Aug 1, 2017 - by MGST3 gene, which maps to chromosome 1q23 is a potential susceptibility gene linked to T2DM in Pima. Indians, Caucasian and Chinese ...
Review Article
ejbps, 2017, Volume 4, Issue 9, 290-298. Banerjee et al.
SJIF Impact Factor 4.382
ISSN 2349-8870 European Journal Biomedical European of Journal of Biomedical and Pharmaceutical Sciences Volume: 4 Issue: 9 AND Pharmaceutical sciences 290-298 Year: 2017
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ASSOCIATION OF ANTIOXIDANT GENE VARIANTS WITH TYPE 2 DIABETES MELLITUS IN DIFFERENT ETHNIC GROUPS Pushpank Vats, Atar Singh Kushwah and Monisha Banerjee* Molecular and Human Genetics Laboratory, Department of Zoology, University of Lucknow, Lucknow-226007, India. *Corresponding Author: Dr. Monisha Banerjee Molecular and Human Genetics Laboratory, Department of Zoology, University of Lucknow, Lucknow-226007, India.
Article Received on 12/07/2017
Article Revised on 01/08/2017
Article Accepted on 22/08/2017
ABSTRACT Type 2 Diabetes Mellitus (T2DM) is a chronic metabolic disorder resulting from oxidative stress due to impairment in antioxidant enzymes and their activities against reactive metabolites (RMs). The glutathione-Stransferases (GSTs) are dimeric cytosolic xenobiotic-metabolizing enzymes that catalyze the conjugation of active xenobiotics to glutathione (GSH). GST M1, T1 and P1 have been reported to be involved in T2DM development and related complications. Once formed, O2•-is dismutated enzymatically to H2O2 and oxygen by superoxide dismutase (SOD) antioxidants which include intracellular (CuZn-SOD), mitochondrial (Mn-SOD), and extracellular (EC-SOD) enzymes. Glutathione peroxidases (GPx) are selenocysteine-containing enzymes that catalyze the reduction of H2O2 and lipid hydroperoxides to H2O and lipid alcohols respectively in a reaction that utilizes glutathione (GSH) as a reducing co-substrate. GPx-1 is a ubiquitous antioxidant enzyme whose deficiency has been shown to promote endothelial dysfunction, heart failure and abnormal structural changes in vasculature and myocardium. Antioxidant gene polymorphism studies are a comprehensive way of understanding the stress sensitive pathways. Several groups all over the world are working to understand the association of T2DM with genetic variants in antioxidant genes. The present review has been undertaken to explore the association of antioxidant gene polymorphisms in various populations of different ethnicities. This will provide an understanding of the role of antioxidant genes in T2DM risk. Association of single nucleotide polymorphisms (SNPs) in antioxidant genes will help to identify risk genotypes/haplotypes for disease susceptibility and enable the development of prognostic markers for T2DM, a step towards personalized medicine. KEYWORDS: Type 2 Diabetes Mellitus, Oxidative Stress, Glutathione-S-Transferases, Polymorphisms, Superoxide Dismutase, Glutathione peroxidases, Abbreviation: T2DM, type 2 diabetes mellitus; CAD, coronary artery disease; DR, diabetic retinopathy; GSH, glutathione. 1. INTRODUCTION Diabetes Mellitus (DM) is a chronic disorder characterized by impaired metabolism of glucose and lipids due to defects in insulin secretion (beta cell dysfunction) or action (insulin resistance). The characteristic properties of diabetes mellitus are chronic hyperglycemia, microvascular (eg. retina, renal glomerulus and peripheral nerve) as well as macrovascular (eg. atherosclerosis, coronary artery disease (CAD), stroke) pathologies with more than 17.5 million deaths worldwide attributed to cardiovascular complications.[1] The global burden of diabetes is presently 415 million affected people, expected to rise to 642 million in 2040 and about 193 million people are still undiagnosed. The Indian estimate shows 69.2 million people affected with T2DM in 2015 which is expected to rise to 123.5 million in 2040.[2] This rise in
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the number of diabetic patients is associated with economic development, ageing population, increasing urbanization, dietary changes, reduced physical activity and changes in life style pattern. T2DM and oxidative stress have a clinical and genetic correlation. The overall play of reactive metabolites (RMs) leads to the development of late onset insulin resistance. RMs is generated inside the body of normal individuals in a scheduled manner and is in feedback control with the antioxidant system. The role of RMs and antioxidants in T2DM provides a lead for research in identifying antioxidant gene variants and risk genotypes in populations of different ethnicity. There are several risk variants of antioxidant enzyme genes for T2DM and associated complications.[3] Recent advances of genomewide studies have provided confirmation of association between common complex diseases and genetic variants. Antioxidant gene polymorphism studies are a comprehensive way of understanding the stress sensitive pathways.
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2. Glutathione-S-transferases (GSTs) The glutathione-S-transferases (GSTs) are dimeric cytosolic xenobiotic-metabolizing enzymes that catalyze the conjugation of an active xenobiotic to GSH, an endogenous water-soluble substrate. They detoxify reactive electrophiles such as those contained in tobacco smoke. Glutathione S-transferases are encoded by eight distinct classes of the soluble cytoplasmic isoforms: alpha, kappa, mu, omega, pi, sigma, theta and zeta that are located on different chromosomes.[4] GSTM1, T1 and P1 have been reported to be involved in T2DM development and various diabetes related complications in different populations.[5-9] Microsomal GST3 encoded by MGST3 gene, which maps to chromosome 1q23 is a potential susceptibility gene linked to T2DM in Pima Indians, Caucasian and Chinese populations.[10] 2.1. GSTM1 gene deletion polymorphism in T2DM Glutathione S-transferase mu1 (GSTM1) is a class of enzymes which functions in the detoxification of electrophilic compounds, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress by conjugation with glutathione. This is organized in a gene cluster on chromosome 1p13.3 that is known to be highly polymorphic. Multiple protein isoforms are encoded by transcript variants of this gene. Genetic variations in GSTM1 can change an individual's susceptibility to carcinogens and toxins as well as affect the toxicity and efficacy of certain drugs. Null mutations in GSTM1 gene have been linked with an increased number of cancers, due to an increased susceptibility to environmental toxins and carcinogens.[4] In individual genotyping studies, there are reports of significant risk for null genotype [p
