Calcium Efflux From the Endoplasmic Reticulum Leads to β-Cell Death

Hara, Takashi; Mahadevan, Jana; Kanekura, Kohsuke; Hara, Mariko; Lu, Simin; Urano, Fumihiko

doi:10.1210/en.2013-1519

Cited by 130 publications

(133 citation statements)

References 42 publications

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“…Pioglitazone was recently shown to reduce ER stress in Wfs1-deficient mice (Yamada et al 2006), a genetic model for ER stress-mediated β-cell loss and diabetes, thus almost preventing the onset of diabetes in those mice (Akiyama et al 2009). Pioglitazone also protects rat insulin-secreting cells from thapsigargin-induced cell death (Hara et al 2014). Similarly, Metformin partially protects INS-1 cells from palmitate-induced ER stress and cell death (Simon-Szabo et al 2014).…”

Section: Existing Treatments Of T2d That Reduce Er Stressmentioning

confidence: 99%

Endoplasmic reticulum stress and the unfolded protein response in pancreatic islet inflammation

Meyerovich

Ortis

Allagnat

et al. 2016

Journal of Molecular Endocrinology

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Insulin-secreting pancreatic β-cells are extremely dependent on their endoplasmic reticulum (ER) to cope with the oscillatory requirement of secreted insulin to maintain normoglycemia. Insulin translation and folding rely greatly on the unfolded protein response (UPR), an array of three main signaling pathways designed to maintain ER homeostasis and limit ER stress. However, prolonged or excessive UPR activation triggers alternative molecular pathways that can lead to β-cell dysfunction and apoptosis. An increasing number of studies suggest a role of these pro-apoptotic UPR pathways in the downfall of β-cells observed in diabetic patients. Particularly, the past few years highlighted a cross talk between the UPR and inflammation in the context of both type 1 (T1D) and type 2 diabetes (T2D). In this article, we describe the recent advances in research regarding the interplay between ER stress, the UPR, and inflammation in the context of β-cell apoptosis leading to diabetes.

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Section: Existing Treatments Of T2d That Reduce Er Stressmentioning

confidence: 99%

Endoplasmic reticulum stress and the unfolded protein response in pancreatic islet inflammation

Meyerovich

Ortis

Allagnat

et al. 2016

Journal of Molecular Endocrinology

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“…An impaired ER stress-response phenotype has been shown in human WFS1 b-cells differentiated from patient-derived pluripotent stem cells that, on exposure to ER stress, show impaired insulin processing and GSIS (Shang et al 2014). Another important consequence of ER stress is the depletion of ER Ca 2C , which results in increased protein misfolding and has been proposed as a UPR-independent trigger for the calpain-2-mediated apoptosis pathway in response to glucolipotoxicity and oxidative and ER stress (Hara et al 2014). An ER membrane sarco(endo)plasmic reticulum ATPase (SERCA) is responsible for maintaining high concentrations of Ca 2C in the ER.…”

Section: Disturbed B-cell Er Homeostasis Causes Diabetesmentioning

confidence: 99%

Oxidative and endoplasmic reticulum stress in β-cell dysfunction in diabetes

Hasnain¹,

Prins²,

McGuckin³

2015

Journal of Molecular Endocrinology

216

167

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The inability of pancreatic b-cells to make sufficient insulin to control blood sugar is a central feature of the aetiology of most forms of diabetes. In this review we focus on the deleterious effects of oxidative stress and endoplasmic reticulum (ER) stress on b-cell insulin biosynthesis and secretion and on inflammatory signalling and apoptosis with a particular emphasis on type 2 diabetes (T2D). We argue that oxidative stress and ER stress are closely entwined phenomena fundamentally involved in b-cell dysfunction by direct effects on insulin biosynthesis and due to consequences of the ER stress-induced unfolded protein response. We summarise evidence that, although these phenomenon can be driven by intrinsic b-cell defects in rare forms of diabetes, in T2D b-cell stress is driven by a range of local environmental factors including increased drivers of insulin biosynthesis, glucolipotoxicity and inflammatory cytokines. We describe our recent findings that a range of inflammatory cytokines contribute to b-cell stress in diabetes and our discovery that interleukin 22 protects b-cells from oxidative stress regardless of the environmental triggers and can correct much of diabetes pathophysiology in animal models. Finally we summarise evidence that b-cell dysfunction is reversible in T2D and discuss therapeutic opportunities for relieving oxidative and ER stress and restoring glycaemic control.

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“…WFS1, the other causative gene for Wolfram syndrome, has been shown to be involved in calcium homeostasis (27,28), suggesting that the loss of function of WFS1 may also cause calpain activation. To evaluate this possibility, we measured calpain activation levels in brain tissues from WFS1 brain-specific knockout and control mice.…”

Section: Significancementioning

confidence: 99%

“…6A). GLP-1, pioglitazone, and rapamycin are FDA-approved drugs and have been shown to confer protection against ER stress-mediated cell death (27,(31)(32)(33). Dantrolene is another FDA-approved drug clinically used for muscle spasticity and malignant hyperthermia (34).…”

Section: Significancementioning

confidence: 99%

A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome

Kanekura

Hara

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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133

164

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Wolfram syndrome is a genetic disorder characterized by diabetes and neurodegeneration and considered as an endoplasmic reticulum (ER) disease. Despite the underlying importance of ER dysfunction in Wolfram syndrome and the identification of two causative genes, Wolfram syndrome 1 (WFS1) and Wolfram syndrome 2 (WFS2), a molecular mechanism linking the ER to death of neurons and β cells has not been elucidated. Here we implicate calpain 2 in the mechanism of cell death in Wolfram syndrome. Calpain 2 is negatively regulated by WFS2, and elevated activation of calpain 2 by WFS2-knockdown correlates with cell death. Calpain activation is also induced by high cytosolic calcium mediated by the loss of function of WFS1. Calpain hyperactivation is observed in the WFS1 knockout mouse as well as in neural progenitor cells derived from induced pluripotent stem (iPS) cells of Wolfram syndrome patients. A small-scale small-molecule screen targeting ER calcium homeostasis reveals that dantrolene can prevent cell death in neural progenitor cells derived from Wolfram syndrome iPS cells. Our results demonstrate that calpain and the pathway leading its activation provides potential therapeutic targets for Wolfram syndrome and other ER diseases.Wolfram syndrome | endoplasmic reticulum | diabetes | neurodegeneration | treatment

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Calcium Efflux From the Endoplasmic Reticulum Leads to β-Cell Death

Cited by 130 publications

References 42 publications

Endoplasmic reticulum stress and the unfolded protein response in pancreatic islet inflammation

Endoplasmic reticulum stress and the unfolded protein response in pancreatic islet inflammation

Oxidative and endoplasmic reticulum stress in β-cell dysfunction in diabetes

A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome

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