Yeungnam Univ J Med.  2021 Apr;38(2):83-94. 10.12701/yujm.2020.00563.

Can antioxidants be effective therapeutics for type 2 diabetes?

• Park S
• Park SY

• KMID: 2515182
• DOI: http://doi.org/10.12701/yujm.2020.00563

Abstract

The global obesity epidemic and the growing elderly population largely contribute to the increasing incidence of type 2 diabetes. Insulin resistance acts as a critical link between the present obesity pandemic and type 2 diabetes. Naturally occurring reactive oxygen species (ROS) regulate intracellular signaling and are kept in balance by the antioxidant system. However, the imbalance between ROS production and antioxidant capacity causes ROS accumulation and induces oxidative stress. Oxidative stress interrupts insulin-mediated intracellular signaling pathways, as supported by studies involving genetic modification of antioxidant enzymes in experimental rodents. In addition, a close association between oxidative stress and insulin resistance has been reported in numerous human studies. However, the controversial results with the use of antioxidants in type 2 diabetes raise the question of whether oxidative stress plays a critical role in insulin resistance. In this review article, we discuss the relevance of oxidative stress to insulin resistance based on genetically modified animal models and human trials.

Keyword

Antioxidants; Insulin resistance; Oxidative stress; Reactive oxygen species

Figure

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  Fig. 1. Intracellular reactive oxygen species (ROS) generation and the antioxidant scavenging system. ROS is produced from mitochondria, peroxisome, nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase, and xanthine oxidase. Among these sources, the mitochondrial electron transport chain is the primary source for ROS production. Superoxide dismutase 2 (SOD2) catalyzes the conversion of superoxide anion (O2–) into hydrogen peroxide (H2O2) in the mitochondria. The H2O2 is then detoxified in the mitochondria or moves to the cytoplasm. Cytoplasmic superoxide anion is generated from NADPH oxidase and xanthine oxidase, and subsequently converted into H2O2 by superoxide dismutase 1 (SOD1). H2O2 is detoxified by glutathione (GSH)/glutaredoxin (GRx)/glutathione reductase (GR), catalase (CAT), peroxiredoxin (Prx), thioredoxin (Trx)/thioredoxin reductase (TrxR), and glutathione peroxidase (GPx). Oxidized methionine (Ox-Met) is reduced by methionine sulfoxide reductase (Msr) to methionine (Met). Nitric oxide (NO) reacts with superoxide anion to form peroxynitrite (ONOO–), which is detoxified by Prx, GSH, and GPx.

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  Fig. 2. Intracellular insulin signaling pathway in skeletal muscle. Binding of insulin to insulin receptors (IR) on the plasma membrane promotes tyrosine autophosphorylation at the IR, which in turn induces tyrosine phosphorylation of the IR substrate (IRS). IRS activates the downstream substrate phosphatidylinositol 3-kinases (PI3K)/protein kinase B (AKT) pathway, and the activated AKT leads to increased glucose uptake and glycogen synthesis by inducing phosphorylation of AKT substrate of 160 kDa (AS160) and glycogen synthase kinase 3 (GSK3), respectively. Activated AS160 increases glucose uptake by mediating the translocation of glucose transporter type 4 (GLUT4) from the cytoplasm to the plasma membrane. Intracellular glucose is used for adenosine triphosphate (ATP) generation and glycogen synthesis. Tyr, tyrosine; Ser, serine; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol (3,4,5)-triphosphate; PDK1, phosphatidylinositide-dependent protein kinase 1; mTORC2, mammalian target of rapamycin complex 2; FOXO1, forkhead box protein O1; GS, glycogen synthase; acetyl-CoA, acetyl coenzyme A; TCA, tricarboxylic acid cycle; ETC, electron transport chain; ROS, reactive oxygen species.

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  Fig. 3. Inhibition of the insulin signaling pathway by oxidative stress. Reactive oxygen species (ROS) interferes with insulin action by altering several substrates of the insulin signaling pathway. ROS activates serine/threonine kinases, including protein kinase C (PKC), c-Jun N-terminal kinase (JNK), and inhibitory κB kinase (IKK), which not only inhibit the activation of insulin receptor substrate (IRS) through serine phosphorylation but also induce inflammation by activating nuclear factor κB (NF-κB). In addition, ROS suppresses glucose absorption by degrading glucose transporter type 4 (GLUT4) in a casein kinase 2 (CK2)-dependent manner. Reactive nitrogen species (RNS) inhibits tyrosine phosphorylation of IRS and protein kinase B (AKT) activation by inducing nitration of tyrosine. Mitochondrial functional defects by ROS not only induce an explosive increase in oxidative stress but also suppress mitochondrial energy production, eventually leading to cell death. Tyr, tyrosine; Ser, serine; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol (3,4,5)-triphosphate; PI3K, phosphatidylinositol 3-kinases; PDK1, phosphatidylinositide-dependent protein kinase 1; mTORC2, mammalian target of rapamycin complex 2; FOXO1, forkhead box protein O1; GSK3, glycogen synthase kinase 3; AS160, AKT substrate of 160 kDa; acetyl-CoA, acetyl coenzyme A; mtDNA, mitochondrial DNA; TCA, tricarboxylic acid cycle; ETC, electron transport chain.

Reference

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