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 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 Lipotoxicity and β-Cell Failure in Type 2 Diabetes: Oxidative Stress Linked to NADPH Oxidase and ER Stress

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3328
Author(s):  
Eloisa Aparecida Vilas-Boas ◽  
Davidson Correa Almeida ◽  
Leticia Prates Roma ◽  
Fernanda Ortis ◽  
Angelo Rafael Carpinelli
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Nadph Oxidase ◽  
Er Stress ◽  
Cell Function ◽  
Caloric Intake ◽  
Β Cells ◽  
Β Cell ◽  
Β Cell Function

A high caloric intake, rich in saturated fats, greatly contributes to the development of obesity, which is the leading risk factor for type 2 diabetes (T2D). A persistent caloric surplus increases plasma levels of fatty acids (FAs), especially saturated ones, which were shown to negatively impact pancreatic β-cell function and survival in a process called lipotoxicity. Lipotoxicity in β-cells activates different stress pathways, culminating in β-cells dysfunction and death. Among all stresses, endoplasmic reticulum (ER) stress and oxidative stress have been shown to be strongly correlated. One main source of oxidative stress in pancreatic β-cells appears to be the reactive oxygen species producer NADPH oxidase (NOX) enzyme, which has a role in the glucose-stimulated insulin secretion and in the β-cell demise during both T1 and T2D. In this review, we focus on the acute and chronic effects of FAs and the lipotoxicity-induced β-cell failure during T2D development, with special emphasis on the oxidative stress induced by NOX, the ER stress, and the crosstalk between NOX and ER stress.

scholarly journals Relationship Between Oxidative Stress, ER Stress, and Inflammation in Type 2 Diabetes: The Battle Continues

2019 ◽  
Vol 8 (9) ◽  
pp. 1385 ◽  
Author(s):  
Burgos-Morón ◽  
Abad-Jiménez ◽  
Marañón ◽  
Iannantuoni ◽  
Escribano-López ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Er Stress ◽  
Mitochondrial Dysfunction ◽  
Current Knowledge ◽  
Β Cells ◽  
The Relationship ◽  
And Oxidative Stress

Type 2 diabetes (T2D) is a metabolic disorder characterized by hyperglycemia and insulin resistance in which oxidative stress is thought to be a primary cause. Considering that mitochondria are the main source of ROS, we have set out to provide a general overview on how oxidative stress is generated and related to T2D. Enhanced generation of reactive oxygen species (ROS) and oxidative stress occurs in mitochondria as a consequence of an overload of glucose and oxidative phosphorylation. Endoplasmic reticulum (ER) stress plays an important role in oxidative stress, as it is also a source of ROS. The tight interconnection between both organelles through mitochondrial-associated membranes (MAMs) means that the ROS generated in mitochondria promote ER stress. Therefore, a state of stress and mitochondrial dysfunction are consequences of this vicious cycle. The implication of mitochondria in insulin release and the exposure of pancreatic β-cells to hyperglycemia make them especially susceptible to oxidative stress and mitochondrial dysfunction. In fact, crosstalk between both mechanisms is related with alterations in glucose homeostasis and can lead to the diabetes-associated insulin-resistance status. In the present review, we discuss the current knowledge of the relationship between oxidative stress, mitochondria, ER stress, inflammation, and lipotoxicity in T2D.

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 Pericytopathy: Oxidative Stress and Impaired Cellular Longevity in the Pancreas and Skeletal Muscle in Metabolic Syndrome and Type 2 Diabetes

2010 ◽  
Vol 3 (5) ◽  
pp. 290-303 ◽  
Author(s):  
Melvin R. Hayden ◽  
Ying Yang ◽  
Javad Habibi ◽  
Sarika V. Bagree ◽  
James R. Sowers
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Metabolic Syndrome ◽  
Screening Method ◽  
Lifestyle Changes ◽  
Pancreatic Stellate Cells ◽  
Rodent Models ◽  
The Metabolic Syndrome

The pericyte's role has been extensively studied in retinal tissues of diabetic retinopathy; however, little is known regarding its role in such tissues as the pancreas and skeletal muscle. This supportive microvascular mural cell plays an important and novel role in cellular and extracellular matrix remodeling in the pancreas and skeletal muscle of young rodent models representing the metabolic syndrome and type 2 diabetes mellitus (T2DM). Transmission electron microscopy can be used to evaluate these tissues from young rodent models of insulin resistance and T2DM, including the transgenic Ren2 rat, db/db obese insulin resistantߞT2DM mouse, and human islet amyloid polypeptide (HIP) rat model of T2DM. With this method, the earliest pancreatic remodeling change was widening of the islet exocrine interface and pericyte hypercellularity, followed by pericyte differentiation into islet and pancreatic stellate cells with early fibrosis involving the islet exocrine interface and interlobular interstitium. In skeletal muscle there was a unique endothelial capillary connectivity via elongated longitudinal pericyte processes in addition to pericyte to pericyte and pericyte to myocyte cellcell connections allowing for paracrine communication. Initial pericyte activation due to moderate oxidative stress signaling may be followed by hyperplasia, migration and differentiation into adult mesenchymal cells. Continued robust oxidative stress may induce pericyte apoptosis and impaired cellular longevity. Circulating antipericyte autoantibodies have recently been characterized, and may provide a screening method to detect those patients who are developing pericyte loss and are at greater risk for the development of complications of T2DM due to pericytopathy and rarefaction. Once detected, these patients may be offered more aggressive treatment strategies such as early pharmacotherapy in addition to lifestyle changes targeted to maintaining pericyte integrity. In conclusion, we have provided a review of current knowledge regarding the pericyte and novel ultrastructural findings regarding its role in metabolic syndrome and T2DM.

Telomere length, telomerase activity and mechanisms change in patients with type 2 diabetes mellitus

2016 ◽  
Vol 62 (1) ◽  
pp. 16-24 ◽  
Author(s):  
Natalia Vasil'evna Brailova ◽  
Ekaterina Nail'evna Dudinskaya ◽  
Olga Nikolaevna Tkacheva ◽  
Marina Vladimirovna Shestakova ◽  
Irina Dmitrievna Strazhesko ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Telomere Length ◽  
Chronic Inflammation ◽  
Telomerase Activity ◽  
Control Group ◽  
Diabetic Patients

Aim.To study the association of chronic inflammation, oxidative stress with telomere biology in people with type 2 diabetes mellitus (T2DM).Material and Methods.A total 50 patients with T2D and without cardiovascular disease (CVD) and 139 people from control group were included in the study. All subjects were measured for carbohydrate metabolism; oxidative stress (malondialdehyde (MDA)); inflammation (C-reactive protein — CRP, fibrinogen, interleukin-6); lymphocyte telomere length, telomerase activity.Results.In diabetic patients telomeres were shorter than in controls (9.59±0.54 and 9.76±0.47; p=0.031), telomerase activity was lower (0.47±0.40 and 0.62±0.36; p=0.039), inflammation (CRP, elevated fibrinogen) was higher. All patients were divided by telomere length. In T2DM group CRP was higher in patients with «short» telomeres (7.39±1.47 and 3.59±0.58 mg/L; p=0.02). There were no significant differences in the level of chronic inflammation and oxidative stress in ‘long’ telomeres group: CRP 3.59±0.58 and 3.66±0.50 mg/L (p=0.93), MDA 2.81±0.78 and 3.24±0.78 mmol/l (p=0.08). Diabetic patients in «short» telomeres group had greater chronic inflammation: CRP 7.39±1.47 and 4.03±0.62 mg/L (p=0.046), increased fibrinogen, 0.371 and 0.159 (p=0.022). All patients were divided by telomerase activity. Severity of chronic inflammation was greatest in T2DM and the «low» activity of telomerase. There were relationship between telomere length and CRP in T2DM patients (r=–0.40; p=0.004).Conclusions. Chronic inflammation and cell aging were more pronounced in patients with T2DM. However, despite diabetes, signs of chronic inflammation were minimal in patients with «long» telomeres compared to healthy people. Perhaps long telomeres protect diabetic patients from the damaging effect of chronic inflammation.

The metabolic syndrome: linking oxidative stress and inflammation to obesity, type 2 diabetes, and the syndrome

2006 ◽  
Vol 67 (7) ◽  
pp. 619-626 ◽  
Author(s):  
Paresh Dandona ◽  
Husam Ghanim ◽  
Priya Mohanty ◽  
Ajay Chaudhuri
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Metabolic Syndrome ◽  
The Metabolic Syndrome

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
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