scholarly journals Setting the Stage for Islet Autoimmunity in Type 2 Diabetes: Obesity-Associated Chronic Systemic Inflammation and Endoplasmic Reticulum (ER) Stress

Diabetes Care ◽  
2019 ◽  
Vol 42 (12) ◽  
pp. 2338-2346 ◽  
Author(s):  
Barbara M. Brooks-Worrell ◽  
Jerry P. Palmer
Keyword(s):  
Type 2 Diabetes ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Systemic Inflammation ◽  
Islet Autoimmunity

Modulation of palmitate-induced endoplasmic reticulum stress and apoptosis in pancreatic β-cells by stearoyl-CoA desaturase and Elovl6

2011 ◽  
Vol 300 (4) ◽  
pp. E640-E649 ◽  
Author(s):  
Christopher D. Green ◽  
L. Karl Olson
Keyword(s):  
Type 2 Diabetes ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Neutral Lipids ◽  
Saturated Fatty Acids ◽  
Mrna Levels ◽  
Β Cells ◽  
Fatty Acid Elongase ◽  
Stearoyl Coa Desaturase

Induction of endoplasmic reticulum (ER) stress and apoptosis by elevated exogenous saturated fatty acids (FAs) plays a role in the pathogenesis of β-cell dysfunction and loss of islet mass in type 2 diabetes. Regulation of monounsaturated FA (MUFA) synthesis through FA desaturases and elongases may alter the susceptibility of β-cells to saturated FA-induced ER stress and apoptosis. Herein, stearoyl-CoA desaturase (SCD)1 and SCD2 mRNA expression were shown to be induced in islets from prediabetic hyperinsulinemic Zucker diabetic fatty (ZDF) rats, whereas SCD1, SCD2, and fatty acid elongase 6 (Elovl6) mRNA levels were markedly reduced in diabetic ZDF rat islets. Knockdown of SCD in INS-1 β-cells decreased desaturation of palmitate to MUFA, lowered FA partitioning into complex neutral lipids, and increased palmitate-induced ER stress and apoptosis. Overexpression of SCD2 increased desaturation of palmitate to MUFA and attenuated palmitate-induced ER stress and apoptosis. Knockdown of Elovl6 limited palmitate elongation to stearate, increasing palmitoleate production and attenuating palmitate-induced ER stress and apoptosis, whereas overexpression of Elovl6 increased palmitate elongation to stearate and palmitate-induced ER stress and apoptosis. Overall, these data support the hypothesis that enhanced MUFA synthesis via upregulation of SCD2 activity can protect β-cells from elevated saturated FAs, as occurs in prediabetic states. Overt type 2 diabetes is associated with diminished islet expression of SCD and Elovl6, and this can disrupt desaturation of saturated FAs to MUFAs, rendering β-cells more susceptible to saturated FA-induced ER stress and apoptosis.

scholarly journals Functional characterization of thousands of type 2 diabetes-associated and chromatin-modulating variants under steady state and endoplasmic reticulum stress

2020 ◽  
Author(s):  
Shubham Khetan ◽  
Susan Kales ◽  
Romy Kursawe ◽  
Alexandria Jillette ◽  
Steven K. Reilly ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Endoplasmic Reticulum ◽  
Steady State ◽  
Er Stress ◽  
Transcriptional Activity ◽  
Chromatin Accessibility ◽  
Stress Conditions ◽  
Gwas Snps

AbstractA major goal in functional genomics and complex disease genetics is to identify functional cis-regulatory elements (CREs) and single nucleotide polymorphisms (SNPs) altering CRE activity in disease-relevant cell types and environmental conditions. We tested >13,000 sequences containing each allele of 6,628 SNPs associated with altered in vivo chromatin accessibility in human islets and/or type 2 diabetes risk (T2D GWAS SNPs) for transcriptional activity in ß cell under steady state and endoplasmic reticulum (ER) stress conditions using the massively parallel reporter assay (MPRA). Approximately 30% (n=1,983) of putative CREs were active in at least one condition. SNP allelic effects on in vitro MPRA activity strongly correlated with their effects on in vivo islet chromatin accessibility (Pearson r=0.52), i.e., alleles associated with increased chromatin accessibility exhibited higher MPRA activity. Importantly, MPRA identified 220/2500 T2D GWAS SNPs, representing 104 distinct association signals, that significantly altered transcriptional activity in ß cells. This study has thus identified functional ß cell transcription-activating sequences with in vivo relevance, uncovered regulatory features that modulate transcriptional activity in ß cells under steady state and ER stress conditions, and substantially expanded the set of putative functional variants that modulate transcriptional activity in ß cells from thousands of genetically-linked T2D GWAS SNPs.

scholarly journals Altered immunometabolism at the interface of increased endoplasmic reticulum (ER) stress in patients with type 2 diabetes

2015 ◽  
Vol 98 (4) ◽  
pp. 615-622 ◽  
Author(s):  
R. Lenin ◽  
A. Sankaramoorthy ◽  
V. Mohan ◽  
M. Balasubramanyam
Keyword(s):  
Type 2 Diabetes ◽  
Endoplasmic Reticulum ◽  
Er Stress

scholarly journals Interaction between Mitochondria and the Endoplasmic Reticulum: Implications for the Pathogenesis of Type 2 Diabetes Mellitus

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Jaechan Leem ◽  
Eun Hee Koh
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Endoplasmic Reticulum ◽  
Type 2 Diabetes Mellitus ◽  
Er Stress ◽  
Mitochondrial Dysfunction ◽  
Apoptotic Cell ◽  
Peripheral Insulin Resistance ◽  
Type 2 Dm

Mitochondrial dysfunction and endoplasmic reticulum (ER) stress are closely associated withβ-cell dysfunction and peripheral insulin resistance. Thus, each of these factors contributes to the development of type 2 diabetes mellitus (DM). The accumulated evidence reveals structural and functional communications between mitochondria and the ER. It is now well established that ER stress causes apoptotic cell death by disturbing mitochondrial Ca2+homeostasis. In addition, recent studies have shown that mitochondrial dysfunction causes ER stress. In this paper, we summarize the roles that mitochondrial dysfunction and ER stress play in the pathogenesis of type 2 DM. Structural and functional communications between mitochondria and the ER are also discussed. Finally, we focus on recent findings supporting the hypothesis that mitochondrial dysfunction and the subsequent induction of ER stress play important roles in the pathogenesis of type 2 DM.

scholarly journals The Effect of Chronic Inflammation and Oxidative and Endoplasmic Reticulum Stress in the Course of Metabolic Syndrome and Its Therapy

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Michalina Alicka ◽  
Krzysztof Marycz
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Metabolic Syndrome ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Chronic Inflammation ◽  
Therapeutic Approaches ◽  
Cellular Therapies ◽  
Disease Occurrence

Metabolic syndrome (MetS) is highly associated with a modern lifestyle. The prevalence of MetS has reached epidemic proportion and is still rising. The main cause of MetS and finally type 2 diabetes occurrence is excessive nutrient intake, lack of physical activity, and inflammatory cytokines secretion. These factors lead to redistribution of body fat and oxidative and endoplasmic reticulum (ER) stress occurrence, resulting in insulin resistance, increase adipocyte differentiation, and much elevated levels of proinflammatory cytokines. Cellular therapies, especially mesenchymal stem cell (MSC) transplantation, seem to be promising in the MetS and type 2 diabetes treatments, due to their immunomodulatory effect and multipotent capacity; adipose-derived stem cells (ASCs) play a crucial role in MSC-based cellular therapies. In this review, we focused on etiopathology of MetS, especially on the crosstalk between chronic inflammation, oxidative stress, and ER stress and their effect on MetS-related disease occurrence, as well as future perspectives of cellular therapies. We also provide an overview of therapeutic approaches that target endoplasmic reticulum and oxidative stress.

scholarly journals DPP4 inhibitor vildagliptin preserves β-cell mass through amelioration of endoplasmic reticulum stress in C/EBPB transgenic mice

2012 ◽  
Vol 49 (2) ◽  
pp. 125-135 ◽  
Author(s):  
Shinobu Shimizu ◽  
Tetsuya Hosooka ◽  
Tomokazu Matsuda ◽  
Shun-ichiro Asahara ◽  
Maki Koyanagi-Kimura ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Endoplasmic Reticulum ◽  
Serum Concentration ◽  
Er Stress ◽  
Cell Mass ◽  
Protective Effects ◽  
Β Cells ◽  
Β Cell ◽  
Dipeptidyl Peptidase 4

The development of type 2 diabetes is accompanied by a progressive decline in β-cell mass and function. Vildagliptin, a dipeptidyl peptidase 4 inhibitor, is representative of a new class of antidiabetic agents that act through increasing the expression of glucagon-like peptide-1. The protective effect of this agent on β cells was studied in diabetic mice. Diabetic pancreatic β cell-specific C/EBPB transgenic (TG) mice exhibit decreased β-cell mass associated with increased apoptosis, decreased proliferation, and aggravated endoplasmic reticulum (ER) stress. Vildagliptin was orally administered to the TG mice for a period of 24 weeks, and the protective effects of this agent on β cells were examined, along with the potential molecular mechanism of protection. Vildagliptin ameliorated hyperglycemia in TG mice by increasing the serum concentration of insulin and decreasing the serum concentration of glucagon. This agent also markedly increased β-cell mass, improved aggravated ER stress, and restored attenuated insulin/IGF1 signaling. A decrease in pancreatic and duodenal homeobox 1 expression was also observed in β cells isolated from our mouse model, but this was also restored by vildagliptin treatment. The expression of C/EBPB protein, but not mRNA, was unexpectedly downregulated in vildagliptin-treated TG mice and in exenatide-treated MIN6 cells. Activation of the GLP1 pathway induced proteasome-dependent C/EBPB degradation in β cells as the proteasome inhibitor MG132 restored the downregulation of C/EBPB protein by exenatide. Vildagliptin elicits protective effects on pancreatic β cells, possibly through C/EBPB degradation, and has potential for preventing the progression of type 2 diabetes.

scholarly journals Pathological β-Cell Endoplasmic Reticulum Stress in Type 2 Diabetes: Current Evidence

2021 ◽  
Vol 12 ◽  
Author(s):  
Neha Shrestha ◽  
Elisa De Franco ◽  
Peter Arvan ◽  
Miriam Cnop
Keyword(s):  
Type 2 Diabetes ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Protein Misfolding ◽  
Cell Function ◽  
Current Evidence ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells

The notion that in diabetes pancreatic β-cells express endoplasmic reticulum (ER) stress markers indicative of increased unfolded protein response (UPR) signaling is no longer in doubt. However, what remains controversial is whether this increase in ER stress response actually contributes importantly to the β-cell failure of type 2 diabetes (akin to ‘terminal UPR’), or whether it represents a coping mechanism that represents the best attempt of β-cells to adapt to changes in metabolic demands as presented by disease progression. Here an intercontinental group of experts review evidence for the role of ER stress in monogenic and type 2 diabetes in an attempt to reconcile these disparate views. Current evidence implies that pancreatic β-cells require a regulated UPR for their development, function and survival, as well as to maintain cellular homeostasis in response to protein misfolding stress. Prolonged ER stress signaling, however, can be detrimental to β-cells, highlighting the importance of “optimal” UPR for ER homeostasis, β-cell function and survival.

scholarly journals The Mitochondrial Antioxidant SS-31 Modulates Oxidative Stress, Endoplasmic Reticulum Stress, and Autophagy in Type 2 Diabetes

2019 ◽  
Vol 8 (9) ◽  
pp. 1322 ◽  
Author(s):  
Irene Escribano-López ◽  
Aranzazu M de Marañon ◽  
Francesca Iannantuoni ◽  
Sandra López-Domènech ◽  
Zaida Abad-Jiménez ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Type 2 Diabetes ◽  
Endoplasmic Reticulum ◽  
Protein Expression ◽  
Er Stress ◽  
Leukocyte Adhesion ◽  
Calcium Content ◽  
Rolling Velocity

Mitochondrial dysfunction has been shown to play a central role in the pathophysiology of type 2 diabetes (T2D), and mitochondria-targeted agents such as SS-31 are emerging as a promising strategy for its treatment. We aimed to study the effects of SS-31 on leukocytes from T2D patients by evaluating oxidative stress, endoplasmic reticulum (ER) stress and autophagy. Sixty-one T2D patients and 53 controls were included. Anthropometric and analytical measurements were performed. We also assessed reactive oxygen species (ROS) production, calcium content, the expression of ER stress markers GRP78, CHOP, P-eIF2α, and autophagy-related proteins Beclin1, LC3 II/I, and p62 in leukocytes from T2D and control subjects treated or not with SS-31. Furthermore, we have evaluated the action of SS-31 on leukocyte-endothelium interactions. T2D patients exhibited elevated ROS concentration, calcium levels and presence of ER markers (GRP78 and CHOP gene expression, and GRP78 and P-eIF2α protein expression), all of which were reduced by SS-31 treatment. SS-31 also led to a drop in BECN1 gene expression, and Beclin1 and LC3 II/I protein expression in T2D patients. In contrast, the T2D group displayed reduced p62 protein levels that were restored by SS-31. SS-20 (with non-antioxidant activity) did not change any analyzed parameter. In addition, SS-31 decreased rolling flux and leukocyte adhesion, and increased rolling velocity in T2D patients. Our findings suggest that SS-31 exerts potentially beneficial effects on leukocytes of T2D patients modulating oxidative stress and autophagy, and ameliorating ER stress.

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 Par-4/NF-κB Mediates the Apoptosis of IsletβCells Induced by Glucolipotoxicity

2016 ◽  
Vol 2016 ◽  
pp. 1-17 ◽  
Author(s):  
Wu QiNan ◽  
Gan XiaGuang ◽  
Lei XiaoTian ◽  
Deng WuQuan ◽  
Zhang Ling ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Mitochondrial Dysfunction ◽  
High Glucose ◽  
Cell Apoptosis ◽  
Mitochondrial Pathway ◽  
Induced Apoptosis

Apoptosis of isletβcells is a primary pathogenic feature of type 2 diabetes, and ER stress and mitochondrial dysfunction play important roles in this process. Previous research has shown that prostate apoptosis response-4 (Par-4)/NF-κB induces cancer cell apoptosis through endoplasmic reticulum (ER) stress and mitochondrial dysfunction. However, the mechanism by which Par-4/NF-κB induces isletβcell apoptosis remains unknown. We used a high glucose/palmitate intervention to mimic type 2 diabetes in vitro. We demonstrated that the high glucose/palmitate intervention induced the expression and secretion of Par-4. It also causes increased expression and activation of NF-κB, which induced NIT-1 cell apoptosis and dysfunction. Overexpression of Par-4 potentiates these effects, whereas downregulation of Par-4 attenuates them. Inhibition of NF-κB inhibited the Par-4-induced apoptosis. Furthermore, these effects occurred through the ER stress cell membrane and mitochondrial pathway of apoptosis. Our findings reveal a novel role for Par-4/NF-κB in isletβcell apoptosis and type 2 diabetes.

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