Cholecystokinin Attenuates β-Cell Apoptosis in both Mouse and Human Islets

2021 ◽  
Author(s):  
Hung Tae Kim ◽  
Arnaldo H. de Souza ◽  
Heidi Umhoefer ◽  
JeeYoung Han ◽  
Lucille Anzia ◽  
...  
Keyword(s):  
Cell Apoptosis ◽  
Human Islets ◽  
Β Cell

Differential activation of ER stress and apoptosis in response to chronically elevated free fatty acids in pancreatic β-cells

2008 ◽  
Vol 294 (3) ◽  
pp. E540-E550 ◽  
Author(s):  
Elida Lai ◽  
George Bikopoulos ◽  
Michael B. Wheeler ◽  
Maria Rozakis-Adcock ◽  
Allen Volchuk
Keyword(s):  
Er Stress ◽  
Cell Lines ◽  
Cell Apoptosis ◽  
Human Islets ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Min6 Cells ◽  
Relative Contribution ◽  
Induced Apoptosis

Chronic exposure to elevated saturated free fatty acid (FFA) levels has been shown to induce endoplasmic reticulum (ER) stress that may contribute to promoting pancreatic β-cell apoptosis. Here, we compared the effects of FFAs on apoptosis and ER stress in human islets and two pancreatic β-cell lines, rat INS-1 and mouse MIN6 cells. Isolated human islets cultured in vitro underwent apoptosis, and markers of ER stress pathways were elevated by chronic palmitate exposure. Palmitate also induced apoptosis in MIN6 and INS-1 cells, although the former were more resistant to both apoptosis and ER stress. MIN6 cells were found to express significantly higher levels of ER chaperone proteins than INS-1 cells, which likely accounts for the ER stress resistance. We attempted to determine the relative contribution that ER stress plays in palmitate-induced β-cell apoptosis. Although overexpressing GRP78 in INS-1 cells partially reduced susceptibility to thapsigargin, this failed to reduce palmitate-induced ER stress or apoptosis. In INS-1 cells, palmitate induced apoptosis at concentrations that did not result in significant ER stress. Finally, MIN6 cells depleted of GRP78 were more susceptible to tunicamycin-induced apoptosis but not to palmitate-induced apoptosis compared with control cells. These results suggest that ER stress is likely not the main mechanism involved in palmitate-induced apoptosis in β-cell lines. Human islets and MIN6 cells were found to express high levels of stearoyl-CoA desaturase-1 compared with INS-1 cells, which may account for the decreased susceptibility of these cells to the cytotoxic effects of palmitate.

scholarly journals Sulfonylurea Induced β-Cell Apoptosis in Cultured Human Islets

2005 ◽  
Vol 90 (1) ◽  
pp. 501-506 ◽  
Author(s):  
Kathrin Maedler ◽  
Richard D. Carr ◽  
Domenico Bosco ◽  
Richard A. Zuellig ◽  
Thierry Berney ◽  
...  
Keyword(s):  
Cell Apoptosis ◽  
Human Islets ◽  
Β Cell

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.

scholarly journals Activation of Melatonin Signaling Promotes β-Cell Survival and Function

2015 ◽  
Vol 29 (5) ◽  
pp. 682-692 ◽  
Author(s):  
Safia Costes ◽  
Marti Boss ◽  
Anthony P. Thomas ◽  
Aleksey V. Matveyenko
Keyword(s):  
Insulin Secretion ◽  
Cell Survival ◽  
Cell Apoptosis ◽  
Cell Function ◽  
Human Islets ◽  
Β Cell ◽  
Amino Terminal ◽  
Chronic Hyperglycemia ◽  
Β Cell Function ◽  
And Function

Abstract Type 2 diabetes mellitus (T2DM) is characterized by pancreatic islet failure due to loss of β-cell secretory function and mass. Studies have identified a link between a variance in the gene encoding melatonin (MT) receptor 2, T2DM, and impaired insulin secretion. This genetic linkage raises the question whether MT signaling plays a role in regulation of β-cell function and survival in T2DM. To address this postulate, we used INS 832/13 cells to test whether activation of MT signaling attenuates proteotoxicity-induced β-cell apoptosis and through which molecular mechanism. We also used nondiabetic and T2DM human islets to test the potential of MT signaling to attenuate deleterious effects of glucotoxicity and T2DM on β-cell function. MT signaling in β-cells (with duration designed to mimic typical nightly exposure) significantly enhanced activation of the cAMP-dependent signal transduction pathway and attenuated proteotoxicity-induced β-cell apoptosis evidenced by reduced caspase-3 cleavage (∼40%), decreased activation of stress-activated protein kinase/Jun-amino-terminal kinase (∼50%) and diminished oxidative stress response. Activation of MT signaling in human islets was shown to restore glucose-stimulated insulin secretion in islets exposed to chronic hyperglycemia as well as in T2DM islets. Our data suggest that β-cell MT signaling is important for the regulation of β-cell survival and function and implies a preventative and therapeutic potential for preservation of β-cell mass and function in T2DM.

scholarly journals Quantitative Assessment of β-Cell Apoptosis and Cell Composition of Isolated, Undisrupted Human Islets by Laser Scanning Cytometry

2010 ◽  
Vol 90 (8) ◽  
pp. 836-842 ◽  
Author(s):  
Ivan Todorov ◽  
Indu Nair ◽  
Alina Avakian-Mansoorian ◽  
Jeffrey Rawson ◽  
Keiko Omori ◽  
...  
Keyword(s):  
Cell Apoptosis ◽  
Laser Scanning ◽  
Quantitative Assessment ◽  
Human Islets ◽  
Β Cell ◽  
Cell Composition ◽  
Laser Scanning Cytometry

scholarly journals Bromodomain protein inhibition protects β-cells from cytokine-induced death and dysfunction via antagonism of NF-κB pathway

2020 ◽  
Author(s):  
Vinny Negi ◽  
Jeongkyung Lee ◽  
Ruya Liu ◽  
Eliana M. Perez-Garcia ◽  
Feng Li ◽  
...  
Keyword(s):  
Cell Apoptosis ◽  
Cell Function ◽  
Cell Mass ◽  
Human Islets ◽  
Β Cells ◽  
Β Cell ◽  
Bet Inhibitors ◽  
Β Cell Function ◽  
Underlying Mechanisms

ABSTRACTCytokine induced β-cell apoptosis is the major pathogenic mechanism in type 1 diabetes (T1D). Despite significant advances in understanding underlying mechanisms, few drugs have been translated to protect β-cells in T1D. Epigenetic modulators such as bromodomain-containing BET (Bromo- and Extra-Terminal) proteins are important regulators of immune responses. Pre-clinical studies have demonstrated a protective effect of BET inhibitors in NOD (non-obese diabetes) mouse model of T1D. However, the role of BET proteins in β-cell function in response to cytokines is unknown. Here we demonstrate that I-BET, a BET protein inhibitor, protected β-cells from cytokine induced dysfunction and death. In vivo administration of I-BET to mice exposed to low-dose STZ (streptozotocin), a model of T1D, significantly reduced β-cell apoptosis and preserved β-cell mass, suggesting a cytoprotective function of I-BET. Furthermore, human islets treated with I-BET displayed better glucose stimulated insulin secretion compared to controls, when exposed to cytokines. Mechanistically, RNA-Seq analysis revealed I-BET treatment suppressed pathways involved in apoptosis, including NF-kB signaling, while maintaining the expression of genes critical for β-cell function, such as Pdx1 and Ins1. Taken together, this study demonstrates that I-BET is effective in protecting β-cells from cytokine-induced dysfunction and apoptosis, and may have potential therapeutic values in T1D.

scholarly journals Cholecystokinin Suppresses β-Cell Apoptosis, Including in Human Islets in a Transplant Model

2021 ◽  
Author(s):  
Hung Tae Kim ◽  
Arnaldo H. de Souza ◽  
Heidi Umhoefer ◽  
JeeYoung Han ◽  
Lucille Anzia ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cell Survival ◽  
Cell Apoptosis ◽  
Cell Mass ◽  
Human Islets ◽  
Dependent Manner ◽  
Pancreatic Β Cell ◽  
Β Cell

AbstractLoss of functional pancreatic β-cell mass and increased β-cell apoptosis are fundamental to the pathophysiology of both type 1 and type 2 diabetes. Pancreatic islet transplantation has the potential to cure type 1 diabetes but is often ineffective due to the death of the islet graft within the first few years after transplant. Therapeutic strategies to directly target pancreatic β-cell survival are needed to prevent and treat diabetes and to improve islet transplant outcomes. Reducing β-cell apoptosis is also a therapeutic strategy for type 2 diabetes. Cholecystokinin (CCK) is a peptide hormone typically produced in the gut after food intake, with positive effects on obesity and glucose metabolism in mouse models and human subjects. We have previously shown that pancreatic islets also produce CCK. The production of CCK within the islet promotes β-cell survival in rodent models of diabetes and aging. Now, we demonstrate a direct effect of CCK to reduce cytokine-mediated apoptosis in a β-cell line and in isolated mouse islets in a receptor-dependent manner. However, whether CCK can protect human β-cells was previously unknown. Here, we report that CCK can also reduce cytokine-mediated apoptosis in isolated human islets and CCK treatment in vivo decreases β-cell apoptosis in human islets transplanted into the kidney capsule of diabetic NOD/SCID mice. Collectively, these data identify CCK as a novel therapy that can directly promote β-cell survival in human islets and has therapeutic potential to preserve β-cell mass in diabetes and as an adjunct therapy after transplant.One Sentence SummaryCholecystokinin ameliorates pancreatic β-cell death under models of stress and after transplant of human islets.

scholarly journals PDX1LOW MAFALOW β-cells contribute to islet function and insulin release

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Daniela Nasteska ◽  
Nicholas H. F. Fine ◽  
Fiona B. Ashford ◽  
Federica Cuozzo ◽  
Katrina Viloria ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Release ◽  
Metabolic Stress ◽  
Human Islets ◽  
Islet Function ◽  
Β Cells ◽  
Β Cell ◽  
Ionic Fluxes ◽  
Transcriptomic Level ◽  
Adult Islet

AbstractTranscriptionally mature and immature β-cells co-exist within the adult islet. How such diversity contributes to insulin release remains poorly understood. Here we show that subtle differences in β-cell maturity, defined using PDX1 and MAFA expression, contribute to islet operation. Functional mapping of rodent and human islets containing proportionally more PDX1HIGH and MAFAHIGH β-cells reveals defects in metabolism, ionic fluxes and insulin secretion. At the transcriptomic level, the presence of increased numbers of PDX1HIGH and MAFAHIGH β-cells leads to dysregulation of gene pathways involved in metabolic processes. Using a chemogenetic disruption strategy, differences in PDX1 and MAFA expression are shown to depend on islet Ca2+ signaling patterns. During metabolic stress, islet function can be restored by redressing the balance between PDX1 and MAFA levels across the β-cell population. Thus, preserving heterogeneity in PDX1 and MAFA expression, and more widely in β-cell maturity, might be important for the maintenance of islet function.

Dihydroartemisinin prevents palmitate-induced β-cell apoptosis

APOPTOSIS ◽  
2021 ◽  
Author(s):  
Zhiyong Wang ◽  
·Yan Hao ◽  
·Haibing Yu ◽  
Pei Wei
Keyword(s):  
Cell Apoptosis ◽  
Β Cell
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