scholarly journals The Class I Histone Deacetylase Inhibitor MS-275 Prevents Pancreatic Beta Cell Death Induced by Palmitate

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Valérie Plaisance ◽  
Laure Rolland ◽  
Valéry Gmyr ◽  
Jean-Sébastien Annicotte ◽  
Julie Kerr-Conte ◽  
...  
Keyword(s):  
Cell Death ◽  
Beta Cell ◽  
Er Stress ◽  
Beta Cells ◽  
Pancreatic Beta Cell ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Activating Transcription Factor 3 ◽  
Beta Cell Death ◽  
Stress Markers

Elevation of the dietary saturated fatty acid palmitate contributes to the reduction of functional beta cell mass in the pathogenesis of type 2 diabetes. The diabetogenic effect of palmitate is achieved by increasing beta cell death through induction of the endoplasmic reticulum (ER) stress markers including activating transcription factor 3 (Atf3) and CAAT/enhancer-binding protein homologous protein-10 (Chop). In this study, we investigated whether treatment of beta cells with the MS-275, a HDAC1 and HDAC3 activity inhibitor which prevents beta cell death elicited by cytokines, is beneficial for combating beta cell dysfunction caused by palmitate. We show that culture of isolated human islets and MIN6 cells with MS-275 reduced apoptosis evoked by palmitate. The protective effect of MS-275 was associated with the attenuation of the expression of Atf3 and Chop. Silencing of HDAC3, but not of HDAC1, mimicked the effects of MS-275 on the expression of the two ER stress markers and apoptosis. These data point to HDAC3 as a potential drug target for preserving beta cells against lipotoxicity in diabetes.

Phenylpropenoic acid glucoside augments pancreatic beta cell mass in high-fat diet-fed mice and protects beta cells from ER stress-induced apoptosis

2014 ◽  
Vol 58 (10) ◽  
pp. 1980-1990 ◽  
Author(s):  
Iris Mathijs ◽  
Daniel A. Da Cunha ◽  
Eddy Himpe ◽  
Laurence Ladriere ◽  
Nireshni Chellan ◽  
...  
Keyword(s):  
Beta Cell ◽  
Er Stress ◽  
Beta Cells ◽  
High Fat Diet ◽  
Pancreatic Beta Cell ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
High Fat ◽  
Induced Apoptosis ◽  
Pancreatic Beta Cell Mass

scholarly journals Update on the Protective Molecular Pathways Improving Pancreatic Beta-Cell Dysfunction

2013 ◽  
Vol 2013 ◽  
pp. 1-14 ◽  
Author(s):  
Alessandra Puddu ◽  
Roberta Sanguineti ◽  
François Mach ◽  
Franco Dallegri ◽  
Giorgio Luciano Viviani ◽  
...  
Keyword(s):  
Beta Cell ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Cell Function ◽  
Pancreatic Beta Cell ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Beta Cell Dysfunction ◽  
Molecular Pathways ◽  
Cell Dysfunction

The primary function of pancreatic beta-cells is to produce and release insulin in response to increment in extracellular glucose concentrations, thus maintaining glucose homeostasis. Deficient beta-cell function can have profound metabolic consequences, leading to the development of hyperglycemia and, ultimately, diabetes mellitus. Therefore, strategies targeting the maintenance of the normal function and protecting pancreatic beta-cells from injury or death might be crucial in the treatment of diabetes. This narrative review will update evidence from the recently identified molecular regulators preserving beta-cell mass and function recovery in order to suggest potential therapeutic targets against diabetes. This review will also highlight the relevance for novel molecular pathways potentially improving beta-cell dysfunction.

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 Glucolipotoxicity-induced Mig6 desensitizes EGFR signaling and promotes pancreatic beta cell death

2020 ◽  
Author(s):  
Yi-Chun Chen ◽  
Andrew J. Lutkewitte ◽  
Halesha D. Basavarajappa ◽  
Patrick T. Fueger
Keyword(s):  
Cell Death ◽  
Growth Factor ◽  
Beta Cell ◽  
Cell Survival ◽  
Beta Cells ◽  
Cell Mass ◽  
Signaling Cascades ◽  
Egfr Signaling ◽  
Mitogenic Signaling ◽  
Beta Cell Death

ABSTRACTA loss of functional beta cell mass is a final etiological event in the development of frank type 2 diabetes (T2D). To preserve or expand beta cells and therefore treat/prevent T2D, growth factors have been considered therapeutically but have largely failed to achieve robust clinical success. The molecular mechanisms preventing the activation of mitogenic signaling pathways from maintaining functional beta cell mass during the development of T2D remain unknown. We speculated that endogenous negative effectors of mitogenic signaling cascades impede beta cell survival/expansion. Thus, we tested the hypothesis that a stress-inducible epidermal growth factor receptor (EGFR) inhibitor, Mitogen-inducible gene 6 (Mig6), regulates beta cell fate in a T2D milieu. To this end, we determined that: 1) glucolipotoxicity (GLT) induces Mig6, thereby blunting EGFR signaling cascades, and 2) Mig6 mediates molecular events regulating beta cell survival/death. We discovered that GLT impairs EGFR activation, and Mig6 is elevated in human islets from T2D donors as well as GLT-treated rodent islets and 832/13 INS-1 beta cells. Mig6 is essential for GLT-induced EGFR desensitization, as Mig6 suppression rescued the GLT-impaired EGFR and ERK1/2 activation. Further, Mig6 mediated EGFR but not insulin-like growth factor-1 receptor nor hepatocyte growth factor receptor activity in beta cells. Finally, we identified that elevated Mig6 augmented beta cell apoptosis, as Mig6 suppression reduced apoptosis during GLT. In conclusion, we established that T2D and GLT induce Mig6 in pancreatic beta cells. The elevated Mig6 desensitizes EGFR signaling and induces beta cell death. Our findings suggest that Mig6 could be a novel therapeutic target for T2D, as blocking Mig6 could possibly enhance mitogenic signaling cascades in a diabetic milieu to promote beta cell survival and prevent beta cell death.

scholarly journals MicroRNA-24 promotes pancreatic beta cells toward dedifferentiation to avoid endoplasmic reticulum stress-induced apoptosis

2019 ◽  
Vol 11 (9) ◽  
pp. 747-760 ◽  
Author(s):  
Yunxia Zhu ◽  
Yi Sun ◽  
Yuncai Zhou ◽  
Yan Zhang ◽  
Tao Zhang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Beta Cell ◽  
Er Stress ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Stress Conditions ◽  
Beta Cell Apoptosis ◽  
Induced Apoptosis

AbstractCurrent research indicates that beta cell loss in type 2 diabetes may be attributed to beta cell dedifferentiation rather than apoptosis; however, the mechanisms by which this occurs remain poorly understood. Our previous study demonstrated that elevation of microRNA-24 (miR-24) in a diabetic setting caused beta cell dysfunction and replicative deficiency. In this study, we focused on the role of miR-24 in beta cell apoptosis and dedifferentiation under endoplasmic reticulum (ER) stress conditions. We found that miR-24 overabundance protected beta cells from thapsigargin-induced apoptosis at the cost of accelerating the impairment of glucose-stimulated insulin secretion (GSIS) and enhancing the presence of dedifferentiation markers. Ingenuity® Pathway Analysis (IPA) revealed that elevation of miR-24 had an inhibitory effect on XBP1 and ATF4, which are downstream effectors of two key branches of ER stress, by inhibiting its direct target, Ire1α. Notably, elevated miR-24 initiated another pathway that targeted Mafa and decreased GSIS function in surviving beta cells, thus guiding their dedifferentiation under ER stress conditions. Our results demonstrated that the elevated miR-24, to the utmost extent, preserves beta cell mass by inhibiting apoptosis and inducing dedifferentiation. This study not only provides a novel mechanism by which miR-24 dominates beta cell turnover under persistent metabolic stress but also offers a therapeutic consideration for treating diabetes by inducing dedifferentiated beta cells to re-differentiation.

TRAIL induces proliferation in rodent pancreatic beta cells via AKT activation

2021 ◽  
Author(s):  
Sevim Kahraman ◽  
Ozlem Yilmaz ◽  
Hasan Ali Altunbas ◽  
Ercument Dirice ◽  
Ahter Dilsad Sanlioglu
Keyword(s):  
Beta Cell ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Pancreatic Beta Cell ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Min6 Cells ◽  
Akt Activation ◽  
Proliferative Effect ◽  
Beta Cell Line

Strategies to increase functional pancreatic beta cell mass is of great interest in diabetes-related research. TNF-related apoptosis-inducing ligand (TRAIL) is well-known to promote proliferation and survival in various cell types, including vascular smooth muscle and endothelial cells. Correlation between the protective nature of TRAIL on these cells and its proliferative effect is noteworthy. TRAIL’s seemingly protective/therapeutic effect in diabetes prompted us to question whether it may act as an inducer of proliferation in pancreatic beta cells. We used rat primary islet cells and MIN6 mouse beta cell line to investigate TRAIL-induced proliferation. Cell viability and/or death was analysed by MTT, WST-1, and annexin-V/PI assays, while proliferation rates and pathways were assessed via immunocytochemical and Western blot analyses. Receptor neutralization antibodies identified the mediator receptors. Recombinant soluble TRAIL (sTRAIL) treatment led to 1.6-fold increased proliferation in insulin-positive cells in dispersed rat islets compared to the untreated group, while adenovirus-mediated overexpression of TRAIL increased the number of proliferating beta cells up to more than 6-fold. sTRAIL or adenoviral vector-mediated TRAIL overexpression induced proliferation in MIN6 cells also. TRAIL’s proliferative effect was mediated via AKT activation, which was suppressed upon specific inhibition. Neutralization of each TRAIL receptor reversed the proliferative effect to some degree, with the highest level of inhibition in death receptor 5 (DR5) blockage in MIN6 cells, and in decoy receptor 1 (DcR1) blockage in primary rat beta cells. Thus, TRAIL induces proliferation in rodent pancreatic beta cells through activation of the AKT pathway.

Regulation of Pancreatic Beta-Cell Mass

2005 ◽  
Vol 85 (4) ◽  
pp. 1255-1270 ◽  
Author(s):  
Luc Bouwens ◽  
Ilse Rooman
Keyword(s):  
Beta Cell ◽  
Progenitor Cells ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Tissue Injury ◽  
Pancreatic Beta Cell ◽  
Cell Mass ◽  
Beta Cell Mass ◽  
Cell Number ◽  
External Stimuli

Beta-cell mass regulation represents a critical issue for understanding diabetes, a disease characterized by a near-absolute (type 1) or relative (type 2) deficiency in the number of pancreatic beta cells. The number of islet beta cells present at birth is mainly generated by the proliferation and differentiation of pancreatic progenitor cells, a process called neogenesis. Shortly after birth, beta-cell neogenesis stops and a small proportion of cycling beta cells can still expand the cell number to compensate for increased insulin demands, albeit at a slow rate. The low capacity for self-replication in the adult is too limited to result in a significant regeneration following extensive tissue injury. Likewise, chronically increased metabolic demands can lead to beta-cell failure to compensate. Neogenesis from progenitor cells inside or outside islets represents a more potent mechanism leading to robust expansion of the beta-cell mass, but it may require external stimuli. For therapeutic purposes, advantage could be taken from the surprising differentiation plasticity of adult pancreatic cells and possibly also from stem cells. Recent studies have demonstrated that it is feasible to regenerate and expand the beta-cell mass by the application of hormones and growth factors like glucagon-like peptide-1, gastrin, epidermal growth factor, and others. Treatment with these external stimuli can restore a functional beta-cell mass in diabetic animals, but further studies are required before it can be applied to humans.

scholarly journals A Model for Human Islet Transplantation to Immunodeficient Streptozotocin-Induced Diabetic Mice

2018 ◽  
Vol 27 (11) ◽  
pp. 1684-1691 ◽  
Author(s):  
Elisabet Estil·les ◽  
Noèlia Téllez ◽  
Montserrat Nacher ◽  
Eduard Montanya
Keyword(s):  
Cell Death ◽  
Beta Cell ◽  
Beta Cells ◽  
Islet Transplantation ◽  
Cell Mass ◽  
Human Islet ◽  
Diabetic Mice ◽  
Beta Cell Death ◽  
Human Beta Cells ◽  
Human Islet Transplantation

Streptozotocin (STZ) is a cytotoxic glucose analogue that causes beta cell death and is widely used to induce experimental diabetes in rodents. The sensitivity of beta cells to STZ is species-specific and human beta cells are resistant to STZ. In experimental islet transplantation to rodents, STZ-diabetes must be induced before transplantation to avoid destruction of grafted islets by STZ. In human islet transplantation, injection of STZ before transplantation is inconvenient and costly, since human islet availability depends on organ donation and frail STZ-diabetic mice must be kept for unpredictable lapses of time until a human islet preparation is available. Based on the high resistance of human beta cells to STZ, we have tested a new model for STZ-diabetes induction in which STZ is injected after human islet transplantation. Human and mouse islets were transplanted under the kidney capsule of athymic nude mice, and 10–14 days after transplantation mice were intraperitoneally injected with five consecutive daily doses of STZ or vehicle. Beta-cell death increased and beta-cell mass was reduced in mouse islet grafts after STZ injection. In contrast, in human islet grafts beta cell death and mass did not change after STZ injection. Mice transplanted with rodent islets developed hyperglycemia after STZ-injection. Mice transplanted with human islets remained normoglycemic and developed hyperglycemia when the graft was harvested. STZ had no detectable toxic effects on beta cell death, mass and function of human transplanted islets. We provide a new, more convenient and cost-saving model for human islet transplantation to STZ-diabetic recipients in which STZ is injected after islet transplantation.

scholarly journals The Protective Role of Calbindin-D9k on Endoplasmic Reticulum Stress-Induced Beta Cell Death

2019 ◽  
Vol 20 (21) ◽  
pp. 5317
Author(s):  
Changhwan Ahn ◽  
Eui-Man Jung ◽  
Beum-Soo An ◽  
Eui-Ju Hong ◽  
Yeong-Min Yoo ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Beta Cell ◽  
Er Stress ◽  
Cell Survival ◽  
Pancreatic Beta Cell ◽  
Beta Cell Death ◽  
Calbindin D9k ◽  
Islet Volume

Intracellular calcium ion content is tightly regulated for the maintenance of cellular functions and cell survival. Calbindin-D9k (CaBP-9k) is responsible for regulating the distribution of cytosolic free-calcium ions. In this study, we aimed to investigate the effect of CaBP-9k on cell survival in pancreatic beta cells. Six-month-old wildtype CaBP-9k, CaBP-28k, and CaBP-9k/28k knockout (KO) mice were used to compare the pathological phenotypes of calcium-binding protein-deleted mice. Subsequently, the endoplasmic reticulum (ER) stress reducer tauroursodeoxycholic acid (TUDCA) was administered to wildtype and CaBP-9k KO mice. In vitro assessment of the role of CaBP-9k was performed following CaBP-9k overexpression and treatment with the ER stress inducer thapsigargin. Six-month-old CaBP-9k KO mice showed reduced islet volume and up-regulation of cell death markers resulting from ER stress, which led to pancreatic beta cell death. TUDCA treatment recovered islet volume, serum insulin level, and abdominal fat storage by CaBP-9k ablation. CaBP-9k overexpression elevated insulin secretion and recovered thapsigargin-induced ER stress in the INS-1E cell line. The results of this study show that CaBP-9k can protect pancreatic beta cell survival from ER stress and contribute to glucose homeostasis, which can reduce the risk of type 1 diabetes and provide the molecular basis for calcium supplementation to diabetic patients.

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