scholarly journals The Endoplasmic Reticulum and Calcium Homeostasis in Pancreatic Beta Cells

Endocrinology ◽  
2019 ◽  
Vol 161 (2) ◽  
Author(s):  
Irina X Zhang ◽  
Malini Raghavan ◽  
Leslie S Satin
Keyword(s):  
Type 2 Diabetes ◽  
Endoplasmic Reticulum ◽  
Type 1 Diabetes ◽  
Beta Cell ◽  
Er Stress ◽  
Beta Cells ◽  
Unfolded Protein ◽  
Protein Response

Abstract The endoplasmic reticulum (ER) mediates the first steps of protein assembly within the secretory pathway and is the site where protein folding and quality control are initiated. The storage and release of Ca2+ are critical physiological functions of the ER. Disrupted ER homeostasis activates the unfolded protein response (UPR), a pathway which attempts to restore cellular equilibrium in the face of ER stress. Unremitting ER stress, and insufficient compensation for it results in beta-cell apoptosis, a process that has been linked to both type 1 diabetes (T1D) and type 2 diabetes (T2D). Both types are characterized by progressive beta-cell failure and a loss of beta-cell mass, although the underlying causes are different. The reduction of mass occurs secondary to apoptosis in the case of T2D, while beta cells undergo autoimmune destruction in T1D. In this review, we examine recent findings that link the UPR pathway and ER Ca2+ to beta cell dysfunction. We also discuss how UPR activation in beta cells favors cell survival versus apoptosis and death, and how ER protein chaperones are involved in regulating ER Ca2+ levels. Abbreviations: BiP, Binding immunoglobulin Protein ER; endoplasmic reticulum; ERAD, ER-associated protein degradation; IFN, interferon; IL, interleukin; JNK, c-Jun N-terminal kinase; KHE, proton-K+ exchanger; MODY, maturity-onset diabetes of young; PERK, PRKR-like ER kinase; SERCA, Sarco/Endoplasmic Reticulum Ca2+-ATPases; T1D, type 1 diabetes; T2D, type 2 diabetes; TNF, tumor necrosis factor; UPR, unfolded protein response; WRS, Wolcott–Rallison syndrome.

scholarly journals Endoplasmic Reticulum-Mitochondria Crosstalk and Beta-Cell Destruction in Type 1 Diabetes

2021 ◽  
Vol 12 ◽  
Author(s):  
Saurabh Vig ◽  
Joost M. Lambooij ◽  
Arnaud Zaldumbide ◽  
Bruno Guigas
Keyword(s):  
Endoplasmic Reticulum ◽  
Type 1 Diabetes ◽  
Beta Cell ◽  
Beta Cells ◽  
Beta Cell Destruction ◽  
Unfolded Protein ◽  
Cell Destruction ◽  
The Unfolded Protein Response ◽  
And Function

Beta-cell destruction in type 1 diabetes (T1D) results from the combined effect of inflammation and recurrent autoimmunity. In response to inflammatory signals, beta-cells engage adaptive mechanisms where the endoplasmic reticulum (ER) and mitochondria act in concert to restore cellular homeostasis. In the recent years it has become clear that this adaptive phase may trigger the development of autoimmunity by the generation of autoantigens recognized by autoreactive CD8 T cells. The participation of the ER stress and the unfolded protein response to the increased visibility of beta-cells to the immune system has been largely described. However, the role of the other cellular organelles, and in particular the mitochondria that are central mediator for beta-cell survival and function, remains poorly investigated. In this review we will dissect the crosstalk between the ER and mitochondria in the context of T1D, highlighting the key role played by this interaction in beta-cell dysfunctions and immune activation, especially through regulation of calcium homeostasis, oxidative stress and generation of mitochondrial-derived factors.

scholarly journals Stearoyl CoA desaturase is a gatekeeper that protects human beta cells against lipotoxicity and maintains their identity

Diabetologia ◽  
2019 ◽  
Vol 63 (2) ◽  
pp. 395-409 ◽  
Author(s):  
Masaya Oshima ◽  
Séverine Pechberty ◽  
Lara Bellini ◽  
Sven O. Göpel ◽  
Mélanie Campana ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Beta Cell ◽  
Beta Cells ◽  
Cell Identity ◽  
Human Beta Cells ◽  
Human Beta Cell ◽  
Stearoyl Coa Desaturase

Abstract Aims/hypothesis During the onset of type 2 diabetes, excessive dietary intake of saturated NEFA and fructose lead to impaired insulin production and secretion by insulin-producing pancreatic beta cells. The majority of data on the deleterious effects of lipids on functional beta cell mass were obtained either in vivo in rodent models or in vitro using rodent islets and beta cell lines. Translating data from rodent to human beta cells remains challenging. Here, we used the human beta cell line EndoC-βH1 and analysed its sensitivity to a lipotoxic and glucolipotoxic (high palmitate with or without high glucose) insult, as a way to model human beta cells in a type 2 diabetes environment. Methods EndoC-βH1 cells were exposed to palmitate after knockdown of genes related to saturated NEFA metabolism. We analysed whether and how palmitate induces apoptosis, stress and inflammation and modulates beta cell identity. Results EndoC-βH1 cells were insensitive to the deleterious effects of saturated NEFA (palmitate and stearate) unless stearoyl CoA desaturase (SCD) was silenced. SCD was abundantly expressed in EndoC-βH1 cells, as well as in human islets and human induced pluripotent stem cell-derived beta cells. SCD silencing induced markers of inflammation and endoplasmic reticulum stress and also IAPP mRNA. Treatment with the SCD products oleate or palmitoleate reversed inflammation and endoplasmic reticulum stress. Upon SCD knockdown, palmitate induced expression of dedifferentiation markers such as SOX9, MYC and HES1. Interestingly, SCD knockdown by itself disrupted beta cell identity with a decrease in mature beta cell markers INS, MAFA and SLC30A8 and decreased insulin content and glucose-stimulated insulin secretion. Conclusions/interpretation The present study delineates an important role for SCD in the protection against lipotoxicity and in the maintenance of human beta cell identity. Data availability Microarray data and all experimental details that support the findings of this study have been deposited in in the GEO database with the GSE130208 accession code.

scholarly journals Endoplasmic Reticulum Stress in theβ-Cell Pathogenesis of Type 2 Diabetes

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Sung Hoon Back ◽  
Sang-Wook Kang ◽  
Jaeseok Han ◽  
Hun-Taeg Chung
Keyword(s):  
Type 2 Diabetes ◽  
Er Stress ◽  
Clinical Evidence ◽  
High Blood Glucose ◽  
Unfolded Protein ◽  
Cell Dysfunction ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Metabolic Stresses

Type 2 diabetes is a complex metabolic disorder characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency byβ-cell failure. Even if the mechanisms underlying the pathogenesis ofβ-cell failure are still under investigation, recent increasing genetic, experimental, and clinical evidence indicate that hyperactivation of the unfolded protein response (UPR) to counteract metabolic stresses is closely related toβ-cell dysfunction and apoptosis. Signaling pathways of the UPR are “a double-edged sword” that can promote adaptation or apoptosis depending on the nature of the ER stress condition. In this paper, we summarized our current understanding of the mechanisms and components related to ER stress in theβ-cell pathogenesis of type 2 diabetes.

scholarly journals Beta Cell Autophagy in the Pathogenesis of Type 1 Diabetes

2021 ◽  
Author(s):  
Charanya Muralidharan ◽  
Amelia K Linnemann
Keyword(s):  
Type 1 Diabetes ◽  
Beta Cell ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Potential Role ◽  
Cell Dysfunction ◽  
Unconventional Secretion ◽  
Insulin Dependent

Type 1 diabetes is an insulin-dependent, autoimmune disease where the pancreatic beta cells are destroyed resulting in hyperglycemia. This multi-factorial disease involves multiple environmental and genetic factors, and has no clear etiology. Accumulating evidence suggests that early signaling defects within the beta cells may promote a change in the local immune mileu, contributing to autoimmunity. Therefore, many studies have been focused on intrinsic beta cell mechanisms that aid in restoration of cellular homeostasis under environmental conditions that cause dysfunction. One of these intrinsic mechanisms to promote homeostasis is autophagy, defects in which are clearly linked with beta cell dysfunction in the context of type 2 diabetes. Recent studies have now also pointed towards beta cell autophagy defects in the context of type 1 diabetes. In this perspectives review, we will discuss the evidence supporting a role for beta cell autophagy in the pathogenesis of type 1 diabetes, including a potential role for unconventional secretion of autophagosomes/lysosomes in the changing dialogue between the beta cell and immune cells.

scholarly journals ER stress increases store-operated Ca2+ entry (SOCE) and augments basal insulin secretion in pancreatic beta cells

2020 ◽  
Vol 295 (17) ◽  
pp. 5685-5700
Author(s):  
Irina X. Zhang ◽  
Jianhua Ren ◽  
Suryakiran Vadrevu ◽  
Malini Raghavan ◽  
Leslie S. Satin
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Beta Cell ◽  
Er Stress ◽  
Beta Cells ◽  
Beta Cell Function ◽  
Cell Function ◽  
Critical Role ◽  
Beta Cell Apoptosis

Type 2 diabetes mellitus (T2DM) is characterized by impaired glucose-stimulated insulin secretion and increased peripheral insulin resistance. Unremitting endoplasmic reticulum (ER) stress can lead to beta-cell apoptosis and has been linked to type 2 diabetes. Although many studies have attempted to link ER stress and T2DM, the specific effects of ER stress on beta-cell function remain incompletely understood. To determine the interrelationship between ER stress and beta-cell function, here we treated insulin-secreting INS-1(832/13) cells or isolated mouse islets with the ER stress–inducer tunicamycin (TM). TM induced ER stress as expected, as evidenced by activation of the unfolded protein response. Beta cells treated with TM also exhibited concomitant alterations in their electrical activity and cytosolic free Ca2+ oscillations. As ER stress is known to reduce ER Ca2+ levels, we tested the hypothesis that the observed increase in Ca2+ oscillations occurred because of reduced ER Ca2+ levels and, in turn, increased store-operated Ca2+ entry. TM-induced cytosolic Ca2+ and membrane electrical oscillations were acutely inhibited by YM58483, which blocks store-operated Ca2+ channels. Significantly, TM-treated cells secreted increased insulin under conditions normally associated with only minimal release, e.g. 5 mm glucose, and YM58483 blocked this secretion. Taken together, these results support a critical role for ER Ca2+ depletion–activated Ca2+ current in mediating Ca2+-induced insulin secretion in response to ER stress.

scholarly journals Next steps in the identification of gene targets for type 1 diabetes

Diabetologia ◽  
2020 ◽  
Vol 63 (11) ◽  
pp. 2260-2269 ◽  
Author(s):  
Struan F. A. Grant ◽  
Andrew D. Wells ◽  
Stephen S. Rich
Keyword(s):  
Type 2 Diabetes ◽  
Type 1 Diabetes ◽  
Beta Cell ◽  
Genetic Risk ◽  
Genetic Risk Score ◽  
Cell Types ◽  
Total Risk ◽  
Chromosome Conformation

Abstract The purpose of this review is to provide a view of the future of genomics and other omics approaches in defining the genetic contribution to all stages of risk of type 1 diabetes and the functional impact and clinical implementations of the associated variants. From the recognition nearly 50 years ago that genetics (in the form of HLA) distinguishes risk of type 1 diabetes from type 2 diabetes, advances in technology and sample acquisition through collaboration have identified over 60 loci harbouring SNPs associated with type 1 diabetes risk. Coupled with HLA region genes, these variants account for the majority of the genetic risk (~50% of the total risk); however, relatively few variants are located in coding regions of genes exerting a predicted protein change. The vast majority of genetic risk in type 1 diabetes appears to be attributed to regions of the genome involved in gene regulation, but the target effectors of those genetic variants are not readily identifiable. Although past genetic studies clearly implicated immune-relevant cell types involved in risk, the target organ (the beta cell) was left untouched. Through emergent technologies, using combinations of genetics, gene expression, epigenetics, chromosome conformation and gene editing, novel landscapes of how SNPs regulate genes have emerged. Furthermore, both the immune system and the beta cell and their biological pathways have been implicated in a context-specific manner. The use of variants from immune and beta cell studies distinguish type 1 diabetes from type 2 diabetes and, when they are combined in a genetic risk score, open new avenues for prediction and treatment.

scholarly journals The type 1 diabetes at-risk allele at rs3842753 associates with increased beta cell INS mRNA in a meta-analysis of single cell RNA sequencing data

2020 ◽  
Author(s):  
Su Wang ◽  
Stephane Flibotte ◽  
Joan Camunas-Soler ◽  
Patrick E. MacDonald ◽  
James D. Johnson
Keyword(s):  
Gene Expression ◽  
At Risk ◽  
Type 1 Diabetes ◽  
Er Stress ◽  
Single Cell ◽  
Beta Cells ◽  
Risk Allele ◽  
Β Cells

ABSTRACTType 1 diabetes is characterized by the autoimmune destruction of insulin secreting beta-cells. Genetic variations upstream at the insulin (INS) locus contribute to ~10% of type 1 diabetes heritable risk. Multiple studies showed an association between rs3842753 C/C genotype and type 1 diabetes susceptibility. Three small studies have reported an association between the rs3842753 C allele and increased whole pancreas INS expression. To date, no large-scale studies have looked at the effect of those genetic variations on insulin expression at the single cell level. We aligned all human islet single cell RNA sequencing datasets available to us in 2020 to the reference genome GRCh38.98 and genotyped rs3842753. We integrated 2315 beta-cells from 13 A/A donors, 23 A/C heterozygous donors, and 35 C/C at-risk donors. The donors included adults without diabetes and with type 2 diabetes. INS expression mean and variance were significantly higher in single β cells from females compared with males. Comparing across all β cells, we found that rs3842753 C containing cells (either homozygous or heterozygous) had the highest INS expression. We also found that β cells with the rs3842753 C allele had significantly higher ER stress marker gene expression compared to the A/A homozygous genotype. These findings support the emerging concept that inherited risk of type 1 diabetes may be associated with elevated insulin production at the mRNA level which may lead to β cell ER stress and fragility.KEY MESSAGESThe type 1 diabetes at risk allele at rs3842753 is associated with increased INS gene expression and ER stress in single human beta-cells.Single beta-cells from female donors and donors with type 2 diabetes exhibit a wider range of INS gene expression.

scholarly journals The miRNAs miR-211-5p and miR-204-5p modulate ER stress in human beta cells

2019 ◽  
Vol 63 (2) ◽  
pp. 139-149 ◽  
Author(s):  
Fabio Arturo Grieco ◽  
Andrea Alex Schiavo ◽  
Flora Brozzi ◽  
Jonas Juan-Mateu ◽  
Marco Bugliani ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Beta Cell ◽  
Er Stress ◽  
Beta Cells ◽  
Cell Apoptosis ◽  
Interleukin 1 ◽  
Pancreatic Beta Cell ◽  
Beta Cell Apoptosis ◽  
Human Beta Cells

miRNAs are a class of small non-coding RNAs that regulate gene expression. Type 1 diabetes is an autoimmune disease characterized by insulitis (islets inflammation) and pancreatic beta cell destruction. The pro-inflammatory cytokines interleukin 1 beta (IL1B) and interferon gamma (IFNG) are released during insulitis and trigger endoplasmic reticulum (ER) stress and expression of pro-apoptotic members of the BCL2 protein family in beta cells, thus contributing to their death. The nature of miRNAs that regulate ER stress and beta cell apoptosis remains to be elucidated. We have performed a global miRNA expression profile on cytokine-treated human islets and observed a marked downregulation of miR-211-5p. By real-time PCR and Western blot analysis, we confirmed cytokine-induced changes in the expression of miR-211-5p and the closely related miR-204-5p and downstream ER stress related genes in human beta cells. Blocking of endogenous miRNA-211-5p and miR-204-5p by the same inhibitor (it is not possible to block separately these two miRs) increased human beta cell apoptosis, as measured by Hoechst/propidium Iodide staining and by determination of cleaved caspase-3 activation. Interestingly, miRs-211-5p and 204-5p regulate the expression of several ER stress markers downstream of PERK, particularly the pro-apoptotic protein DDIT3 (also known as CHOP). Blocking CHOP expression by a specific siRNA partially prevented the increased apoptosis observed following miR-211-5p/miR-204-5p inhibition. These observations identify a novel crosstalk between miRNAs, ER stress and beta cell apoptosis in early type 1 diabetes.

scholarly journals The Role of Endoplasmic Reticulum Stress in Autoimmune-Mediated Beta-Cell Destruction in Type 1 Diabetes

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Jixin Zhong ◽  
Xiaoquan Rao ◽  
Jun-Fa Xu ◽  
Ping Yang ◽  
Cong-Yi Wang
Keyword(s):  
Endoplasmic Reticulum ◽  
Type 1 Diabetes ◽  
Er Stress ◽  
Autoimmune Response ◽  
Potential Implication ◽  
Beta Cell Destruction ◽  
Cell Destruction

Unlike type 2 diabetes which is caused by the loss of insulin sensitivity, type 1 diabetes (T1D) is manifested by the absolute deficiency of insulin secretion due to the loss ofβmass by autoimmune response againstβ-cell self-antigens. Although significant advancement has been made in understanding the pathoetiology for type 1 diabetes, the exact mechanisms underlying autoimmune-mediatedβ-cell destruction, however, are yet to be fully addressed. Accumulated evidence demonstrates that endoplasmic reticulum (ER) stress plays an essential role in autoimmune-mediatedβ-cell destruction. There is also evidence supporting that ER stress regulates the functionality of immune cells relevant to autoimmune progression during T1D development. In this paper, we intend to address the role of ER stress in autoimmune-mediatedβ-cell destruction during the course of type 1 diabetes. The potential implication of ER stress in modulating autoimmune response will be also discussed. We will further dissect the possible pathways implicated in the induction of ER stress and summarize the potential mechanisms underlying ER stress for mediation ofβ-cell destruction. A better understanding of the role for ER stress in T1D pathoetiology would have great potential aimed at developing effective therapeutic approaches for the prevention/intervention of this devastating disorder.

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