Interplay of toxic metal levels and endoplasmic reticulum stress gene profile in type 2 diabetes mellitus

IF 0.9 Q4 GENETICS & HEREDITY Gene Reports Pub Date : 2024-09-02 DOI:10.1016/j.genrep.2024.102019

Shefali Singh , Juhi Verma , Nikhil Gupta , Anumesh K. Pathak , Vandana Tiwari , Manish Singh Rajput , Manish Raj Kulshrestha

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Abstract

The increasing global prevalence of type 2 diabetes mellitus (T2DM) necessitates investigating its complex etiology. This study aimed to explore the relationship between exposure to toxic metals, expression of endoplasmic reticulum stress response (ERSR) genes, and various biochemical parameters, including glycated hemoglobin (HbA1c), insulin resistance (HOMA-IR)/sensitivity (QUICKI), lipid profile, and estimated glomerular filtration rate (eGFR) in T2DM patients. T2DM patients and control subjects were matched for age, gender, and lifestyle factors. Biochemical parameters, toxic metal levels, and ERSR gene expression were analyzed using inductively coupled plasma mass spectrometry (ICPMS) and quantitative reverse transcription PCR (qRT-PCR), respectively. T2DM patients exhibit dysregulated lipid profiles and significantly higher fasting blood sugar (FBS), HbA1c, and insulin levels (all p < 0.0001). The insulin sensitivity was lower in T2DM patients (0.32 ± 0.09) than in the control group (0.35 ± 0.02, p = 0.02). Insulin resistance was significantly higher in the T2DM group (5.38 ± 3.15) than in the control group (1.98 ± 0.86, p = 0.0001). Nickel (4.75 ± 2.45 ppb, p < 0.0001) and arsenic (1.85 ± 1.78 ppb, p < 0.0001) levels were significantly elevated in T2DM patients. There was significant upregulation of ER stress genes: GRP78, CHOP, IRE1, ATF4, ATF6, and XBP1 (all p < 0.0001), while PERK was significantly down regulated (0.68-fold, p < 0.0001). Nickel levels were positively correlated with HOMA-IR (r = 0.49, p < 0.0001) and HbA1c (r = 0.35, p = 0.002). Arsenic levels were correlated with insulin (r = 0.34, p < 0.0001), insulin resistance (r = 0.51,p < 0.0001), HbA1c (r = 0.53, p < 0.0001), Arsenic levels (β = 0.37, p < 0.001), XBP1 (β = 0.36, p < 0.0001) independently associated with HbA1c.This study has revealed a significant association between arsenic exposure and the upregulation of XBP1 at the onset of T2DM. The overexpression of XBP1 and high levels of arsenic were independently associated with HbA1c and insulin resistance.

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2 型糖尿病患者体内有毒金属水平与内质网应激基因谱的相互作用

随着全球 2 型糖尿病（T2DM）发病率的不断上升，有必要对其复杂的病因进行研究。本研究旨在探讨T2DM患者接触有毒金属、内质网应激反应（ERSR）基因表达与各种生化指标（包括糖化血红蛋白（HbA1c）、胰岛素抵抗（HOMA-IR）/敏感性（QUICKI）、血脂概况和估计肾小球滤过率（eGFR））之间的关系。T2DM 患者和对照组受试者的年龄、性别和生活方式因素均匹配。生化参数、有毒金属水平和 ERSR 基因表达分别采用电感耦合血浆质谱法（ICPMS）和定量反转录 PCR 法（qRT-PCR）进行分析。T2DM 患者的血脂状况失调，空腹血糖 (FBS)、HbA1c 和胰岛素水平显著升高（均为 p < 0.0001）。T2DM 患者的胰岛素敏感性（0.32 ± 0.09）低于对照组（0.35 ± 0.02，P = 0.02）。T2DM 组的胰岛素抵抗（5.38 ± 3.15）明显高于对照组（1.98 ± 0.86，P = 0.0001）。T2DM 患者体内镍（4.75 ± 2.45 ppb，p = 0.0001）和砷（1.85 ± 1.78 ppb，p = 0.0001）水平明显升高。ER应激基因明显上调：GRP78、CHOP、IRE1、ATF4、ATF6 和 XBP1（均 p < 0.0001），而 PERK 则明显下调（0.68 倍，p < 0.0001）。镍水平与 HOMA-IR (r = 0.49, p < 0.0001) 和 HbA1c (r = 0.35, p = 0.002) 呈正相关。砷水平与胰岛素（r = 0.34, p < 0.0001）、胰岛素抵抗（r = 0.51,p < 0.0001）、HbA1c（r = 0.53, p < 0.0001）、砷水平（β = 0.37, p < 0.本研究揭示了砷暴露与 T2DM 发病时 XBP1 上调之间的显著关联。XBP1的过表达和高水平的砷与HbA1c和胰岛素抵抗独立相关。

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来源期刊

Gene Reports Biochemistry, Genetics and Molecular Biology-Genetics

CiteScore

3.30

自引率

7.70%

发文量

246

审稿时长

49 days

期刊介绍： Gene Reports publishes papers that focus on the regulation, expression, function and evolution of genes in all biological contexts, including all prokaryotic and eukaryotic organisms, as well as viruses. Gene Reports strives to be a very diverse journal and topics in all fields will be considered for publication. Although not limited to the following, some general topics include: DNA Organization, Replication & Evolution -Focus on genomic DNA (chromosomal organization, comparative genomics, DNA replication, DNA repair, mobile DNA, mitochondrial DNA, chloroplast DNA). Expression & Function - Focus on functional RNAs (microRNAs, tRNAs, rRNAs, mRNA splicing, alternative polyadenylation) Regulation - Focus on processes that mediate gene-read out (epigenetics, chromatin, histone code, transcription, translation, protein degradation). Cell Signaling - Focus on mechanisms that control information flow into the nucleus to control gene expression (kinase and phosphatase pathways controlled by extra-cellular ligands, Wnt, Notch, TGFbeta/BMPs, FGFs, IGFs etc.) Profiling of gene expression and genetic variation - Focus on high throughput approaches (e.g., DeepSeq, ChIP-Seq, Affymetrix microarrays, proteomics) that define gene regulatory circuitry, molecular pathways and protein/protein networks. Genetics - Focus on development in model organisms (e.g., mouse, frog, fruit fly, worm), human genetic variation, population genetics, as well as agricultural and veterinary genetics. Molecular Pathology & Regenerative Medicine - Focus on the deregulation of molecular processes in human diseases and mechanisms supporting regeneration of tissues through pluripotent or multipotent stem cells.