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Erschienen in: Journal of Diabetes & Metabolic Disorders 2/2023

29.07.2023 | Research article

VDR downregulation and promoter hypermethylation as one of the causes for triggering type 2 diabetes mellitus: Clinical and molecular studies

verfasst von: Najeebul Tarfeen, Shariq Rashid Masoodi, Khair Ul Nisa, Shafat Ali, Mir Bilal Ahmad, Bashir Ahmad Ganai

Erschienen in: Journal of Diabetes & Metabolic Disorders | Ausgabe 2/2023

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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 (n = 100) and controls (n = 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 (P > 0.05). The T2DM was shown to be strongly correlated with hypermethylation (p-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 (p < 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 (p < 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.
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Literatur
1.
Zurück zum Zitat Tarfeen N, et al. Metabolic and genetic association of vitamin D with calcium signaling and insulin resistance. Indian J Clin Biochem. 2022;1–11. Tarfeen N, et al. Metabolic and genetic association of vitamin D with calcium signaling and insulin resistance. Indian J Clin Biochem. 2022;1–11.
2.
Zurück zum Zitat Xu H, et al. Dietary acid load, insulin sensitivity and risk of type 2 diabetes in community-dwelling older men. Diabetologia. 2014;57(8):1561–8.CrossRefPubMed Xu H, et al. Dietary acid load, insulin sensitivity and risk of type 2 diabetes in community-dwelling older men. Diabetologia. 2014;57(8):1561–8.CrossRefPubMed
3.
Zurück zum Zitat Liu Z-H, et al. 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.CrossRefPubMedPubMedCentral Liu Z-H, et al. 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.CrossRefPubMedPubMedCentral
4.
Zurück zum Zitat Fu D, et al. 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.CrossRefPubMedPubMedCentral Fu D, et al. 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.CrossRefPubMedPubMedCentral
5.
Zurück zum Zitat Tardieu M, Mikaeloff Y. Multiple sclerosis in children: environmental risk factors. Bulletin de L’academie Nationale de Med. 2008;192(3):507–9 discussion 509. Tardieu M, Mikaeloff Y. Multiple sclerosis in children: environmental risk factors. Bulletin de L’academie Nationale de Med. 2008;192(3):507–9 discussion 509.
6.
Zurück zum Zitat van Driel M, van Leeuwen JP. Vitamin D endocrinology of bone mineralization. Mol Cell Endocrinol. 2017;453:46–51.CrossRefPubMed van Driel M, van Leeuwen JP. Vitamin D endocrinology of bone mineralization. Mol Cell Endocrinol. 2017;453:46–51.CrossRefPubMed
7.
Zurück zum Zitat Autier P, et al. Vitamin D status and ill health: a systematic review. Lancet Diabetes Endocrinol. 2014;2(1):76–89.CrossRefPubMed Autier P, et al. Vitamin D status and ill health: a systematic review. Lancet Diabetes Endocrinol. 2014;2(1):76–89.CrossRefPubMed
8.
Zurück zum Zitat Kempinska-Podhorodecka A, et al. Decreased expression of vitamin D receptor affects an immune response in primary biliary cholangitis via the VDR-miRNA155-SOCS1 pathway. Int J Mol Sci. 2017;18(2):289.CrossRefPubMedPubMedCentral Kempinska-Podhorodecka A, et al. Decreased expression of vitamin D receptor affects an immune response in primary biliary cholangitis via the VDR-miRNA155-SOCS1 pathway. Int J Mol Sci. 2017;18(2):289.CrossRefPubMedPubMedCentral
10.
Zurück zum Zitat Mahajan M, Sharma R. Current understanding of role of vitamin D in Type 2 diabetes mellitus. Int J Recent Sci Res. 2015;6:2602–4. Mahajan M, Sharma R. Current understanding of role of vitamin D in Type 2 diabetes mellitus. Int J Recent Sci Res. 2015;6:2602–4.
11.
Zurück zum Zitat Rasoul MA, et al. Relationship of four vitamin D receptor gene polymorphisms with type 1 diabetes mellitus susceptibility in Kuwaiti children. BMC Pediatr. 2019;19:1–13.CrossRef Rasoul MA, et al. Relationship of four vitamin D receptor gene polymorphisms with type 1 diabetes mellitus susceptibility in Kuwaiti children. BMC Pediatr. 2019;19:1–13.CrossRef
12.
Zurück zum Zitat Vélayoudom-Céphise F-L, et al. Vitamin D deficiency, vitamin D receptor gene polymorphisms and cardiovascular risk factors in Caribbean patients with type 2 diabetes. Diabetes Metab. 2011;37(6):540–5.CrossRefPubMed Vélayoudom-Céphise F-L, et al. Vitamin D deficiency, vitamin D receptor gene polymorphisms and cardiovascular risk factors in Caribbean patients with type 2 diabetes. Diabetes Metab. 2011;37(6):540–5.CrossRefPubMed
13.
Zurück zum Zitat Cyganek K, et al. Clinical risk factors and the role of VDR gene polymorphisms in diabetic retinopathy in Polish type 2 diabetes patients. Acta Diabetol. 2006;43:114–9.CrossRefPubMed Cyganek K, et al. Clinical risk factors and the role of VDR gene polymorphisms in diabetic retinopathy in Polish type 2 diabetes patients. Acta Diabetol. 2006;43:114–9.CrossRefPubMed
14.
Zurück zum Zitat Ma L, et al. Diminished 25-OH vitamin D3 levels and vitamin D receptor variants are associated with susceptibility to type 2 diabetes with coronary artery diseases. J Clin Lab Anal. 2020;34(4):e23137.CrossRefPubMed Ma L, et al. Diminished 25-OH vitamin D3 levels and vitamin D receptor variants are associated with susceptibility to type 2 diabetes with coronary artery diseases. J Clin Lab Anal. 2020;34(4):e23137.CrossRefPubMed
15.
Zurück zum Zitat Malik R, et al. Association of Vitamin D receptor gene polymorphism in adults with type 2 diabetes in the Kashmir Valley. Can J Diabetes. 2018;42(3):251–6.CrossRefPubMed Malik R, et al. Association of Vitamin D receptor gene polymorphism in adults with type 2 diabetes in the Kashmir Valley. Can J Diabetes. 2018;42(3):251–6.CrossRefPubMed
16.
Zurück zum Zitat Selvaraj P, et al. Plasma 1, 25 dihydroxy vitamin D 3 level and expression of vitamin D receptor and cathelicidin in pulmonary tuberculosis. J Clin Immunol. 2009;29:470–8.CrossRefPubMed Selvaraj P, et al. Plasma 1, 25 dihydroxy vitamin D 3 level and expression of vitamin D receptor and cathelicidin in pulmonary tuberculosis. J Clin Immunol. 2009;29:470–8.CrossRefPubMed
17.
Zurück zum Zitat Shirvani SS, et al. The expression and methylation status of vitamin D receptor gene in Behcet’s disease. Immun Inflamm Dis. 2019;7(4):308–17.CrossRefPubMedPubMedCentral Shirvani SS, et al. The expression and methylation status of vitamin D receptor gene in Behcet’s disease. Immun Inflamm Dis. 2019;7(4):308–17.CrossRefPubMedPubMedCentral
18.
Zurück zum Zitat Daroach M, et al. Correlation of vitamin D and vitamin D receptor expression in patients with alopecia areata: a clinical paradigm. Int J Dermatol. 2018;57(2):217–22.CrossRefPubMed Daroach M, et al. Correlation of vitamin D and vitamin D receptor expression in patients with alopecia areata: a clinical paradigm. Int J Dermatol. 2018;57(2):217–22.CrossRefPubMed
19.
Zurück zum Zitat Krill D, et al. Expression patterns of vitamin D receptor in human prostate. J Cell Biochem. 2001;82(4):566–72.CrossRefPubMed Krill D, et al. Expression patterns of vitamin D receptor in human prostate. J Cell Biochem. 2001;82(4):566–72.CrossRefPubMed
20.
Zurück zum Zitat Saccone D, Asani F, Bornman L. Regulation of the vitamin D receptor gene by environment, genetics and epigenetics. Gene. 2015;561(2):171–80.CrossRefPubMed Saccone D, Asani F, Bornman L. Regulation of the vitamin D receptor gene by environment, genetics and epigenetics. Gene. 2015;561(2):171–80.CrossRefPubMed
22.
Zurück zum Zitat Afshan FU, et al. Promoter hypermethylation regulates vitamin D receptor (VDR) expression in colorectal cancer-A study from Kashmir valley. Cancer Genet. 2021;252:96–106.CrossRefPubMed Afshan FU, et al. Promoter hypermethylation regulates vitamin D receptor (VDR) expression in colorectal cancer-A study from Kashmir valley. Cancer Genet. 2021;252:96–106.CrossRefPubMed
23.
Zurück zum Zitat Pilon C, et al. Methylation status of vitamin D receptor gene promoter in benign and malignant adrenal tumors. Int J Endocrinol. 2015;2015. Pilon C, et al. Methylation status of vitamin D receptor gene promoter in benign and malignant adrenal tumors. Int J Endocrinol. 2015;2015.
24.
Zurück zum Zitat Hussein TM, et al. Assessment of serum vitamin D level and seminal vitamin D receptor gene methylation in a sample of Egyptian men with idiopathic infertility. Andrologia. 2021;53(9):e14172.CrossRefPubMed Hussein TM, et al. Assessment of serum vitamin D level and seminal vitamin D receptor gene methylation in a sample of Egyptian men with idiopathic infertility. Andrologia. 2021;53(9):e14172.CrossRefPubMed
25.
Zurück zum Zitat Belfki H, et al. Association between C-reactive protein and type 2 diabetes in a Tunisian population. Inflammation. 2012;35(2):684–9.CrossRefPubMed Belfki H, et al. Association between C-reactive protein and type 2 diabetes in a Tunisian population. Inflammation. 2012;35(2):684–9.CrossRefPubMed
26.
Zurück zum Zitat Phosat C, et al. 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):1–8.CrossRef Phosat C, et al. 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):1–8.CrossRef
27.
Zurück zum Zitat Din I, et al. Combinatorial effect of leptin, tumor necrosis factor-Αlpha, and vitamin d in progression of type 2 diabetes in kashmiri population. Asian J Pharm Clin Res. 2018;11:477–81.CrossRef Din I, et al. Combinatorial effect of leptin, tumor necrosis factor-Αlpha, and vitamin d in progression of type 2 diabetes in kashmiri population. Asian J Pharm Clin Res. 2018;11:477–81.CrossRef
28.
Zurück zum Zitat Donath MY. Targeting inflammation in the treatment of type 2 diabetes: time to start. Nat Rev Drug Discovery. 2014;13(6):465–76.CrossRefPubMed Donath MY. Targeting inflammation in the treatment of type 2 diabetes: time to start. Nat Rev Drug Discovery. 2014;13(6):465–76.CrossRefPubMed
29.
Zurück zum Zitat Nussrat SW, Ad’hiah AH. Interleukin‐39 is a novel cytokine associated with type 2 diabetes mellitus and positively correlated with body mass index. Endocrinol Diabetes Metab. 2023;e409. Nussrat SW, Ad’hiah AH. Interleukin‐39 is a novel cytokine associated with type 2 diabetes mellitus and positively correlated with body mass index. Endocrinol Diabetes Metab. 2023;e409.
30.
Zurück zum Zitat Parhi A, et al. The level and role of Interleukin-17 in patients of type 2 diabetes mellitus with and without complications. J Diabetes Mellitus. 2019;9(04):176–85.CrossRef Parhi A, et al. The level and role of Interleukin-17 in patients of type 2 diabetes mellitus with and without complications. J Diabetes Mellitus. 2019;9(04):176–85.CrossRef
31.
Zurück zum Zitat Cimini F, et al. Circulating IL-8 levels are increased in patients with type 2 diabetes and associated with worse inflammatory and cardiometabolic profile. Acta Diabetol. 2017;54:961–7.CrossRefPubMed Cimini F, et al. Circulating IL-8 levels are increased in patients with type 2 diabetes and associated with worse inflammatory and cardiometabolic profile. Acta Diabetol. 2017;54:961–7.CrossRefPubMed
32.
Zurück zum Zitat Darogha SN. Serum levels of TNF-a and IFN-g gene polymorphism in type 2 diabetes mellitus in kurdish patients. Cell Mol Biol (Noisy-le-grand). 2021;67(2):171–7.CrossRefPubMed Darogha SN. Serum levels of TNF-a and IFN-g gene polymorphism in type 2 diabetes mellitus in kurdish patients. Cell Mol Biol (Noisy-le-grand). 2021;67(2):171–7.CrossRefPubMed
33.
Zurück zum Zitat Qiao, Y-C., et al. Changes of transforming growth factor beta 1 in patients with type 2 diabetes and diabetic nephropathy: a PRISMA-compliant systematic review and meta-analysis. Med, 2017; 96(15). Qiao, Y-C., et al. Changes of transforming growth factor beta 1 in patients with type 2 diabetes and diabetic nephropathy: a PRISMA-compliant systematic review and meta-analysis. Med, 2017; 96(15).
35.
Zurück zum Zitat Bashir H, et al. Inter-relationship of Pro-and Anti-inflammatory Biomarkers with the development of Type 2 Diabetes Mellitus. Heliyon. 2022;8(11):e11329.CrossRefPubMedPubMedCentral Bashir H, et al. Inter-relationship of Pro-and Anti-inflammatory Biomarkers with the development of Type 2 Diabetes Mellitus. Heliyon. 2022;8(11):e11329.CrossRefPubMedPubMedCentral
36.
Zurück zum Zitat Li LL, et al. Associations between 45T/G polymorphism of the adiponectin gene and plasma adiponectin levels with type 2 diabetes. Clin Exp Pharmacol Physiol. 2007;34(12):1287–90.CrossRefPubMed Li LL, et al. Associations between 45T/G polymorphism of the adiponectin gene and plasma adiponectin levels with type 2 diabetes. Clin Exp Pharmacol Physiol. 2007;34(12):1287–90.CrossRefPubMed
37.
Zurück zum Zitat Sanceau J, et al. 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 (Baltimore, Md: 1950). 1991;147(8):2630–7.CrossRef Sanceau J, et al. 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 (Baltimore, Md: 1950). 1991;147(8):2630–7.CrossRef
38.
Zurück zum Zitat Suguna S, et al. Genomic DNA isolation from human whole blood samples by non enzymatic salting out method. Int J Pharm Pharm Sci. 2014;6(6):198–9. Suguna S, et al. Genomic DNA isolation from human whole blood samples by non enzymatic salting out method. Int J Pharm Pharm Sci. 2014;6(6):198–9.
39.
Zurück zum Zitat Health, UDo, H. Services. Smoking and Diabetes Factsheet, US Department of Health and Human Services, Centers for Disease Control and Prevention. National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, Atlanta, GA, 2014. Health, UDo, H. Services. Smoking and Diabetes Factsheet, US Department of Health and Human Services, Centers for Disease Control and Prevention. National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, Atlanta, GA, 2014.
40.
Zurück zum Zitat Bashir H, et al. 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.PubMedPubMedCentral Bashir H, et al. 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.PubMedPubMedCentral
41.
Zurück zum Zitat Wimalawansa SJ. Associations of vitamin D with insulin resistance, obesity, type 2 diabetes, and metabolic syndrome. J Steroid Biochem Mol Biol. 2018;175:177–89.CrossRefPubMed Wimalawansa SJ. Associations of vitamin D with insulin resistance, obesity, type 2 diabetes, and metabolic syndrome. J Steroid Biochem Mol Biol. 2018;175:177–89.CrossRefPubMed
42.
Zurück zum Zitat Zhang J, McCullough PA, Tecson KM. Vitamin D deficiency in association with endothelial dysfunction: Implications for patients with COVID-19. Rev Cardiovasc Med. 2020;21(3):339–44.CrossRefPubMed Zhang J, McCullough PA, Tecson KM. Vitamin D deficiency in association with endothelial dysfunction: Implications for patients with COVID-19. Rev Cardiovasc Med. 2020;21(3):339–44.CrossRefPubMed
43.
Zurück zum Zitat Bird AP. CpG-rich islands and the function of DNA methylation. Nature. 1986;321(6067):209–13.CrossRefPubMed Bird AP. CpG-rich islands and the function of DNA methylation. Nature. 1986;321(6067):209–13.CrossRefPubMed
44.
Zurück zum Zitat 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):523–32.CrossRefPubMed 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):523–32.CrossRefPubMed
Metadaten
Titel
VDR downregulation and promoter hypermethylation as one of the causes for triggering type 2 diabetes mellitus: Clinical and molecular studies
verfasst von
Najeebul Tarfeen
Shariq Rashid Masoodi
Khair Ul Nisa
Shafat Ali
Mir Bilal Ahmad
Bashir Ahmad Ganai
Publikationsdatum
29.07.2023
Verlag
Springer International Publishing
Erschienen in
Journal of Diabetes & Metabolic Disorders / Ausgabe 2/2023
Elektronische ISSN: 2251-6581
DOI
https://doi.org/10.1007/s40200-023-01266-6

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