG) and glucolipotoxic (GLT) conditions in beta cells. We identified that Mig6 interacts dynamically with NumbL; whereas Mig6 associates with NumbL under NG, this interaction is disrupted under GLT conditions. Further, we demonstrate that siRNA-mediated suppression of NumbL expression in beta cells prevented apoptosis under GLT conditions by blocking activation of NF-κB signaling. Using co-immunoprecipitation experiments we observed that NumbL’s interactions with TRAF6, a key component of NFκB signaling, are increased under GLT conditions. The interactions among Mig6, NumbL, and TRAF6 are dynamic and context-dependent. We propose a model wherein these interactions activate pro-apoptotic NF-κB signaling while blocking pro-survival EGF signaling under diabetogenic conditions, leading to beta cell apoptosis. These findings indicate that NumbL should be further investigated as a candidate anti-diabetic therapeutic target.

scholarly journals Mechanisms of Beta-Cell Apoptosis in Type 2 Diabetes-Prone Situations and Potential Protection by GLP-1-Based Therapies

2021 ◽  
Vol 22 (10) ◽  
pp. 5303
Author(s):  
Safia Costes ◽  
Gyslaine Bertrand ◽  
Magalie A. Ravier
Keyword(s):  
Type 2 Diabetes ◽  
Beta Cell ◽  
Beta Cells ◽  
Cell Apoptosis ◽  
Molecular Mechanisms ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Beta Cell Apoptosis ◽  
Chronic Hyperglycemia

Type 2 diabetes (T2D) is characterized by chronic hyperglycemia secondary to the decline of functional beta-cells and is usually accompanied by a reduced sensitivity to insulin. Whereas altered beta-cell function plays a key role in T2D onset, a decreased beta-cell mass was also reported to contribute to the pathophysiology of this metabolic disease. The decreased beta-cell mass in T2D is, at least in part, attributed to beta-cell apoptosis that is triggered by diabetogenic situations such as amyloid deposits, lipotoxicity and glucotoxicity. In this review, we discussed the molecular mechanisms involved in pancreatic beta-cell apoptosis under such diabetes-prone situations. Finally, we considered the molecular signaling pathways recruited by glucagon-like peptide-1-based therapies to potentially protect beta-cells from death under diabetogenic situations.

scholarly journals The role of apoptosis in pathogenesis of type 1 diabetes mellitus

2010 ◽  
Vol 13 (1) ◽  
pp. 45-49
Author(s):  
Elena Vladimirovna Pekareva ◽  
Tatiana Vasil'evna Nikonova ◽  
Olga Mikhailovna Smirnova
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Beta Cell ◽  
Type 1 Diabetes Mellitus ◽  
Beta Cells ◽  
Cell Apoptosis ◽  
Pancreatic Beta Cells ◽  
Beta Cell Apoptosis

Type 1 diabetes mellitus (DM1) is known to be associated with progressive destruction of pancreatic beta-cells. Apoptosis plays the key role in this destructiveprocess. The paper focuses on major mechanisms underlying activation of beta-cell apoptosis and its role in regulation of immune processes inpatients with DM1.

scholarly journals The miRNAs miR-211-5p and miR-204-5p modulate ER stress in human beta cells

2019 ◽  
Vol 63 (2) ◽  
pp. 139-149 ◽  
Author(s):  
Fabio Arturo Grieco ◽  
Andrea Alex Schiavo ◽  
Flora Brozzi ◽  
Jonas Juan-Mateu ◽  
Marco Bugliani ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Beta Cell ◽  
Er Stress ◽  
Beta Cells ◽  
Cell Apoptosis ◽  
Interleukin 1 ◽  
Pancreatic Beta Cell ◽  
Beta Cell Apoptosis ◽  
Human Beta Cells

miRNAs are a class of small non-coding RNAs that regulate gene expression. Type 1 diabetes is an autoimmune disease characterized by insulitis (islets inflammation) and pancreatic beta cell destruction. The pro-inflammatory cytokines interleukin 1 beta (IL1B) and interferon gamma (IFNG) are released during insulitis and trigger endoplasmic reticulum (ER) stress and expression of pro-apoptotic members of the BCL2 protein family in beta cells, thus contributing to their death. The nature of miRNAs that regulate ER stress and beta cell apoptosis remains to be elucidated. We have performed a global miRNA expression profile on cytokine-treated human islets and observed a marked downregulation of miR-211-5p. By real-time PCR and Western blot analysis, we confirmed cytokine-induced changes in the expression of miR-211-5p and the closely related miR-204-5p and downstream ER stress related genes in human beta cells. Blocking of endogenous miRNA-211-5p and miR-204-5p by the same inhibitor (it is not possible to block separately these two miRs) increased human beta cell apoptosis, as measured by Hoechst/propidium Iodide staining and by determination of cleaved caspase-3 activation. Interestingly, miRs-211-5p and 204-5p regulate the expression of several ER stress markers downstream of PERK, particularly the pro-apoptotic protein DDIT3 (also known as CHOP). Blocking CHOP expression by a specific siRNA partially prevented the increased apoptosis observed following miR-211-5p/miR-204-5p inhibition. These observations identify a novel crosstalk between miRNAs, ER stress and beta cell apoptosis in early type 1 diabetes.

scholarly journals The Secretome of Mesenchymal Stem Cells Prevents Islet Beta Cell Apoptosis via an IL-10-Dependent Mechanism

2020 ◽  
Vol 6 (1) ◽  
pp. 1-12
Author(s):  
Buthainah Al-Azzawi ◽  
Declan H. McGuigan ◽  
Fiona N. Manderson Koivula ◽  
Ajile Elttayef ◽  
Tina P. Dale ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Beta Cell ◽  
Cell Lines ◽  
Cell Apoptosis ◽  
Pancreatic Beta Cell ◽  
Beta Cell Apoptosis ◽  
Islet Beta Cell ◽  
Tnf Α ◽  
Ifn Γ

Background: Type 1 Diabetes Mellitus (T1DM) is partly driven by autoimmune destruction of the pancreatic beta cell, facilitated by the release of inflammatory cytokines, including IFN-γ, TNF-α and IL-1β by cells of the innate immune system. Mesenchymal Stem Cells (MSCs) have been used to counteract autoimmunity in a range of therapeutic settings due to their secretion of trophic and immunomodulatory factors that ameliorate disease independently of the cells themselves. Objective: The aim of this study was to assess the effect of the secretome of human bone-marrow derived MSCs on cytokine-driven beta cell apoptosis. Methods: All experiments were conducted in two insulin-secreting islet cell lines (BRIN-BD11 and βTC1.6) with selected experiments confirmed in primary islets. MSC secretome was generated by conditioning serum-free media (MSC-CM) for 24 hours on sub-confluent MSC populations. The media was then removed and filtered in readiness for use. Results: Exposure to IFN-γ, TNF-α and IL-1β induced apoptosis in cell lines and primary islets. The addition of MSC-CM to cell lines and primary islets partially reversed cytokine-driven apoptosis. MSC-CM also restored glucose-stimulated insulin secretion in cytokine-treated cell lines, which was linked to improved cell viability following from cytokine challenge. Characterization of MSC-CM revealed significant concentrations of IL-4, IL-10, PIGF and VEGF. Of these, IL-10 alone prevented cytokine-driven apoptosis. Furthermore, the inhibition of IL-10 through the addition of a blocking antibody reversed the anti-apoptotic effects of MSC-CM. Conclusion: Overall, the protective effects of MSC-CM on islet beta cell survival appear to be largely IL-10-dependent.

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