Reactive metabolites and antioxidant gene polymorphisms in Type 2 diabetes mellitus

Monisha Banerjee, Pushpank Vats, Monisha Banerjee, Pushpank Vats

Abstract

Type 2 diabetes mellitus (T2DM), by definition is a heterogeneous, multifactorial, polygenic syndrome which results from insulin receptor dysfunction. It is an outcome of oxidative stress caused by interactions of reactive metabolites (RMs) interactions with lipids, proteins and other mechanisms of human body. Production of RMs mainly superoxide (O2(-)) has been found in a variety of predominating cellular enzyme systems including NAD(P)H oxidase, xanthine oxidase (XO), cyclooxygenase (COX), uncoupled endothelial nitric oxide synthase (eNOS) and myeloperoxidase (MPO). The four main RM related molecular mechanisms are: increased polyol pathway flux; increased advanced glycation end-product (AGE) formation; activation of protein kinase C (PKC) isoforms and increased hexosamine pathway flux which have been implicated in glucose-mediated vascular damage. Superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST), nitric oxide synthase (NOS) are antioxidant enzymes involved in scavenging RMs in normal individuals. Functional polymorphisms of these antioxidant enzymes have been reported to be involved in pathogenesis of T2DM individuals. The low levels of antioxidant enzymes or their non-functionality results in excessive RMs which initiate stress related pathways thereby leading to insulin resistance and T2DM. An attempt has been made to review the role of RMs and antioxidant enzymes in oxidative stress resulting in T2DM.

Keywords: Antioxidants; Oxidative stress; Polymorphisms; Reactive metabolites; Type 2 diabetes mellitus.

Copyright © 2013 The Authors. Published by Elsevier B.V. All rights reserved.

Figures

Graphical abstract
Graphical abstract
Fig. 1
Fig. 1
Outline of various sources of reactive oxygen species (ROS) and action of antioxidant enzymes. Superoxide anion O2− is formed by several metabolic and enzymatic sources within the cell. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase uses NADPH as a substrate, and is considered an important source of ROS. The lipoxygenases (LO) and cyclooxygenases (COX) generate ROS indirectly by promoting formation of inflammatory mediators. Arachidonic acid (AA) cleaved from the membrane by phospholipase A2 (PLA2) is metabolized by 5-LO in the presence of accessory protein (FLAP) to form leukotrienes (LTs). Mitochondria also generate superoxide as electrons are transferred from complexes I to IV during normal cellular respiration. Xanthine oxidase (XO), which converts hypoxanthine and xanthine to uric acid is an additional source of ROS. Finally, endothelial nitric oxide synthase (eNOS) uncouples to generate superoxide in preference to NO. Q indicates coenzyme Q; C, cytochrome C; FAD flavin adenine dinucelotide; FMN, flavin mononucleotide; FE, heme iron; BH4, tetrahydrobiopterin; GPx Glutathione peroxidase; GSH Glutathione; GSSG Glutathione disulfide; and G6PD Glucose-6-phosphate dehydrogenase.
Fig. 2
Fig. 2
Schematic representation of oxidative stress and the pathways leading to T2DM and its complications. Reactive oxygen species (ROS), reactive nitrogen species (RNS) and oxidative stress induced by elevations in glucose and free fatty acid (FFA) levels play a key role in causing insulin resistance and β-cell dysfunction by activating stress-sensitive signaling pathways. The proposed sequences of events include other stress pathways such as, increased production of advanced glycosylated end (AGE) products, sorbitol, cytokines, prostanoids and hexosamines. ROS and RNS play a key role in the pathogenesis of diabetes by inflicting macromolecular damage. ROS also function as signaling molecules to activate several stress-sensitive pathways such as nuclear factor kappa-light-chain-enhancer of activated cells (NF-kB), p38 class of mitogen activated protein kinases (P38MAPK), janus kinase/signal transducer and activator of transcription (JAK/STAT) by elevations in glucose and possibly FFA levels leading to both insulin resistance and impaired insulin secretion.

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