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New Insights into Oxidative Stress and Inflammation in Diabetes

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Special Issue Information
Keywords
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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Metabolism".

Deadline for manuscript submissions: closed (31 August 2021) | Viewed by 36526

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Special Issue Editors

Prof. Dr. In-Kyu Lee

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Guest Editor

Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Korea
Interests: diabetes; metabolic regulation; mitochondrial dynamics to diabetes; mitochondrial dynamics

Dr. Dipanjan Chanda

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Guest Editor

Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu 41404, Korea
Interests: nuclear receptors; transcriptional regulation; kinase signaling; mitochondrial dynamics; autophagy; insulin resistance

Special Issue Information

Dear Colleagues,

Amassing evidence has described a coordinated crosstalk between inflammation and oxidative stress in the development of metabolic dysfunction, including diabetes and diabetes-associated complications. Increased prevalence of insulin resistance (a prediabetes condition) and diabetes has reached an epidemic proportion all over the world. According to the WHO, the global diabetes epidemic currently affects over 400 million adults, and the number is expected to rise to 550 million by the year 2030. Progressive deterioration in metabolic control with existing therapeutic modalities necessitates better understanding and newer therapeutic interventions for the effective management of diabetes. Oxidative stress and inflammation affects a multitude of cellular responses in various organs, and the progression of insulin resistance is known to be associated with chronic systemic inflammation and increased oxidative stress. The positive feedback cycle involving the abnormal formation of reactive oxygen species, changes in inflammatory gene expression profile, and the progression of insulin resistance contributes to several diabetes-associated complications, including cardiovascular diseases, nephropathy, neuropathy, retinopathy, urological diseases, and cancer. This Special Issue aims to highlight bidirectional relationships between inflammation and oxidative stress and their role in the pathophysiology and treatment of diabetes.

Specifically, this Issue entitled “New Insights into Oxidative Stress and Inflammation in Diabetes” solicits original research and review articles on topics including but not restricted to the role and contribution of oxidative stress and inflammation in diabetes. Research related to metabolism may be broadly defined (e.g., biomarkers and processes related to metabolic disorders; interventions or lifestyle factors such as diet and exercise; cellular metabolism and mitochondrial function), and all manuscripts should include the measurement of (or discussion of for reviews) at least one aspect of inflammation or oxidative stress.

Prof. In-Kyu Lee
Dr. Dipanjan Chanda
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Oxidative stress
Inflammation
Insulin resistance
Diabetes
Metabolism
Glucose intolerance
Mitochondrial dysfunction
Biomarkers

Published Papers (10 papers)

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Research

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9 pages, 859 KiB

Open AccessFeature PaperArticle

Relationship between the Plasma Proteome and Changes in Inflammatory Markers after Bariatric Surgery

by Helene A. Fachim, Zohaib Iqbal, J. Martin Gibson, Ivona Baricevic-Jones, Amy E. Campbell, Bethany Geary, Akheel A. Syed, Antony Whetton, Handrean Soran, Rachelle P. Donn and Adrian H. Heald

Cells 2021, 10(10), 2798; https://doi.org/10.3390/cells10102798 - 19 Oct 2021

Cited by 5 | Viewed by 2217

Abstract

Severe obesity is a disease associated with multiple adverse effects on health. Metabolic bariatric surgery (MBS) can have significant effects on multiple body systems and was shown to improve inflammatory markers in previous short-term follow-up studies. We evaluated associations between changes in inflammatory markers (CRP, IL6 and TNFα) and circulating proteins after MBS. Methods: Sequential window acquisition of all theoretical mass spectra (SWATH-MS) proteomics was performed on plasma samples taken at baseline (pre-surgery) and 6 and 12 months after MBS, and concurrent analyses of inflammatory/metabolic parameters were carried out. The change in absolute abundances of those proteins, showing significant change at both 6 and 12 months, was tested for correlation with the absolute and percentage (%) change in inflammatory markers. Results: We found the following results: at 6 months, there was a correlation between %change in IL-6 and fold change in HSPA4 (rho = −0.659; p = 0.038) and in SERPINF1 (rho = 0.714, p = 0.020); at 12 months, there was a positive correlation between %change in IL-6 and fold change in the following proteins—LGALS3BP (rho = 0.700, p = 0.036), HSP90B1 (rho = 0.667; p = 0.05) and ACE (rho = 0.667, p = 0.05). We found significant inverse correlations at 12 months between %change in TNFα and the following proteins: EPHX2 and ACE (for both rho = −0.783, p = 0.013). We also found significant inverse correlations between %change in CRP at 12 months and SHBG (rho = −0.759, p = 0.029), L1CAM (rho = −0.904, p = 0.002) and AMBP (rho = −0.684, p = 0.042). Conclusion: Using SWATH-MS, we identified several proteins that are involved in the inflammatory response whose levels change in patients who achieve remission of T2DM after bariatric surgery in tandem with changes in IL6, TNFα and/or CRP. Future studies are needed to clarify the underlying mechanisms in how MBS decreases low-grade inflammation. Full article

(This article belongs to the Special Issue New Insights into Oxidative Stress and Inflammation in Diabetes)

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14 pages, 6439 KiB

Open AccessArticle

Intestinal Region-Specific and Layer-Dependent Induction of TNFα in Rats with Streptozotocin-Induced Diabetes and after Insulin Replacement

by Nikolett Bódi, Lalitha Chandrakumar, Afnan al Doghmi, Diána Mezei, Zita Szalai, Bence Pál Barta, János Balázs and Mária Bagyánszki

Cells 2021, 10(9), 2410; https://doi.org/10.3390/cells10092410 - 13 Sep 2021

Cited by 6 | Viewed by 2250

Abstract

Tumour necrosis factor alpha (TNFα) is essential in neuroinflammatory modulation. Therefore, the goal of this study is to reveal the effects of chronic hyperglycaemia and insulin treatment on TNFα expression in different gut segments and intestinal wall layers. TNFα expression was mapped by fluorescent immunohistochemistry and quantitative immunogold electron microscopy in myenteric ganglia of duodenum, ileum and colon. Tissue TNFα levels were measured by enzyme-linked immunosorbent assays in muscle/myenteric plexus-containing (MUSCLE-MP) and mucosa/submucosa/submucous plexus-containing (MUC-SUBMUC-SP) homogenates. Increasing density of TNFα-labelling gold particles is observed in myenteric ganglia from proximal to distal segments and TNFα tissue levels are much more elevated in MUSCLE-MP homogenates than in MUC-SUBMUC-SP samples in healthy controls. In the diabetics, the number of TNFα gold labels is significantly increased in the duodenum, decreased in the colon and remained unchanged in the ileal ganglia, while insulin does not prevent these diabetes-related TNFα changes. TNFα tissue concentration is also increased in MUSCLE-MP homogenates of diabetic duodenum, while decreased in MUC-SUBMUC-SP samples of diabetic ileum and colon. These findings support that type 1 diabetes has region-specific and intestinal layer-dependent effects on TNFα expression, contributing to the regional damage of myenteric neurons and their intestinal milieu. Full article

(This article belongs to the Special Issue New Insights into Oxidative Stress and Inflammation in Diabetes)

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16 pages, 3262 KiB

Open AccessFeature PaperArticle

Dapagliflozin Restores Impaired Autophagy and Suppresses Inflammation in High Glucose-Treated HK-2 Cells

by Jing Xu, Munehiro Kitada, Yoshio Ogura, Haijie Liu and Daisuke Koya

Cells 2021, 10(6), 1457; https://doi.org/10.3390/cells10061457 - 10 Jun 2021

Cited by 62 | Viewed by 5729

Abstract

Sodium-glucose cotransporter2 (SGLT2) inhibitors have a reno-protective effect in diabetic kidney disease. However, the detailed mechanism remains unclear. In this study, human proximal tubular cells (HK-2) were cultured in 5 mM glucose and 25 mM mannitol (control), 30 mM glucose (high glucose: HG), or HG and SGLT2 inhibitor, dapagliflozin-containing medium for 48 h. The autophagic flux was decreased, accompanied by the increased phosphorylation of S6 kinase ribosomal protein (p-S6RP) and the reduced phosphorylation of AMP-activated kinase (p-AMPK) expression in a HG condition. Compared to those of the control, dapagliflozin and SGLT2 knockdown ameliorated the HG-induced alterations of p-S6RP, p-AMPK, and autophagic flux. In addition, HG increased the nuclear translocation of nuclear factor-κB p65 (NF-κB) p65 and the cytoplasmic nucleotide-binding oligomerization domain-like receptor 3 (NLRP3), mature interleukin-1β (IL-1β), IL-6, and tumor necrosis factorα (TNFα) expression. Dapagliflozin, SGLT2 knockdown, and NF-κB p65 knockdown reduced the extent of these HG-induced inflammatory alterations. The inhibitory effect of dapagliflozin on the increase in the HG-induced nuclear translocation of NF-κB p65 was abrogated by knocking down AMPK. These data indicated that in diabetic renal proximal tubular cells, dapagliflozin ameliorates: (1) HG-induced autophagic flux reduction, via increased AMPK activity and mTOR suppression; and (2) inflammatory alterations due to NF-κB pathway suppression. Full article

(This article belongs to the Special Issue New Insights into Oxidative Stress and Inflammation in Diabetes)

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17 pages, 1860 KiB

Open AccessArticle

Systemic Administration of Insulin Receptor Antagonist Results in Endothelial and Perivascular Adipose Tissue Dysfunction in Mice

by Bartosz Proniewski, Anna Bar, Anna Kieronska-Rudek, Joanna Suraj-Prażmowska, Elżbieta Buczek, Krzysztof Czamara, Zuzanna Majka, Izabela Czyzynska-Cichon, Grzegorz Kwiatkowski, Karolina Matyjaszczyk-Gwarda and Stefan Chlopicki

Cells 2021, 10(6), 1448; https://doi.org/10.3390/cells10061448 - 09 Jun 2021

Cited by 7 | Viewed by 2706

Abstract

Hyperglycemia linked to diabetes results in endothelial dysfunction. In the present work, we comprehensively characterized effects of short-term hyperglycemia induced by administration of an insulin receptor antagonist, the S961 peptide, on endothelium and perivascular adipose tissue (PVAT) in mice. Endothelial function of the thoracic and abdominal aorta in 12-week-old male C57Bl/6Jrj mice treated for two weeks with S961 infusion via osmotic pumps was assessed in vivo using magnetic resonance imaging and ex vivo by detection of nitric oxide (NO) production using electron paramagnetic resonance spectroscopy. Additional methods were used to analyze PVAT, aortic segments and endothelial-specific plasma biomarkers. Systemic disruption of insulin signaling resulted in severe impairment of NO-dependent endothelial function and a loss of vasoprotective function of PVAT affecting the thoracic as well as abdominal parts of the aorta, however a fall in adiponectin expression and decreased uncoupling protein 1-positive area were more pronounced in the thoracic aorta. Results suggest that dysfunctional PVAT contributes to vascular pathology induced by altered insulin signaling in diabetes, in the absence of fat overload and obesity. Full article

(This article belongs to the Special Issue New Insights into Oxidative Stress and Inflammation in Diabetes)

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14 pages, 2020 KiB

Open AccessFeature PaperArticle

Th2 Cytokines Increase the Expression of Fibroblast Growth Factor 21 in the Liver

by Seul-Gi Kang, Seong-Eun Lee, Min-Jeong Choi, Joon-Young Chang, Jung-Tae Kim, Ben-Yuan Zhang, Yea-Eun Kang, Ju-Hee Lee, Hyon-Seung Yi and Minho Shong

Cells 2021, 10(6), 1298; https://doi.org/10.3390/cells10061298 - 24 May 2021

Cited by 4 | Viewed by 2594

Abstract

Interleukin-4 (IL-4) and IL-13 are the major T helper 2 (Th2) cytokines, and they are involved in the regulation of metabolism in the adipose tissue. The liver contains diverse innate and adaptive immune cells, but it remains to be determined whether Th2 cytokines modulate energy metabolism in the liver. Here, using gene expression data from the Gene Expression Omnibus (GEO) and the BXD mouse reference population, we determined that the Th2 cytokines IL-4 and IL-13 increase the secretion of fibroblast growth factor 21 (FGF21) in the liver. In vitro experiments confirmed that FGF21 was highly expressed in response to IL-4 and IL-13, and this response was abolished by the Janus kinase (JAK)-signal transducer and activator of transcription 6 (STAT6) blockade. Moreover, FGF21 expression in response to Th2 cytokines was augmented by selective peroxisome proliferator-activated receptor α (PPARα) inhibition. In vivo administration of IL-4 increased FGF21 protein levels in the liver in a STAT6-dependent manner, but FGF21 secretion in response to IL-4 was not observed in the epididymal white adipose tissue (eWAT) despite the activation of STAT6. Intraperitoneal administration of IL-33, an activator of type 2 immune responses, significantly increased the level of FGF21 in the serum and liver after 24 h, but repeated administration of IL-33 attenuated this effect. Taken together, these data demonstrate that the IL-4/IL-13–STAT6 axis regulates metabolic homeostasis through the induction of FGF21 in the liver. Full article

(This article belongs to the Special Issue New Insights into Oxidative Stress and Inflammation in Diabetes)

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20 pages, 4240 KiB

Open AccessArticle

Excessive Iron Induces Oxidative Stress Promoting Cellular Perturbations and Insulin Secretory Dysfunction in MIN6 Beta Cells

by Voni Blesia, Vinood B. Patel, Hisham Al-Obaidi, Derek Renshaw and Mohammed Gulrez Zariwala

Cells 2021, 10(5), 1141; https://doi.org/10.3390/cells10051141 - 09 May 2021

Cited by 18 | Viewed by 3175

Abstract

Exposure to high levels of glucose and iron are co-related to reactive oxygen species (ROS) generation and dysregulation of insulin synthesis and secretion, although the precise mechanisms are not well clarified. The focus of this study was to examine the consequences of exposure to high iron levels on MIN6 β-cells. MIN6 pseudoislets were exposed to 20 µM (control) or 100 µM (high) iron at predefined glucose levels (5.5 mM and 11 mM) at various time points (3, 24, 48, and 72 h). Total iron content was estimated by a colourimetric FerroZine™ assay in presence or absence of transferrin-bound iron. Cell viability was assessed by a resazurin dye-based assay, and ROS-mediated cellular oxidative stress was assessed by estimating malondialdehyde levels. β-cell iron absorption was determined by a ferritin immunoassay. Cellular insulin release and content was measured by an insulin immunoassay. Expression of SNAP-25, a key protein in the core SNARE complex that modulates vesicle exocytosis, was measured by immunoblotting. Our results demonstrate that exposure to high iron levels resulted in a 15-fold (48 h) and 4-fold (72 h) increase in cellular iron accumulation. These observations were consistent with data from oxidative stress analysis which demonstrated 2.7-fold higher levels of lipid peroxidation. Furthermore, exposure to supraphysiological (11 mM) levels of glucose and high iron (100 µM) at 72 h exerted the most detrimental effect on the MIN6 β-cell viability. The effect of high iron exposure on total cellular iron content was identical in the presence or absence of transferrin. High iron exposure (100 µM) resulted in a decrease of MIN6 insulin secretion (64% reduction) as well as cellular insulin content (10% reduction). Finally, a significant reduction in MIN6 β-cell SNAP-25 protein expression was evident at 48 h upon exposure to 100 µM iron. Our data suggest that exposure to high iron and glucose concentrations results in cellular oxidative damage and may initiate insulin secretory dysfunction in pancreatic β-cells by modulation of the exocytotic machinery. Full article

(This article belongs to the Special Issue New Insights into Oxidative Stress and Inflammation in Diabetes)

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Review

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15 pages, 1436 KiB

Open AccessReview

Diabetes Mellitus and Periodontitis Share Intracellular Disorders as the Main Meeting Point

by Juliana Portes, Beatriz Bullón, José Luis Quiles, Maurizio Battino and Pedro Bullón

Cells 2021, 10(9), 2411; https://doi.org/10.3390/cells10092411 - 13 Sep 2021

Cited by 17 | Viewed by 4458

Abstract

Diabetes and periodontitis are two of the most prevalent diseases worldwide that negatively impact the quality of life of the individual suffering from them. They are part of the chronic inflammatory disease group or, as recently mentioned, non-communicable diseases, with inflammation being the meeting point among them. Inflammation hitherto includes vascular and tissue changes, but new technologies provide data at the intracellular level that could explain how the cells respond to the aggression more clearly. This review aims to emphasize the molecular pathophysiological mechanisms in patients with type 2 diabetes mellitus and periodontitis, which are marked by different impaired central regulators including mitochondrial dysfunction, impaired immune system and autophagy pathways, oxidative stress, and the crosstalk between adenosine monophosphate-activated protein kinase (AMPK) and the renin-angiotensin system (RAS). All of them are the shared background behind both diseases that could explain its relationship. These should be taken in consideration if we would like to improve the treatment outcomes. Currently, the main treatment strategies in diabetes try to reduce glycemia index as the most important aspect, and in periodontitis try to reduce the presence of oral bacteria. We propose to add to the therapeutic guidelines the handling of all the intracellular disorders to try to obtain better treatment success. Full article

(This article belongs to the Special Issue New Insights into Oxidative Stress and Inflammation in Diabetes)

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14 pages, 1193 KiB

Open AccessReview

Communications between Mitochondria and Endoplasmic Reticulum in the Regulation of Metabolic Homeostasis

by Pengcheng Zhang, Daniels Konja, Yiwei Zhang and Yu Wang

Cells 2021, 10(9), 2195; https://doi.org/10.3390/cells10092195 - 25 Aug 2021

Cited by 17 | Viewed by 3842

Abstract

Mitochondria associated membranes (MAM), which are the contact sites between endoplasmic reticulum (ER) and mitochondria, have emerged as an important hub for signaling molecules to integrate the cellular and organelle homeostasis, thus facilitating the adaptation of energy metabolism to nutrient status. This review explores the dynamic structural and functional features of the MAM and summarizes the various abnormalities leading to the impaired insulin sensitivity and metabolic diseases. Full article

(This article belongs to the Special Issue New Insights into Oxidative Stress and Inflammation in Diabetes)

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17 pages, 1075 KiB

Open AccessReview

CD36 Signal Transduction in Metabolic Diseases: Novel Insights and Therapeutic Targeting

by Udayakumar Karunakaran, Suma Elumalai, Jun-Sung Moon and Kyu-Chang Won

Cells 2021, 10(7), 1833; https://doi.org/10.3390/cells10071833 - 20 Jul 2021

Cited by 21 | Viewed by 5531

Abstract

The cluster of differentiation 36 (CD36) is a scavenger receptor present on various types of cells and has multiple biological functions that may be important in inflammation and in the pathogenesis of metabolic diseases, including diabetes. Here, we consider recent insights into how the CD36 response becomes deregulated under metabolic conditions, as well as the therapeutic benefits of CD36 inhibition, which may provide clues for developing strategies aimed at the treatment or prevention of diabetes associated with metabolic diseases. To facilitate this process further, it is important to pinpoint regulatory mechanisms that are relevant under physiological and pathological conditions. In particular, understanding the mechanisms involved in dictating specific CD36 downstream cellular outcomes will aid in the discovery of potent compounds that target specific CD36 downstream signaling cascades. Full article

(This article belongs to the Special Issue New Insights into Oxidative Stress and Inflammation in Diabetes)

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12 pages, 1320 KiB

Open AccessReview

NADPH Oxidase (NOX) Targeting in Diabetes: A Special Emphasis on Pancreatic β-Cell Dysfunction

by Suma Elumalai, Udayakumar Karunakaran, Jun-Sung Moon and Kyu-Chang Won

Cells 2021, 10(7), 1573; https://doi.org/10.3390/cells10071573 - 22 Jun 2021

Cited by 19 | Viewed by 2785

Abstract

In type 2 diabetes, metabolic stress has a negative impact on pancreatic β-cell function and survival (T2D). Although the pathogenesis of metabolic stress is complex, an imbalance in redox homeostasis causes abnormal tissue damage and β-cell death due to low endogenous antioxidant expression levels in β-cells. Under diabetogenic conditions, the susceptibility of β-cells to oxidative damage by NADPH oxidase has been related to contributing to β-cell dysfunction. Here, we consider recent insights into how the redox response becomes deregulated under diabetic conditions by NADPH oxidase, as well as the therapeutic benefits of NOX inhibitors, which may provide clues for understanding the pathomechanisms and developing strategies aimed at the treatment or prevention of metabolic stress associated with β-cell failure. Full article

(This article belongs to the Special Issue New Insights into Oxidative Stress and Inflammation in Diabetes)

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