Fructus Corni suppresses hepatic gluconeogenesis related gene transcription, enhances glucose responsiveness of pancreatic beta-cells, and prevents toxin induced beta-cell death

2008 ◽  
Vol 117 (3) ◽  
pp. 483-490 ◽  
Author(s):  
Chien-Chih Chen ◽  
Chia-Yun Hsu ◽  
Chin-Ying Chen ◽  
Hui-Kang Liu
Keyword(s):  
Cell Death ◽  
Beta Cell ◽  
Beta Cells ◽  
Gene Transcription ◽  
Pancreatic Beta Cells ◽  
Related Gene ◽  
Hepatic Gluconeogenesis ◽  
Beta Cell Death ◽  
Glucose Responsiveness

Role of pancreatic beta-cells in the process of beta-cell death

Diabetes ◽  
2001 ◽  
Vol 50 (Supplement 1) ◽  
pp. S52-S57 ◽  
Author(s):  
D. Pipeleers ◽  
A. Hoorens ◽  
M. Marchial-Pipeleers ◽  
M. Van de Casteele ◽  
L. Bouwens ◽  
...  
Keyword(s):  
Cell Death ◽  
Beta Cell ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Beta Cell Death

scholarly journals Prevention of Oxidative Stress-Induced Pancreatic Beta Cell Damage by Broussonetia kazinoki Siebold Fruit Extract via the ERK-Nox4 Pathway

Antioxidants ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 406 ◽  
Author(s):  
Hyo-Jin Kim ◽  
Donghee Kim ◽  
Haelim Yoon ◽  
Cheol Soo Choi ◽  
Yoon Sin Oh ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Beta Cell ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Cell Damage ◽  
Beta Cell Death ◽  
Min6 Cells ◽  
Erk Phosphorylation ◽  
Beta Cell Damage

Pancreatic beta cells are vulnerable to oxidative stress, which causes beta cell death and dysfunction in diabetes mellitus. Broussonetia kazinoki Siebold (BK) is a widely used herbal medicine, but its potential effects against beta cell death-induced diabetes have not been studied. Therefore, we investigated the protective effect of an ethanolic extract of BK fruit (BKFE) against streptozotocin (STZ)-induced toxicity in pancreatic beta cells. Intraperitoneal injection of STZ in mice induced hyperglycemia; however, oral administration of BKFE significantly decreased the blood glucose level as well as HbA1c levels. BKFE treatment improved glucose tolerance and increased body weight in diabetic mice. Moreover, BKFE treatment resulted in increased serum insulin levels and insulin expression in the pancreas as well as decreased 4-hydroxynonenal levels induced by oxidative stress. Treatment with STZ decreased cell viability of mouse insulinoma cells (MIN6), which was blocked by BKFE pretreatment. BKFE significantly inhibited apoptotic cells and decreased the expression levels of cleaved-caspase-3 and cleaved-poly (ADP-ribose) polymerase (PARP) induced by STZ treatment. Production of reactive oxygen species in STZ-treated MIN6 cells was also significantly decreased by treatment with BKFE. Erk phosphorylation and Nox4 levels increased in STZ-treated MIN6 cells and the pancreas of mice injected with STZ and this increase was inhibited by treatment with BKFE. Inhibition of Erk phosphorylation by treatment with the PD98059 inhibitor or siRNA Erk also blocked the expression of Nox4 induced by STZ treatment. In conclusion, BKFE inhibits Erk phosphorylation, which in turn prevents STZ-induced oxidative stress and beta cell apoptosis. These results suggested that BKFE can be used to prevent or treat beta cell damage in diabetes.

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 The microRNA Landscape of Acute Beta Cell Destruction in Type 1 Diabetic Recipients of Intraportal Islet Grafts

2021 ◽  
Author(s):  
Geert Antoine Martens ◽  
Geert Stange ◽  
Lorenzo Piemonti ◽  
Jasper Anckaert ◽  
Zhidong Ling ◽  
...  
Keyword(s):  
Cell Death ◽  
Beta Cell ◽  
Beta Cells ◽  
Islet Transplantation ◽  
Beta Cell Death ◽  
Beta Cell Destruction ◽  
Cell Destruction ◽  
Graft Outcome ◽  
Plasma Microrna

Ongoing beta cell death in type 1 diabetes (T1D) can be detected using biomarkers selectively discharged by dying beta cells into plasma. MicroRNA-375 (miR-375) ranks among top biomarkers based on studies in animal models and human islet transplantation. Our objective was to identify additional microRNAs that are co-released with miR-375 proportionate to the amount of beta cell destruction. RT-PCR profiling of 733 microRNAs in a discovery cohort of T1D patients 1 hour before/after islet transplantation indicated increased plasma levels of 22 microRNAs. Sub-selection for beta cell selectivity resulted in 15 microRNAs that were subjected to double-blinded multicenter analysis. This led to identification of 8 microRNAs that were consistently increased during early graft destruction: besides miR-375, these included miR-132/204/410/200a/429/125b, microRNAs with known function and enrichment in beta cells. Their potential clinical translation was investigated in a third independent cohort of 46 transplant patients, by correlating post-transplant microRNA levels to C-peptide levels 2 months later. Only miR-375 and miR-132 had prognostic potential for graft outcome and none of the newly identified microRNAs outperformed miR-375 in multiple regression. In conclusion, this study reveals multiple beta cell-enriched microRNAs that are co-released with miR-375 and can be used as complementary biomarkers of beta cell death.

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.

In vitro profiling of endocrine cell death using UCHL1 and GAD65 as soluble biomarkers

2016 ◽  
Author(s):  
Benedicte Brackeva ◽  
Sarah Roels ◽  
Geert Stangé ◽  
Gamze Ates ◽  
Olivier R. Costa ◽  
...  
Keyword(s):  
Cell Death ◽  
Beta Cell ◽  
Beta Cells ◽  
Islet Transplantation ◽  
High Sensitivity ◽  
Low Grade ◽  
Variable Degree ◽  
Beta Cell Death

AbstractBACKGROUNDPancreatic islet grafts are cultured in vitro prior to transplantation and this is associated to a variable degree of beta cell loss. Optimization of culture conditions is currently hampered by the lack of a specific and sensitive in vitro indicator of beta cell death.METHODSWe developed a high-sensitivity duplex bead-based immunoassay for two protein-type biomarkers of beta cell destruction, GAD65 and UCHL1, and investigated its proficiency for in vitro toxicity profiling on rodent and human beta cells, as compared to a semi-automatic and manual image-based assessment of beta cell death, and in vivo after intraportal islet transplantation.RESULTSBoth GAD65 and UCHL1 were discharged by necrotic and apoptotic beta cells proportionate to the number of dead beta cells as counted by microscopic methods. In vitro, UCHL1 was superior to GAD65, in terms of biomarker stability providing more sensitive detection of low grade beta cell death. In vivo, however, GAD65 was consistently detected after islet transplantation while UCHL1 remained undetectable.CONCLUSIONThe use of soluble biomarkers represents a fast, selective and sensitive method for beta cell toxicity profiling in vitro. UCHL1 is superior to GAD65 in vitro but not in vivo.

scholarly journals Prolactin protects against cytokine-induced beta-cell death by NFκB and JNK inhibition

2018 ◽  
Vol 61 (1) ◽  
pp. 25-36 ◽  
Author(s):  
Tarlliza R Nardelli ◽  
Emerielle C Vanzela ◽  
Keli C Benedicto ◽  
Flora Brozzi ◽  
André Fujita ◽  
...  
Keyword(s):  
Cell Death ◽  
Beta Cell ◽  
Beta Cells ◽  
Target Genes ◽  
Interleukin 1 ◽  
Beta Cell Proliferation ◽  
No Production ◽  
Protective Effects ◽  
Beta Cell Death ◽  
Autoimmune Attack

Type 1 diabetes is caused by an autoimmune assault that induces progressive beta-cell dysfunction and dead. Pro-inflammatory cytokines, such as interleukin 1 beta (IL1B), tumor necrosis factor (TNF) and interferon gamma (IFNG) contribute for beta-cell death, which involves the activation of the nuclear factor kappa B (NFκB) and c- Jun N-terminal kinase (JNK). Prolactin (PRL), a physiological mediator for beta-cell proliferation, was shown to protect beta cells against cytokines pro-apoptotic effects. We presently investigated the mechanisms involved in the protective effects of prolactin against cytokine-induced beta-cell death. The findings obtained indicate that STAT3 activation is involved in the anti-apoptotic role of PRL in rat beta cells. PRL prevents the activation of JNK via AKT and promotes a shift from expression of pro- to anti-apoptotic proteins downstream of the JNK cascade. Furthermore, PRL partially prevents the activation of NFκB and the transcription of its target genes IkBa, Fas, Mcp1, A20 and Cxcl10 and also decreases NO production. On the other hand, the pro-survival effects of PRL do not involve modulation of cytokine-induced endoplasmic reticulum stress. These results suggest that the beneficial effects of PRL in beta cells involve augmentation of anti-apoptotic mechanisms and, at the same time, reduction of pro-apoptotic effectors, rendering beta cells better prepared to deal with inflammatory insults. The better understanding of the pro-survival mechanisms modulated by PRL in beta cells can provide tools to prevent cell demise during an autoimmune attack or following islet transplantation.

Sign in / Sign up

Export Citation Format

Share Document