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Unfolded protein response, islet cell

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https://www.readbyqxmd.com/read/28424159/prolonged-elimination-of-negative-feedback-control-mechanisms-along-the-insulin-signalling-pathway-impairs-%C3%AE-cell-function-in-vivo
#1
Roi Isaac, Yaron Vinik, Sigalit Boura-Halfon, Lydia Farack, Sarina Streim, Eytan Elhanany, Zvi Kam, Yehiel Zick
Cellular stress and pro-inflammatory cytokines induce phosphorylation of insulin receptor substrate (IRS) proteins at Ser sites that inhibit insulin and IGF-1 signalling. We therefore examined the effects of mutation of five 'inhibitory' Ser phosphorylation sites on IRS2 function in transgenic mice that overexpress, selectively in pancreatic β cells, either wild-type (WT) or a mutated IRS2 protein (IRS2(5A)). Islets size, number, and mRNA levels of catalase and superoxide dismutase, were increased, while those of nitric oxide synthase were decreased in 7-10 weeks old IRS2(5A)-β mice compared to IRS2(WT)-β mice...
April 19, 2017: Diabetes
https://www.readbyqxmd.com/read/28321016/4%C3%AE-8c-inhibits-insulin-secretion-independent-of-ire1%C3%AE-rnase-activity
#2
Hitomi Sato, Yoko Shiba, Yuichi Tsuchiya, Michiko Saito, Kenji Kohno
IRE1α plays an important role in the unfolded protein response (UPR), which is activated by the accumulation of unfolded proteins in the endoplasmic reticulum. 4μ8C, a well-known inhibitor of IRE1α RNase activity, is commonly used to analyze IRE1α function during ER stress in cultured mammalian cells. However, the off-target effects of 4μ8C remain elusive. Pancreatic β-cells synthesize a large amount of insulin in response to high glucose stimulation, and IRE1α plays an important role in insulin secretion from pancreatic β-cells...
March 18, 2017: Cell Structure and Function
https://www.readbyqxmd.com/read/28252345/evidence-of-stress-in-%C3%AE-cells-obtained-with-laser-capture-microdissection-from-pancreases-of-brain-dead-donors
#3
Aref Ebrahimi, Min-Ho Jung, Jonathan M Dreyfuss, Hui Pan, Dennis Sgroi, Susan Bonner-Weir, Gordon C Weir
Isolated islets used for transplantation are known to be stressed, which can result from the circumstances of death, in particular brain death, the preservation of the pancreas with its warm and cold ischemia, from the trauma of the isolation process, and the complex events that occur during tissue culture. The current study focused upon the events that occur before the islet isolation procedure. Pancreases were obtained from brain dead donors (n = 7) with mean age 50 (11) and normal pancreatic tissue obtained at surgery done for pancreatic neoplasms (n = 7), mean age 69 (9)...
March 4, 2017: Islets
https://www.readbyqxmd.com/read/27757583/ciclopirox-enhances-pancreatic-islet-health-by-modulating-the-unfolded-protein-response-in-diabetes
#4
Chrysovalantou Mihailidou, Ioulia Chatzistamou, Athanasios G Papavassiliou, Hippokratis Kiaris
Pancreatic dysfunction during diabetes is linked to the induction of endoplasmic reticulum (ER) stress on pancreatic beta (β) cells. Our laboratory recently discovered that p21 protects from diabetes by modifying the outcome of ER stress response. In the present study, we explored the antidiabetic activity of ciclopirox (CPX), an iron chelator and recently described activator of p21 expression. The effects of CPX in beta cell survival and function were assessed in cultured islets in vitro as well as in diabetic mice in vivo...
November 2016: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/27740623/tm7sf3-a-novel-p53-regulated-homeostatic-factor-attenuates-cellular-stress-and-the-subsequent-induction-of-the-unfolded-protein-response
#5
Roi Isaac, Ido Goldstein, Noa Furth, Neta Zilber, Sarina Streim, Sigalit Boura-Halfon, Eytan Elhanany, Varda Rotter, Moshe Oren, Yehiel Zick
Earlier reported small interfering RNA (siRNA) high-throughput screens, identified seven-transmembrane superfamily member 3 (TM7SF3) as a novel inhibitor of pancreatic β-cell death. Here we show that TM7SF3 maintains protein homeostasis and promotes cell survival through attenuation of ER stress. Overexpression of TM7SF3 inhibits caspase 3/7 activation. In contrast, siRNA-mediated silencing of TM7SF3 accelerates ER stress and activation of the unfolded protein response (UPR). This involves inhibitory phosphorylation of eukaryotic translation initiation factor 2α activity and increased expression of activating transcription factor-3 (ATF3), ATF4 and C/EBP homologous protein, followed by induction of apoptosis...
January 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/27613867/peroxisome-proliferator-activated-receptor-%C3%AE-activation-augments-the-%C3%AE-cell-unfolded-protein-response-and-rescues-early-glycemic-deterioration-and-%C3%AE-cell-death-in-non-obese-diabetic-mice
#6
Aarthi V Maganti, Sarah A Tersey, Farooq Syed, Jennifer B Nelson, Stephanie C Colvin, Bernhard Maier, Raghavendra G Mirmira
Type 1 diabetes is an autoimmune disorder that is characterized by a failure of the unfolded protein response in islet β cells with subsequent endoplasmic reticulum stress and cellular death. Thiazolidinediones are insulin sensitizers that activate the nuclear receptor PPAR-γ and have been shown to partially ameliorate autoimmune type 1 diabetes in humans and non-obese diabetic (NOD) mice. We hypothesized that thiazolidinediones reduce β cell stress and death independently of insulin sensitivity. To test this hypothesis, female NOD mice were administered pioglitazone during the pre-diabetic phase and assessed for insulin sensitivity and β cell function relative to controls...
October 21, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27587006/mechanisms-of-islet-damage-mediated-by-pancreas-cold-ischemia-rewarming
#7
Keiko Omori, Eiji Kobayashi, Jeffrey Rawson, Masafumi Takahashi, Yoko Mullen
Prolonged pancreas cold ischemia is known to negatively correlate with islet isolation outcomes, hindering successful islet transplantation to treat Type-1 Diabetes. Due to poor islet isolation outcome, pancreata with over 16 h cold ischemia are currently not considered for islet transplantation. Mechanisms involved in pancreas cold ischemia/rewarming mediated islet damage during islet isolation and culture are not well understood. Using an en bloc cold preserved rat pancreas preparation, we attempted to clarify possible mechanisms of islet death associated with prolonged pancreas cold ischemia and subsequent rewarming...
October 2016: Cryobiology
https://www.readbyqxmd.com/read/27580811/gene-expression-in-mouse-thyrotrope-adenoma-transcription-elongation-factor-stimulates-proliferation
#8
Peter Gergics, Helen C Christian, Monica S Choo, Adnan Ajmal, Sally A Camper
Thyrotrope hyperplasia and hypertrophy are common responses to primary hypothyroidism. To understand the genetic regulation of these processes, we studied gene expression changes in the pituitaries of Cga(-/-) mice, which are deficient in the common α-subunit of TSH, LH, and FSH. These mice have thyrotrope hypertrophy and hyperplasia and develop thyrotrope adenoma. We report that cell proliferation is increased, but the expression of most stem cell markers is unchanged. The α-subunit is required for secretion of the glycoprotein hormone β-subunits, and mutants exhibit elevated expression of many genes involved in the unfolded protein response, consistent with dilation and stress of the endoplasmic reticulum...
September 2016: Endocrinology
https://www.readbyqxmd.com/read/27505441/discovery-synthesis-and-evaluation-of-2-4-diaminoquinazolines-as-a-novel-class-of-pancreatic-%C3%AE-cell-protective-agents-against-endoplasmic-reticulum-er-stress
#9
Hongliang Duan, Jae Wook Lee, Sung Won Moon, Daleep Arora, Yu Li, Hui-Ying Lim, Weidong Wang
Pancreatic insulin-producing β-cell dysfunction and death plays central roles in the onset and progression of both type 1 and type 2 diabetes. Current antidiabetic drugs cannot halt the ongoing progression of β-cell dysfunction and death. In diabetes, a major cause for the decline in β-cell function and survival is endoplasmic reticulum (ER) stress. Here, we identified quinazoline derivatives as a novel class of β-cell protective agents against ER stress-induced dysfunction and death. A series of quinazoline derivatives were synthesized from dichloroquiazoline utilizing a sequence of nucleophilic reactions...
September 8, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27425895/unconventional-neurotrophic-factors-cdnf-and-manf-structure-physiological-functions-and-therapeutic-potential
#10
REVIEW
Maria Lindahl, Mart Saarma, Päivi Lindholm
Cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF) promote the survival of midbrain dopaminergic neurons which degenerate in Parkinson's disease (PD). However, CDNF and MANF are structurally and functionally clearly distinct from the classical, target-derived neurotrophic factors (NTFs) that are solely secreted proteins. In cells, CDNF and MANF localize in the endoplasmic reticulum (ER) and evidence suggests that MANF, and possibly CDNF, is important for the maintenance of ER homeostasis...
January 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/27384111/mir-204-targets-perk-and-regulates-upr-signaling-and-%C3%AE-cell-apoptosis
#11
Guanlan Xu, Junqin Chen, Gu Jing, Truman B Grayson, Anath Shalev
Endoplasmic reticulum (ER) stress plays an important role in the pathogenesis of diabetes and the associated β-cell apoptosis. Although microRNAs (miRNAs) have been widely studied in various diseases including diabetes, the role of miRNAs in ER stress and β-cell apoptosis has only started to be elucidated. We recently showed that diabetes increases β-cell miR-204 and have now discovered that miR-204 directly targets the 3'untranslated region of protein kinase R-like ER kinase (PERK), 1 of the 3 ER transmembrane sensors and a key factor of the unfolded protein response (UPR)...
August 2016: Molecular Endocrinology
https://www.readbyqxmd.com/read/27222391/a-reevaluation-of-the-role-of-the-unfolded-protein-response-in-islet-dysfunction-maladaptation-or-a-failure-to-adapt
#12
Terence P Herbert, D Ross Laybutt
Endoplasmic reticulum (ER) stress caused by perturbations in ER homeostasis activates an adaptive response termed the unfolded protein response (UPR) whose function is to resolve ER stress. If unsuccessful, the UPR initiates a proapoptotic program to eliminate the malfunctioning cells from the organism. It is the activation of this proapoptotic UPR in pancreatic β-cells that has been implicated in the onset of type 2 diabetes and thus, in this context, is considered a maladaptive response. However, there is growing evidence that β-cell death in type 2 diabetes may not be caused by a maladaptive UPR but by the inhibition of the adaptive UPR...
June 2016: Diabetes
https://www.readbyqxmd.com/read/27146479/the-role-of-er-stress-in-lipid-metabolism-and-lipotoxicity
#13
Jaeseok Han, Randal J Kaufman
The endoplasmic reticulum (ER) is a cellular organelle important for regulating calcium homeostasis, lipid metabolism, protein synthesis, and posttranslational modification and trafficking. Numerous environmental, physiological, and pathological insults disturb ER homeostasis, referred to as ER stress, in which a collection of conserved intracellular signaling pathways, termed the unfolded protein response (UPR), are activated to maintain ER function for cell survival. However, excessive and/or prolonged UPR activation leads to initiation of self-destruction through apoptosis...
August 2016: Journal of Lipid Research
https://www.readbyqxmd.com/read/27117420/kat2b-is-required-for-pancreatic-beta-cell-adaptation-to-metabolic-stress-by-controlling-the-unfolded-protein-response
#14
Nabil Rabhi, Pierre-Damien Denechaud, Xavier Gromada, Sarah Anissa Hannou, Hongbo Zhang, Talha Rashid, Elisabet Salas, Emmanuelle Durand, Olivier Sand, Amélie Bonnefond, Loic Yengo, Carine Chavey, Caroline Bonner, Julie Kerr-Conte, Amar Abderrahmani, Johan Auwerx, Lluis Fajas, Philippe Froguel, Jean-Sébastien Annicotte
The endoplasmic reticulum (ER) unfolded protein response (UPR(er)) pathway plays an important role in helping pancreatic β cells to adapt their cellular responses to environmental cues and metabolic stress. Although altered UPR(er) gene expression appears in rodent and human type 2 diabetic (T2D) islets, the underlying molecular mechanisms remain unknown. We show here that germline and β cell-specific disruption of the lysine acetyltransferase 2B (Kat2b) gene in mice leads to impaired insulin secretion and glucose intolerance...
May 3, 2016: Cell Reports
https://www.readbyqxmd.com/read/27067637/endoplasmic-reticulum-stress-and-the-unfolded-protein-response-in-pancreatic-islet-inflammation
#15
REVIEW
Kira Meyerovich, Fernanda Ortis, Florent Allagnat, Alessandra K Cardozo
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...
July 2016: Journal of Molecular Endocrinology
https://www.readbyqxmd.com/read/27044747/ubiquitin-d-regulates-ire1%C3%AE-c-jun-n-terminal-kinase-jnk-protein-dependent-apoptosis-in-pancreatic-beta-cells
#16
Flora Brozzi, Sarah Gerlo, Fabio Arturo Grieco, Matilda Juusola, Alexander Balhuizen, Sam Lievens, Conny Gysemans, Marco Bugliani, Chantal Mathieu, Piero Marchetti, Jan Tavernier, Décio L Eizirik
Pro-inflammatory cytokines contribute to pancreatic beta cell apoptosis in type 1 diabetes at least in part by inducing endoplasmic reticulum (ER) stress and the consequent unfolded protein response (UPR). It remains to be determined what causes the transition from "physiological" to "apoptotic" UPR, but accumulating evidence indicates that signaling by the ER transmembrane protein IRE1α is critical for this transition. IRE1α activation is regulated by both intra-ER and cytosolic cues. We evaluated the role for the presently discovered cytokine-induced and IRE1α-interacting protein ubiquitin D (UBD) on the regulation of IRE1α and its downstream targets...
June 3, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27039902/hypoxia-reduces-er-to-golgi-protein-trafficking-and-increases-cell-death-by-inhibiting-the-adaptive-unfolded-protein-response-in-mouse-beta-cells
#17
Mohammed Bensellam, Emma L Maxwell, Jeng Yie Chan, Jude Luzuriaga, Phillip K West, Jean-Christophe Jonas, Jenny E Gunton, D Ross Laybutt
AIMS/HYPOTHESIS: Hypoxia may contribute to beta cell failure in type 2 diabetes and islet transplantation. The adaptive unfolded protein response (UPR) is required for endoplasmic reticulum (ER) homeostasis. Here we investigated whether or not hypoxia regulates the UPR in beta cells and the role the adaptive UPR plays during hypoxic stress. METHODS: Mouse islets and MIN6 cells were exposed to various oxygen (O2) tensions. DNA-damage inducible transcript 3 (DDIT3), hypoxia-inducible transcription factor (HIF)1α and HSPA5 were knocked down using small interfering (si)RNA; Hspa5 was also overexpressed...
July 2016: Diabetologia
https://www.readbyqxmd.com/read/26998692/genetic-predisposition-for-beta-cell-fragility-underlies-type-1-and-type-2-diabetes
#18
James Dooley, Lei Tian, Susann Schonefeldt, Viviane Delghingaro-Augusto, Josselyn E Garcia-Perez, Emanuela Pasciuto, Daniele Di Marino, Edward J Carr, Nikolay Oskolkov, Valeriya Lyssenko, Dean Franckaert, Vasiliki Lagou, Lut Overbergh, Jonathan Vandenbussche, Joke Allemeersch, Genevieve Chabot-Roy, Jane E Dahlstrom, D Ross Laybutt, Nikolai Petrovsky, Luis Socha, Kris Gevaert, Anton M Jetten, Diether Lambrechts, Michelle A Linterman, Chris C Goodnow, Christopher J Nolan, Sylvie Lesage, Susan M Schlenner, Adrian Liston
Type 1 (T1D) and type 2 (T2D) diabetes share pathophysiological characteristics, yet mechanistic links have remained elusive. T1D results from autoimmune destruction of pancreatic beta cells, whereas beta cell failure in T2D is delayed and progressive. Here we find a new genetic component of diabetes susceptibility in T1D non-obese diabetic (NOD) mice, identifying immune-independent beta cell fragility. Genetic variation in Xrcc4 and Glis3 alters the response of NOD beta cells to unfolded protein stress, enhancing the apoptotic and senescent fates...
May 2016: Nature Genetics
https://www.readbyqxmd.com/read/26786350/endoplasmic-reticulum-associated-degradation-of-the-mouse-pc1-3-n222d-hypomorph-and-human-pcsk1-mutations-contributes-to-obesity
#19
P Stijnen, B Brouwers, E Dirkx, B Ramos-Molina, L Van Lommel, F Schuit, L Thorrez, J Declercq, J W M Creemers
BACKGROUND: The proprotein convertase 1/3 (PC1/3), encoded by proprotein convertase subtilisin/kexin type 1 (PCSK1), cleaves and hence activates several orexigenic and anorexigenic proproteins. Congenital inactivation of PCSK1 leads to obesity in human but not in mice. However, a mouse model harboring the hypomorphic mutation N222D is obese. It is not clear why the mouse models differ in phenotype. METHODS: Gene expression analysis was performed with pancreatic islets from Pcsk1(N222D/N222D) mice...
June 2016: International Journal of Obesity: Journal of the International Association for the Study of Obesity
https://www.readbyqxmd.com/read/26636105/molecular-structure-membrane-interactions-and-toxicity-of-the-islet-amyloid-polypeptide-in-type-2-diabetes-mellitus
#20
REVIEW
Lucie Caillon, Anais R F Hoffmann, Alexandra Botz, Lucie Khemtemourian
Human islet amyloid polypeptide (hIAPP) is the major component of the amyloid deposits found in the pancreatic islets of patients with type 2 diabetes mellitus (T2DM). Mature hIAPP, a 37-aa peptide, is natively unfolded in its monomeric state but forms islet amyloid in T2DM. In common with other misfolded and aggregated proteins, amyloid formation involves aggregation of monomers of hIAPP into oligomers, fibrils, and ultimately mature amyloid deposits. hIAPP is coproduced and stored with insulin by the pancreatic islet β-cells and is released in response to the stimuli that lead to insulin secretion...
2016: Journal of Diabetes Research
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