Abstract
Oxidative stress is a major risk factor in the onset and progression of type 2 diabetes mellitus (T2DM). NF-E2 related factor 2 (NRF2) is a pivotal transcription factor in oxidative stress related illnesses. This study included 2174 subjects with 879 cases of newly-diagnosed T2DM and 1295 healthy controls. Compared to individuals with the CC genotype, those with the AA genotype had lower total anti-oxidative capacity, superoxide dismutase, catalase, glutathione, glutathione peroxidase activity; and lower homeostasis model assessment of β-cell function index. Those with the AA genotype also had a higher malondialdehyde concentration and homeostasis model assessment of insulin resistance index values. The frequency of allele A was significantly higher in T2DM subjects (29.4%), compared to control subjects (26.1%; p = 0.019). Individuals with the AA genotype had a significantly higher risk of developing T2DM (OR 1.56; 95% CI 1.11, 2.20; p = 0.011), relative to those with the CC genotype, even after adjusting for known T2DM risk factors. Our results suggest that the NRF2 rs6721961 polymorphism was significantly associated with oxidative stress, anti-oxidative status, and risk of newly-diagnosed T2DM. This polymorphism may also contribute to impaired insulin secretory capacity and increased insulin resistance in a Chinese population.
Highlights
Increases in the prevalence of diabetes have occurred internationally
Our study found that compared to individuals with the CC genotype, those with the AA genotype had a significant decrease in plasma CAT activity, erythrocyte superoxide dismutase (SOD) and
Our findings showed that polymorphisms in the NF-E2 related factor 2 (NRF2) genes were significantly associated with decreased antioxidant activity
Summary
Increases in the prevalence of diabetes have occurred internationally. It has been estimated that between 1980 and 2008, the number of adults with diabetes rose from 153 to 347 million [1]. Research suggests that oxidative stress is a major risk factor in the onset and progression of type 2 diabetes mellitus (T2DM) [2]. Recent evidence suggests that NF-E2 related factor 2 (NRF2) is a pivotal transcription factor of the antioxidant response in oxidative stress related illnesses [3,4,5]. NRF2 is a member of the cap “n” collar (CNC) subfamily of basic leucine zipper transcription factors [6]. NRF2 has highly conserved domains named Nrf2-erythroid-derived CNC homology protein homology (Neh) domains [7]. Neh domain is the CNC and basic leucine zipper domain, which interacts with partner proteins for heterodimerization [6]. The Neh domain, which is located in the N-terminus of NRF2, is a regulatory domain that responds to oxidative stress. Neh mediates binding with Kelch-like erythroid-derived protein with CNC homology-associated protein 1 (Keap1), and it negatively regulates NRF2 function [10]
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