VDR Downregulation and Promoter Hypermethylation As One of the Causes for Triggering Type 2 Diabetes Mellitus: Clinical and Molecular Studies

Overview

Journal J Diabetes Metab Disord

Specialty Endocrinology

Date 2023 Nov 17

PMID 37975142

Authors

Najeebul Tarfeen

Shariq Rashid Masoodi

Khair Ul Nisa

Shafat Ali

Mir Bilal Ahmad

Bashir Ahmad Ganai

Affiliations

Soon will be listed here.

Abstract

Background: Our present study was to investigate the methylation and Gene expression of the vitamin D receptor (VDR) gene in the causing T2DM and to determine the inflammatory biomarkers in exaggerating T2DM in Kashmiri population.

Methods: In this study, T2DM cases ( = 100) and controls ( = 100) of Kashmiri population were designed. Blood samples were taken from both groups, and serum vitamin D levels, inflammatory biomarkers (TNF-α, IL-6, IL-10, CRP, Leptin and adiponectin) were estimated by ELISA. By using methylation-specific PCR (MS-PCR) and RT-PCR, respectively, the levels of methylation and expression were measured after the extraction of DNA and RNA.

Results: Studies using RT-PCR demonstrated that patients with diabetes had a lower degree of VDR expression than control subjects ( > 0.05). The T2DM was shown to be strongly correlated with hypermethylation (-value < 0.001, OR 2.9; 95%CI 1.6-5.54). When compared to control groups, T2DM patients' levels of vitamin D in their serum were considerably lower ( < 0.01). Pro-inflammatory mediators like TNF-α, CRP, IL-6, and leptin levels were discovered to be higher, and concentrations of anti-inflammatory mediators like IL-10 and adiponectin were observed to be lower in people with T2DM than in people without the condition ( < 0.05).

Conclusions: This study suggests the hypermethylation and down expression of VDR as one of the basis for causing T2DM in kashmiri individuals, exaggerated by enhanced degree of TNF-α, CRP, IL-6 and leptin and diminished concentration of IL-10 and adiponectin in T2DM.

Supplementary Information: The online version contains supplementary material available at 10.1007/s40200-023-01266-6.

References

Malik R, Farooq R, Mehta P, Ishaq S, Din I, Shah P . Association of Vitamin D Receptor Gene Polymorphism in Adults With Type 2 Diabetes in the Kashmir Valley. Can J Diabetes. 2017; 42(3):251-256. DOI: 10.1016/j.jcjd.2017.06.003. View

Zhang J, McCullough P, Tecson K . Vitamin D deficiency in association with endothelial dysfunction: Implications for patients with COVID-19. Rev Cardiovasc Med. 2020; 21(3):339-344. DOI: 10.31083/j.rcm.2020.03.131. View

Tarfeen N, Ul Nisa K, Ahmad M, Waza A, Ganai B . Metabolic and Genetic Association of Vitamin D with Calcium Signaling and Insulin Resistance. Indian J Clin Biochem. 2023; 38(4):407-417. PMC: 10516840. DOI: 10.1007/s12291-022-01105-0. View

Seydi Shirvani S, Nouri M, Sakhinia E, Babaloo Z, Jadideslam G, Shahriar A . The expression and methylation status of vitamin D receptor gene in Behcet's disease. Immun Inflamm Dis. 2019; 7(4):308-317. PMC: 6842822. DOI: 10.1002/iid3.275. View

Donath M . Targeting inflammation in the treatment of type 2 diabetes: time to start. Nat Rev Drug Discov. 2014; 13(6):465-76. DOI: 10.1038/nrd4275. View

Meyer V, Bornman L . Cdx-2 polymorphism in the vitamin D receptor gene (VDR) marks VDR expression in monocyte/macrophages through VDR promoter methylation. Immunogenetics. 2018; 70(8):523-532. DOI: 10.1007/s00251-018-1063-5. View

Krill D, DeFlavia P, Dhir R, Luo J, Becich M, Lehman E . Expression patterns of vitamin D receptor in human prostate. J Cell Biochem. 2001; 82(4):566-72. DOI: 10.1002/jcb.1185. View

Selvaraj P, Prabhu Anand S, Harishankar M, Alagarasu K . Plasma 1,25 dihydroxy vitamin D3 level and expression of vitamin d receptor and cathelicidin in pulmonary tuberculosis. J Clin Immunol. 2009; 29(4):470-8. DOI: 10.1007/s10875-009-9277-9. View

Bashir H, Bhat S, Majid S, Hamid R, Koul R, Rehman M . Role of inflammatory mediators (TNF-α, IL-6, CRP), biochemical and hematological parameters in type 2 diabetes mellitus patients of Kashmir, India. Med J Islam Repub Iran. 2020; 34:5. PMC: 7139256. DOI: 10.34171/mjiri.34.5. View

10.

Fu D, Cong X, Ma Y, Cai H, Cai M, Li D . Genetic polymorphism of glucokinase on the risk of type 2 diabetes and impaired glucose regulation: evidence based on 298,468 subjects. PLoS One. 2013; 8(2):e55727. PMC: 3575415. DOI: 10.1371/journal.pone.0055727. View

11.

White J . Vitamin D signaling, infectious diseases, and regulation of innate immunity. Infect Immun. 2008; 76(9):3837-43. PMC: 2519414. DOI: 10.1128/IAI.00353-08. View

12.

Bashir H, Majid S, Khan M, Bhat M, Hamid R, Ashraf R . Inter-relationship of Pro- and Anti- inflammatory Biomarkers with the development of Type 2 Diabetes Mellitus. Heliyon. 2022; 8(11):e11329. PMC: 9641208. DOI: 10.1016/j.heliyon.2022.e11329. View

13.

Phosat C, Panprathip P, Chumpathat N, Prangthip P, Chantratita N, Soonthornworasiri N . Elevated C-reactive protein, interleukin 6, tumor necrosis factor alpha and glycemic load associated with type 2 diabetes mellitus in rural Thais: a cross-sectional study. BMC Endocr Disord. 2017; 17(1):44. PMC: 5512726. DOI: 10.1186/s12902-017-0189-z. View

14.

Belfki H, Ben Ali S, Bougatef S, Ahmed D, Haddad N, Jmal A . Association between C-reactive protein and type 2 diabetes in a Tunisian population. Inflammation. 2011; 35(2):684-9. DOI: 10.1007/s10753-011-9361-1. View

15.

van Driel M, van Leeuwen J . Vitamin D endocrinology of bone mineralization. Mol Cell Endocrinol. 2017; 453:46-51. DOI: 10.1016/j.mce.2017.06.008. View

16.

Liu Z, Ding Y, Xiu L, Pan H, Liang Y, Zhong S . A meta-analysis of the association between TNF-α -308G>A polymorphism and type 2 diabetes mellitus in Han Chinese population. PLoS One. 2013; 8(3):e59421. PMC: 3601959. DOI: 10.1371/journal.pone.0059421. View

17.

Sanceau J, Wijdenes J, Revel M, Wietzerbin J . IL-6 and IL-6 receptor modulation by IFN-gamma and tumor necrosis factor-alpha in human monocytic cell line (THP-1). Priming effect of IFN-gamma. J Immunol. 1991; 147(8):2630-7. View

18.

Ul Afshan F, Masood A, Nissar B, Chowdri N, Naykoo N, Majid M . Promoter hypermethylation regulates vitamin D receptor (VDR) expression in colorectal cancer-A study from Kashmir valley. Cancer Genet. 2021; 252-253:96-106. DOI: 10.1016/j.cancergen.2021.01.002. View

19.

Ma L, Wang S, Chen H, Cui L, Liu X, Yang H . Diminished 25-OH vitamin D levels and vitamin D receptor variants are associated with susceptibility to type 2 diabetes with coronary artery diseases. J Clin Lab Anal. 2019; 34(4):e23137. PMC: 7171300. DOI: 10.1002/jcla.23137. View

20.

Wimalawansa S . Associations of vitamin D with insulin resistance, obesity, type 2 diabetes, and metabolic syndrome. J Steroid Biochem Mol Biol. 2016; 175:177-189. DOI: 10.1016/j.jsbmb.2016.09.017. View