The role of epigenetic modifications in the formation of heterogeneous phenotypes in diabetes mellitus (a literature review)


  • O.V. Zinych SI “V.P. Komissarenko Institute of Endocrinology and Metabolism of the National Academy of Medical Science”, Vyshhorodska str., 69, Kyiv, 04114, Ukraine
  • A.A. Shuprovych SI “V.P. Komissarenko Institute of Endocrinology and Metabolism of the National Academy of Medical Science”, Vyshhorodska str., 69, Kyiv, 04114, Ukraine
  • O.M. Trofymenko SI “V.P. Komissarenko Institute of Endocrinology and Metabolism of the National Academy of Medical Science”, Vyshhorodska str., 69, Kyiv, 04114, Ukraine
  • K.P. Komisarenko SI “V.P. Komissarenko Institute of Endocrinology and Metabolism of the National Academy of Medical Science”, Ukraine



type 2 diabetes, epigenetic modifications, gene expression, DNA methylation


This review article provides a summary and update on the role of epigenetic mechanisms in predisposition and progression of diabetes, analyzes the data concerning the cause-and-effect relationship between epigenetic changes and the emergence of distinct metabolic phenotypes. Extensive genetic research has enabled the isolation of a group of genes associated with a high risk of developing diabetes. However, numerous data point to the key role of so-called epigenetic modifications in the interaction between genes and the environment, which arise during ontogenesis based on the existing genotype under the influence of external factors. These modifications do not affect the primary DNA sequence, but influence gene expression through chemical modification and alteration of the secondary structure of DNA molecules and chromatin. Epigenetic mechanisms can program pathological phenotypes in subsequent generations. The main molecular mechanisms of epigenetic modifications are DNA methylation, histone and miRNA modification. Changes in the expression of genes that ensure the synthesis of key enzymes and regulatory molecules lead to disruption in the main signaling metabolic pathways. Deregulation of genes responsible for inflammatory, atherosclerotic and other pathological processes, in particular, leads to endothelial dysfunction and development of diabetic complications, such as cardiovascular diseases, diabetic nephropathy, retinopathy, neuropathy. Hyperglycemia, oxidative stress, inflammatory factors are known as mediators in the pathogenesis of type 2 diabetes and its complications. Since epigenetic modifications are reversible, the methylation process can be influenced by exercise, dietary, lifestyle changes and pharmacological agents such as methyl group donors. For example, S-adenosylmethionine, through participation in methylation reactions, can modulate the folate cycle function and production of homocysteine, an endothelium-toxic substance. Thus, the study of molecular modifications in chromatin structure and the features of activation and inhibition of various signaling pathways is a pressing task, the resolution of which will enable a deeper understanding of the pathogenesis of diabetes and the development of approaches to correct metabolic disorders.


Korpachev VV, Prybyla OV, Korpacheva-Zinych OV, Kushnareva NM, Gurina NM, Kovalchuk AV. [Anthropometric, hormonal and biochemical markers of metabolic phenotype in patients with type 2 diabetes]. [Internet]. Universum: medicine and pharmacology: electron scientific magazine. 2016 [cited 2023 Apr 17];1-2(24). Russian. Available from:

Cavalli G, Heard E. Advances in epigenetics link genetics to the environment and disease. Nature. 2019 Jul;571(7766):489-99. doi:

Glotka LI. [Role of genetic and epigenetic factors in formation of obesity and cardiometabolic disorders in boys]. Ukrainian Journal of Pediatric Endocrinology. 2020;4:4-7. Ukrainian. doi:

Savelyeva-Kulik NA. [Obesity and diabetes: reversible epigenetics and lifestyle – the key to success?]. Ukrainian medical journal. 2019;05:02. Russian.

Wang L, Dong C, Lu C, Li S, Fu L, Cong B. A study of strong nucleosomes in the human genome. Science. 2022 Jun 13;25(7):104593. doi:

Hale PJ, López-Yunez AM, Chen JY. Genome-wide meta-analysis of genetic susceptible genes for Type 2 Diabetes. BMC Syst Biol. 2012;6(Suppl 3):S16. doi:

DeForest N, Majithia AR. Genetics of Type 2 Diabetes: Implications from Large-Scale Studies. Curr Diab Rep. 2022 May;22(5):227-35. doi:

Wu Y, Tian H, Wang W, Li W, Duan H, Zhang D. DNA methylation and waist-to-hip ratio: an epigenome-wide association study in Chinese monozygotic twins. J Endocrinol Invest. 2022 Dec;45(12):2365-76. doi:

ElSayed NA, Aleppo G, Aroda VR, Bannuru RR, Brown F, Bruemmer D, et al. on behalf of the American Diabetes Association. Diabetes Technology: Standards of Care in Diabetes-2023. Diabetes Care. 2023;46(Suppl 1):S19-S40. doi:

Dashti M, Nizam R, Hebbar P, Jacob S, Sumi E, Channanath A, et al. Differentially methylated and expres¬sed genes in familial type 1 diabetes. Sci Rep. 2022;12:11045. doi:

Piko P, Werissa NA, Fiatal S, Sandor J, Adany R. Impact of genetic factors on the age of onset for type 2 diabetes mellitus in addition to the conventional risk factors. J Pers Med. 2020;11(1):6. doi:

Touré M, Samb A, Sène M, Thiam S, Mané CA, et al. Impact of the interaction between the polymorphisms and hypermethylation of the CD36 gene on a new biomarker of type 2 diabetes mellitus: circulating soluble CD36 (sCD36) in Senegalese females. BMC Med Genomics. 2022;15(1):186. doi:

Ling CJ, Rönn T. Epigenetics in human obesity and type 2 diabetes. Cell Metab. 2019;29:1028-44. doi:

Ling CJ. Epigenetic regulation of insulin action and secretion – role in the pathogenesis of type 2 diabetes. Intern Med. 2020 Aug;288(2):158-67. doi:

Suárez R, Chapela SP, Álvarez-Córdova L, Bautista-Valarezo E, Sarmiento-Andrade Y, Verde L, et al. Epigenetics in Obesity and Diabetes Mellitus: New Insights. Nutrients. 2023;15(4):811. doi:

Parveen N, Dhawan S. DNA Methylation Patter-ning and the Regulation of Beta Cell Homeostasis. Front Endocrinol (Lausanne). 2021;12:651258. doi:

Maden SK, Walsh B, Ellrott K, Hansen KD, Thompson RF, Nellore A. recountmethylation enables flexible analysis of public blood DNA methylation array data. Bioinform Adv. 2023 Feb 20;3(1):vbad020. doi:

Zatterale F, Raciti GA, Prevenzano I, Leone A, Campitelli M, De Rosa V, et al. Epigenetic Reprogram-ming of the Inflammatory Response in Obesity and Type 2 Diabetes. Biomolecules. 2022 Jul 14;12(7):982. doi:

Akbari M, Hassan-Zadeh V. The inflammatory effect of epigenetic factors and modifications in type 2 diabetes. Inflammopharmacology. 2020 Apr;28(2):345-62. doi:

Wang X, Yang W, Zhu Y, Zhang S, Jiang M, Hu J, et al. Genomic DNA methylation in diabetic chronic complications in patients with type 2 diabetes mellitus. Front Endocrinol. 2022;13:896511. doi:

Zhang H, Han X, Wang M, Hu Q, Li S, Wang M, et al. The association between genomic DNA methylation and diabetic peripheral neuropathy in patients with type 2 diabetes mellitus. J Diabetes Res. 2019;2019:2494057. doi:

Vaiserman A, Lushchak O. Developmental origins of type 2 diabetes: Focus on epigenetics. Ageing Res Rev. 2019 Nov;55:100957. doi:

Novak A, Bowman P, Kraljevic I, Tripolski M, Houghton JA, De Franco E, et al. Transient Neonatal Diabetes: An Etiologic Clue for the Adult Diabetologist. Can J Diabetes. 2020 Mar;44(2):128-30. doi:

Khan AI. Do second generation sequencing tech-niques identify documented genetic markers for neonatal diabetes mellitus? Heliyon. 2021 Aug 30;7(9):e07903. doi:

Tolstikova OO, Aharkov SF. [Modern views on metabolic syndrome in children and adolescents]. Likarska sprava. 2019;5-6:27-39. Ukrainian. doi:

Meyre D, Andress EJ, Sharma T, Snippe M, Asif H, Maharaj A, et al. Contribution of rare coding mutations in CD36 to type 2 diabetes and cardio-meta-bolic complications. Sci Rep. 2019 Nov 20;9(1):17123. doi:

Mansour A, Mousa M, Abdelmannan D, Tay G, Hassoun A, Alsafar H. Microvascular and macrovascular complications of type 2 diabetes mellitus: Exome wide association analyses. Front Endocrinol (Lausanne). 2023 Mar 23;14:1143067. doi:

Reznikov OG, Sachynska OV, Falіush OA, Lymaryeva AA, Perchyk IG. [Endocrine disruptors — prenatal factors of reproductive health disorders]. Endokrynologia. 2023;28(1):21-35. Ukrainian. doi:

Kern B, Podkrajšek K, Kovač J, Šket R, Bizjan B, Tesovnik T, et al. The role of epigenetic modifications in late complications in type 1 diabetes. Genes. 2022;13(4):705. doi:

Sokolova L, Pushkarev V, Kovzun E, Pushkarev V, Tronko N. Metabolic-associated diseass and the role of epigenetics and epigenetic age in their prevention. Ukrainian J Cardiol [Internet]. 2017Jan.1;(6):104-15. Available from:

Shtanko VA, Tikhonova SA, Khyzhnyak OV, Marish MYu, Tesliuk GB. [The role of genetic and epigenetic factors in the formation of hypertensive phenotype and associated metabolic disorders in patients with arterial hypertension]. Integrative Anthropology. 2015;1:38-41. Ukrainian.

Kumric M, Ticinovic Kurir T, Borovac JA, Bo-zic J. Role of novel biomarkers in diabetic cardio¬myo-pathy. World J Diabetes. 2021;12(6):685-705. doi:

Prandi F, Lecis D, Illuminato F, Milite M, Celotto R, Lerakis S, et al. Epigenetic modifications and non-coding RNA indiabetes-mellitus-induced coronary artery disease: pathophysiological link and new therapeutic frontiers. Int J Mol Sci. 2022;23:4589. doi:

Geng T, Zhu K, Lu Q, Wan Z, Chen X, Liu L, et al. Healthy lifestyle behaviors, mediating biomarkers, and risk of microvascular complications among individuals with type 2 diabetes: A cohort study. PLoS Med. 2023 Jan 10;20(1):e1004135. doi:

Rönn T, Volkov P, Davegårdh C, Dayeh T, Hall E, et al. A six months exercise intervention influences the genome-wide DNA methylation pattern in human adipose tissue. PloS Genet. 2013;9(6):e1003572. doi:

Garcia LA, Zapata-Bustos R, Day SE, Campos B, Hamzaoui Y, Wu L, et al. Can exercise training alter human skeletal muscle DNA methylation? Metabolites. 2022;12(3):222. doi:

Światowy WJ, Drzewiecka H, Kliber M, Sąsia-dek M, Karpiński P, Pławski A, et al. Physical Activity and DNA Methylation in Humans. Int J Mol Sci. 2021 Nov 30;22(23):12989. doi:

Sun C, Förster F, Gutsmann B, Moulla Y, Stroh C, Dietrich A, et al. Metabolic effects of the waist-to-hip ratio associated locus GRB14/COBLL1 are related to GRB14 expression in adipose tissue. Int J Mol Sci. 2022;23(15):8558. doi:

Nicoletti CF, Roschel H, Merege-Filho C, Lima AP, Gil S, Pinhel MA, et al. Exercise training and DNA methylation profile in post-bariatric women: Results from an exploratory study. Front Sports Act Living. 2023 Feb 8;5:1092050. doi:

Hunter DJ, James LS, Hussey B, Ferguson RA, Lindley MR, Mastana SS. Impacts of Eccentric Resistance Exercise on DNA Methylation of Candidate Genes for Inflammatory Cytokines in Skeletal Muscle and Leukocytes of Healthy Males. Genes (Basel). 2023 Feb 13;14(2):478. doi:

Garcia LA, Zapata-Bustos R, Day SE, Campos B, Hamzaoui Y, Wu L, et al. Can exercise training alter hu-man skeletal muscle DNA methylation? Metabolites. 2022;12(3):222. doi:

Raghubeer S, Matsha T. Methylenetetrahydrofolate (MTHFR), the one-carbon cycle, and cardiovascular risks. Nutrients. 2021;13(12):4562. doi:

Zhao M, Yuan M, Yuan L, Huang LL, Liao JH, Yu XL, et al. Chronic folate deficiency induces glucose and lipid metabolism disorders and subsequent cognitive dysfunction in mice. PLoS One. 2018;13(8):e0202910. doi:

Elias MF, Brown CJ. New Evidence for Homocysteine Lowering for Management of Treatment-Resis-tant Hypertension. Am J Hypertens. 2022 Apr 2;35(4):303-5. doi:

Smyth L, Kilner J, Nair V, Liu H, Brennan E, Kerr K, et al. Assessment of differentially methylated loci in individuals with end-stage kidney disease attributed to diabetic kidney disease: An exploratorystudy. Clin. Epigenetics 2021;13(1):99. doi:

Singh R, Chandel S, Dey D, Ghosh A, Roy S, Ravichandiran V, et al. Epigenetic modification and therapeutic targets of diabetes mellitus. Biosci Rep. 2020 Sep 30;40(9):BSR20202160. doi:

Shuprovych A, Trofymenko O. Shuprovych A, Trofymenko O. [Significance of folate cycle gene polymorphisms and their epigenetic modifications in the pathogenesis of type 2 diabetes and its complications]. Endokrynolohiia. 2022 Sep 30;27(3):243-50. Ukrainian. doi:

Kolesnikova OV, Zaprovalna OE, Potapenko AV. [Metabolic-associated diseases and the role of epigenetics, eoigenetic age in their prevention]. Therapeutic Journal. 2020;3:52-60. Ukrainian. doi:

Zinych OV, Shuprovich AA, Prybyla OV, Kushnareva NM, Kovalchuk AV, Korpachev VV, et al. [Peculiarities of anabolic-catabolic balance in type 2 diabetic patients with different metabolic phenotypes]. 2023;80(1):22-9. Ukrainian. doi:



How to Cite

Zinych O, Shuprovych A, Trofymenko O, Komisarenko K. The role of epigenetic modifications in the formation of heterogeneous phenotypes in diabetes mellitus (a literature review). Med. perspekt. [Internet]. 2023Sep.29 [cited 2024Feb.29];28(3):28-35. Available from: