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Frontiers of Medicine

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Front. Med.    2020, Vol. 14 Issue (5) : 583-600    https://doi.org/10.1007/s11684-019-0729-1
REVIEW
Oxidative stress and diabetes: antioxidative strategies
Pengju Zhang1, Tao Li1, Xingyun Wu1, Edouard C. Nice2, Canhua Huang1(), Yuanyuan Zhang1()
1. Department of Pharmacology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, China
2. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
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Abstract

Diabetes mellitus is one of the major public health problems worldwide. Considerable recent evidence suggests that the cellular reduction–oxidation (redox) imbalance leads to oxidative stress and subsequent occurrence and development of diabetes and related complications by regulating certain signaling pathways involved in β-cell dysfunction and insulin resistance. Reactive oxide species (ROS) can also directly oxidize certain proteins (defined as redox modification) involved in the diabetes process. There are a number of potential problems in the clinical application of antioxidant therapies including poor solubility, storage instability and non-selectivity of antioxidants. Novel antioxidant delivery systems may overcome pharmacokinetic and stability problem and improve the selectivity of scavenging ROS. We have therefore focused on the role of oxidative stress and antioxidative therapies in the pathogenesis of diabetes mellitus. Precise therapeutic interventions against ROS and downstream targets are now possible and provide important new insights into the treatment of diabetes.
Keywords diabetes      oxidative stress      redox modification      antioxidative therapy      novel antioxidant delivery     
Corresponding Author(s): Canhua Huang,Yuanyuan Zhang   
Just Accepted Date: 30 December 2019   Online First Date: 07 April 2020    Issue Date: 12 October 2020
 Cite this article:   
Pengju Zhang,Tao Li,Xingyun Wu, et al. Oxidative stress and diabetes: antioxidative strategies[J]. Front. Med., 2020, 14(5): 583-600.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-019-0729-1
https://academic.hep.com.cn/fmd/EN/Y2020/V14/I5/583
Fig.1  The sources of ROS/RNS and their harmful effects. ROS/RNS arise from mitochondrial electron transport chain or/and non-mitochondrial pathways. When cells and tissues are exposed to hypoxia, inflammation and immune response, particularly hyperglycemia, and high free fatty acids, the generation of ROS/RNS will be elevated. The overproduction of ROS/RNS leads to oxidative stress that regulates important cell signaling pathways which govern cell proliferation, inflammation, and cell survival. Abbreviations: NOX, nicotinamide adenine nucleotide phosphate oxidase; NADPH, nicotinamide adenine nucleotide phosphate; O2•−, superoxide; HO, hemeoxygenase; XO, xanthine oxidase; COX, cyclooxygenases; iNOS, inducible NOS; eNOS, endothelial NOS; NOS, nitric oxide synthase; ONOO−, peroxynitrite; NO, nitric oxide; ETC, electron transport chain; CI, complex 1; MAO, monoamine oxidase; α-GD, α-glycerophosphate dehydrogenase; H2O2, hydrogen peroxide; ROS, reactive oxygen species; RNS, reactive nitrogen species; JNK, c-jun N-terminal kinase; PKC, protein kinase C; IKKβ, IκB kinase β; PI3K, phosphatidylinositide 3-kinase; PARP-1, poly (ADP-ribose) polymerases; NF-kB, nuclear transcription factor κB; Nrf2, nuclear factor E2-ralated factor 2; FOXO, forkhead box protein O.
Major antioxidants Main functions References
Enzymatic antioxidants
?SOD Catalyzes 2O2•− + 2H+⇄ O2 + H2O2 [66]
?CAT Catalyzes 2H2O2→ O2 + H2O [67]
?GPx Catalyzes the breakdown of H2O2 and lipid hydroperoxides to H2O and lipid alcohols [68]
Vitaminic antioxidants
?Vitamin C Scavenges free radicals [69]
?Vitamin E Scavenges lipid peroxide radicals in membranes [71]
?Vitamin D Modulates the expression of antioxidants [155]
?Vitamin B9 Inhibits NOX4/Vav2/NLRP3 signaling [156]
Other antioxidants
?GSH Scavenges free radicals [157]
?CoQ10 Improves mitochondrial dysfunction [158]
?NAC Reduces glutathione [159]
?LA Cofactor for pyruvate dehydrogenase complex [160]
?Trace elements Involves in redox cycling reactions [27]
Tab.1  Antioxidants
Fig.2  Oxidative stress and pancreatic β-cell dysfunction. Oxidative stress mainly influences β-cell function from two perspectives: reducing insulin secretion and promoting β-cell apoptosis. On the one hand, ROS overproduction suppresses insulin production and secretion by opening ATP-sensitive K+ channels and inhibiting insulin genes transcription. On the other hand, oxidative stress induces β-cell apoptosis by activating p21, JNK, p38 MAPK, and NF-kB. Abbreviations: NOX4, nicotinamide adenine nucleotide phosphate oxidase; KATP, ATP-sensitive K+ channels; VGCC, voltage-gated calcium channels; p21, a cyclin-dependent kinase inhibitor; JNK, c-jun N-terminal kinase; p38 MAPK, p38 AMP-activated protein kinase; NF-kB, nuclear transcription factor κB; FOXO1, forkhead box protein O 1; PDX1, pancreas duodenal homeobox factor 1; MaFA, musculoaponeurotic fibrosarcoma protein A; INS, insulin genes.
Fig.3  Oxidative stress and insulin resistance in skeletal cells. Glucose traverses the membrane of muscle cells by a facilitative diffusion process which relies on the GLUT4 glucose transporter translocation from intracellular storage depots to the sarcolemmal membrane and T-tubules upon muscle contraction. The GLUT4 translocation is modulated by insulin through the activation of a complex cascade of signaling events. Under oxidative stress due to sustained hyperglycemia, elevated FFA inhibits glucose transportation by impairing insulin signals. ROS decreases insulin sensitivity by activating casein kinase-2 (CK2) which promotes the translocation of GLUT4 to lysosomes rather than the sarcolemmal membrane. Abbreviations: NOX, nicotinamide adenine nucleotide phosphate oxidase; IR, insulin receptor; IRS-1/2, insulin receptor substrates-1/2; H2O2, hydrogen peroxide; O2•− , superoxide; ROS, reactive oxygen species; JNK, c-jun N-terminal kinase; IKKβ, IκB kinase β; CK2, casein kinase-2; GLUT4, glucose transporter 4; PI3K, phosphatidylinositide 3-kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol-3,4,5-triphosphate; PDK1, 3-phosphoinositide-dependent kinase; mTOR2, mechanistic target of rapamycin 2; TBC1D1/2, Tre-2/BUB2/cdc 1 domain family 1/2.
Fig.4  Oxidative stress and vascular endothelial dysfunction. There are four major mechanisms associated with vascular endothelial cell dysfunction, including the PKC, AGEs/RAGE, polyol and hexosamine pathways. The PKC and hexosamine pathways diminish the generation of NO which is a critical regulatory factor to normalize vascular function. The polyol and AGEs/RAGE pathways elevate the levels of ROS in endothelia cells and then activate NF-kB which induces the inflammation and thrombosis of vascular endothelia by enhancing several genes expression including VEGF, VCAM-1 and ET-1. Abbreviations: eNOS, endothelial nitric oxide synthase; O-GLcNAC, O-N-acetylglucosamine; NO, nitric oxide; PKC, protein kinase C; ROS, reactive oxygen species; AGE, advanced glycosylation end products; RAGE, receptor for advanced glycosylation end products; UDP-GlcNAc, uridine diphosphate N-acetylglucosamine; G-6-P, glucose 6 phosphate; F-6-P, fructose 6 phosphate; DAG, diacylglycerol; GFAT, glutamine fructose-6-phosphate aminotransferase; GADPH, D-glyceraldehyde-3-phosphate dehydrogenase; GSH, glutathione; NF-kB, nuclear transcription factor κB; VEGF, vascular endothelial growth factor; VCAM-1, vascular adhesion molecular-1; ET-1, endothelin-1.
Fig.5  Patterns of redox protein modification. The highly reactive thiol groups of proteins are easily oxidized to sulfenic acid (RSOH) by ROS, or are oxidized to S-nitrosylation in response to RNS. Sulfenic acid (RSOH) has the capacity to react with nearby thiols to form intramolecular or intermolecular disulfide bonds due to its highly reactive nature. Sulfenic acid (RSOH) can also react with GSH to generate S-glutathiolation. These redox proteins modifications are reversible and these reaction products can be restored into free thiols by cellular reductants. However, sulfenic acid (RSOH) can also be further oxidized to irreversible products (including RSO2H and RSO3H). Abbreviations: ROS, reactive oxygen species; RNS, reactive nitrogen species; GSH, glutathione.
Antioxidative strategies Main functions References
Lifestyle interventions
?Exercise Increases muscle mitochondrial oxidative capacity and enhances NO bioavailability [161]
?Dietary Decreases uptake of free fatty acids [142]
NDDS
?Microparticle Promotes the entry of antioxidants with poor membrane permeability [143]
?Nanoparticle Increases the bioavailability of antioxidants [144]
?Liposome Improves antioxidative capacity of antioxidants [145]
Agents targeting ROS sources
?MitoQ-TPP Prevents mitochondrial oxidative damage [162]
?TEMPOL Prevents mitochondrial oxidative damage and improves tissue oxygenation [163]
?GKT137831 Inhibits the activation of caspase-3 and cell death resulted from high glucose [148]
Agents targetingredox modification
?Bardoxolone methyl Regulates the Nrf2/Keap1/ARE pathway through Keap1 post-translational modification [150]
?tBHQ Regulates the Nrf2/Keap1/ARE pathway through Keap1 post-translational modification [151]
?Selenocompounds Modifies PKC C-terminal catalytic domain and inhibits cellular PKC activity [152]
Tab.2  Therapeutic antioxidative strategies for diabetes
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