Article PDF


type 2 diabetes mellitus, nephropathy, TNFα, rs1800629

Abstract views: 209
PDF Downloads: 121

How to Cite

Ziablitsev, S., Chernobrytsevs, O., & Ziablytsev, D. (2018). SIGNIFICANCE OF THE TUMOR NECROTIC FACTOR ALPHA IN DEVELOPMENT OF NEPHROPATHY IN TYPE 2 DIABETES MELLITUS. Medical Science of Ukraine (MSU), 14(3-4), 43-51.


Relevance. The value of tumor necrosis factor alpha (TNFα) and the polymorphism of its gene rs1800629 for the development of type 2 diabetes mellitus (DM) has been shown in some studies but the mechanism of such an effect and role in some ethnic populations of patients is not fully understood.

Objective: to find out the value of TNFα and polymorphism of its gene rs1800629 in the development of type 2 DM and its vascular complications.

Materials and methods. The study involved data from 152 Ukrainian patients with type 2 DM, aged 34-80 years (53.9±8.4 years) and 95 healthy persons (control). According to the results of clinical and laboratory examinations, the presence of complications was determined and the stage of the disease was established. The blood level of TNFα was determined by the immuneenzyme method (Bender Medsystems, Austria); polymorphism rs1800629 – by real time polymerase chain reaction (TaqMan Mutation Detection Assays Life-Technology, USA). Statistical data processing was used by Statistica 10 (StatSoft, Inc., USA).

Results. The blood level of TNFα in type 2 DM significantly increased in accordance with the severity of the disease (the maximum in the third stage – 7,1 times; p=3,2e-17), which influenced the development of retinopathy (β=0,012; p=0,049), nephropathy by glomerular filtration rate (β=0,011; p=0,007) and arterial hypertension (β=0,007; p=0,042); the maximum was the effect on the development of macroangiopathy of the lower extremities (β=0.033; p<0.001). Minor allele A rs1800629 increased (OR=1,71; 95% CI 1,11-2.65; p=0,015) risk of type 2 DM. For genotypes the connection with the disease is confirmed by the dominant model of inheritance (G/G versus G/A+A/A; OR=1,87; 95% CI 1,10-3,18; p=0,020). Allele A contributed to a decrease in the velocity of glomerular filtration and was associated with the development of nephropathy (χ2=6,38; p=0,041). This could be due to higher TNFα levels in  G/A genotypes-carriers (1,2 times) and A/A (1,7 fold) compared to genotype G/G-carriers (p<0,001).

Conclusion. The presence of the allele A rs1800629 was an important factor in the diabetic nephropathy development; one of the mechanisms of the vascular diabetic complications development was excessive expression of the TNFα gene, resulting in excessive synthesis of TNFα.
Article PDF


Copps K.D., White M.F. Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2 // Diabetologia. 2012. Vol. 55, No. 10. P. 2565-2582. DOI: 10.1007/s00125-012-2644-8.

Dhamodharan U., Viswanathan V., Krishnamoorthy E., Rajaram R., Aravindhan V. Genetic association of IL-6, TNF-α and SDF-1 polymorphisms with serum cytokine levels in diabetic foot ulcer // Gene. 2015. Vol. 565, No. 1. P. 62-67. DOI: 10.1016/j.gene.2015.03.063.

Doody N.E., Dowejko M.M., Akam E.C., Cox N.J., Bhatti J.S., Singh P., Mastana S.S. The role of TLR4, TNF-α and IL-1β in type 2 diabetes mellitus development within a North Indian population // Ann Hum Genet. 2017. Vol. 81, No. 4. P. 141-146. DOI: 10.1111/ahg.12197

Hameed I., Masoodi S.R., Malik P.A., Mir S.A., Ghazanfar K., Ganai B.A. Genetic variations in key inflammatory cytokines exacerbates the risk of diabetic nephropathy by influencing the gene expression // Gene. 2018. Vol. 661. P. 51-59. DOI: 10.1016/j.gene.2018.03.095.

IDF Diabetes Atlas Eighth Edition // 2017. 149.

IRS1 – Insulin receptor substrate 1 – Homo sapiens (Human) – IRS1 gene & protein". Retrieved 2016-04-21.

Jamil K., Jayaraman A., Ahmad J., Joshi S., Yerra S.K. TNF-alpha -308G/A and -238G/A polymorphisms and its protein network associated with type 2 diabetes mellitus // Saudi J Biol Sci. 2017. Vol. 24, No. 6. P. 1195-1203. DOI: 10.1016/j.sjbs.2016.05.012

Liu C., Feng X., Li Q., Wang Y., Li Q., Hua M. Adiponectin, TNF-α and inflammatory cytokines and risk of type 2 diabetes: A systematic review and meta-analysis // Cytokine. 2016. Vol. 86. P. 100-109. DOI: 10.1016/j.cyto.2016.06.028.

Liu Z.H., Ding Y.L., Xiu L.C., Pan H.Y., Liang Y., Zhong S.Q., Liu W.W., Rao S.Q., Kong D.L. A meta-analysis of the association between TNF-α -308G>A polymorphism and type 2 diabetes mellitus in Han Chinese population // PLoS One. 2013. Vol. 8, No. 3. e59421. DOI: 10.1371/journal.pone.0059421.

Luna G.I., da Silva I.C., Sanchez M.N. Association between -308G/A TNFA polymorphism and susceptibility to type 2 diabetes mellitus: a systematic review // J Diabetes Res. 2016. DOI: 2016:6309484

Order of the Ministry of Health of Ukraine; dated December 21, 2012, No. 1118 "On Approval and Implementation of Medical-Technological Documents for the Standardization of Medical Aid in Type 2 Diabetes". Unified clinical protocol for primary and secondary (specialized) medical aid "Diabetes type 2" / 2012. Kyiv. [In Ukrainian]

Pankiv VI. Diabetes mellitus: diagnostic criteria, etiology and pathogenesis // International Endocrinology Journal. 2013. Vol. 8, No. 56. P. 53-64. [In Russian]

Sesti L.F., Crispim D., Canani L.H., Polina E.R., Rheinheimer J., Carvalho P.S., Gross J.L., Santos K.G. The -308G>A polymorphism of the TNF gene is associated with proliferative diabetic retinopathy in Caucasian Brazilians with type 2 diabetes // Invest Ophthalmol Vis Sci. 2015. Vol. 56, No. 2. P. 1184-1190. DOI: 10.1167/iovs.14-15758.

Sinyachenko O.V., Ziablitsev S.V., Chernobryvtsev P.A. [Endothelial dysfunction in glomerulonephritis] / Donetsk: New World, 2006. 152 s. [In Russian]

Takaguri A. [Elucidation of a new mechanism of onset of insulin resistance: effects of statins and tumor necrosis factor-α on insulin signal transduction] // Yakugaku Zasshi. 2018. Vol. 138, No. 11. P. 1329-1334. DOI: 10.1248/yakushi.18-00116. [In Japanese]

Umapathy D., Krishnamoorthy E., Mariappanadar V., Viswanathan V., Ramkumar K.M. Increased levels of circulating (TNF-α) is associated with (-308G/A) promoter polymorphism of TNF-α gene in Diabetic Nephropathy // Int J Biol Macromol. 2018. Vol. 107 (Pt B). P. 2113-2121. DOI: 10.1016/j.ijbiomac.2017.10.078.

Van Asten V.S.A., Nichols A., La Fontaine J., Bhavan K., Peters E.J., Lavery L.A. The value of inflammatory markers to diagnose and monitor diabetic foot osteomyelitis // Int Wound J. 2017. Vol. 14, No. 1. P. 40-45. DOI: 10.1111/iwj.12545.

Van Asten V.S.A., Peters G.E.J., Xi Y., Lavery L.A. The role of biomarkers to diagnose diabetic foot osteomyelitis. A meta-analysis // Curr Diabetes Rev. 2016. Vol. 12, No. 4. P. 396-402.

Zagozda M., Sarnecka A., Staszczak Z., Gałkowska H., Andziak P., Olszewski W.L., Durlik M. Genetic polymorphism and messenger ribonucleic acid concentrations of TNFα and TGFβ genes in patients with chronic lower limb infections // Surg Infect (Larchmt). 2015. Vol. 16, No. 6. P. 822-828. DOI: 10.1089/sur.2014.205.

Zhao Y., Li Z., Zhang L., Zhang Y., Yang Y., Tang Y., Fu P. The TNF-alpha -308G/A polymorphism is associated with type 2 diabetes mellitus: an updated meta-analysis // Mol Biol Rep. 2014. Vol. 41, No. 1. P. 73-83. DOI: 10.1007/s11033-013-2839-1

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.