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  • Review Article
  • Published:

Epigenetics of type 2 diabetes mellitus and weight change — a tool for precision medicine?

Nature Reviews Endocrinology volume 18, pages 433–448 (2022)Cite this article

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Abstract

Pioneering studies performed over the past few decades demonstrate links between epigenetics and type 2 diabetes mellitus (T2DM), the metabolic disorder with the most rapidly increasing prevalence in the world. Importantly, these studies identified epigenetic modifications, including altered DNA methylation, in pancreatic islets, adipose tissue, skeletal muscle and the liver from individuals with T2DM. As non-genetic factors that affect the risk of T2DM, such as obesity, unhealthy diet, physical inactivity, ageing and the intrauterine environment, have been associated with epigenetic modifications in healthy individuals, epigenetics probably also contributes to T2DM development. In addition, genetic factors associated with T2DM and obesity affect the epigenome in human tissues. Notably, causal mediation analyses found DNA methylation to be a potential mediator of genetic associations with metabolic traits and disease. In the past few years, translational studies have identified blood-based epigenetic markers that might be further developed and used for precision medicine to help patients with T2DM receive optimal therapy and to identify patients at risk of complications. This Review focuses on epigenetic mechanisms in the development of T2DM and the regulation of body weight in humans, with a special focus on precision medicine.

Key points

  • Type 2 diabetes mellitus (T2DM) is a common metabolic disease that involves insulin resistance of adipose tissue, skeletal muscle and the liver, and impaired insulin secretion from the pancreatic islets.

  • As a multifactorial disease, T2DM has a genetic component; epigenetics might explain the missing heritability, and it is also strongly influenced by non-genetic factors, for example, exercise, diet, obesity and ageing.

  • Epigenetic alterations, including DNA methylation, are found in several tissues from patients with T2DM and are also associated with environmental factors known to increase risk of the disease.

  • Human studies demonstrate how the epigenome mediates the effects of both genetic variation and environmental exposures on gene expression and cell functions associated with T2DM and obesity.

  • Epigenetic factors might be induced by the environment, heritable, or stochastic, and they act together to define the epigenetic profile of each cell and tissue.

  • Epigenetic marks can potentially be used as biomarkers for prediction of T2DM, risk of vascular complications, and response to therapy and lifestyle interventions, thereby offering a tool for precision medicine.

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Fig. 1: Epigenetic modifications in human pancreatic islets and their impact on insulin secretion and type 2 diabetes mellitus.
Fig. 2: Do epigenetic modifications cause pancreatic islet dysfunction?
Fig. 3: Epigenetic modifications in human skeletal muscle, adipose tissue and liver and their effect on insulin resistance and type 2 diabetes mellitus.
Fig. 4: Interactions between genetic variance and the epigenome.
Fig. 5: Epigenetic biomarkers for precision medicine in type 2 diabetes mellitus and obesity.
Fig. 6: Targeting the epigenome in type 2 diabetes mellitus therapy.
Fig. 7: The role of epigenetics in type 2 diabetes mellitus and obesity.

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References

  1. Volkov, P. et al. Whole-genome bisulfite sequencing of human pancreatic islets reveals novel differentially methylated regions in type 2 diabetes pathogenesis. Diabetes 66, 1074–1085 (2017).

    Article  CAS  PubMed  Google Scholar 

  2. Jones, P. A. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat. Rev. Genet. 13, 484–492 (2012).

    Article  CAS  PubMed  Google Scholar 

  3. Eliasson, L. & Regazzi, R. Micro(RNA) management and mismanagement of the islet. J. Mol. Biol. 432, 1419–1428 (2020).

    Article  CAS  PubMed  Google Scholar 

  4. Mahajan, A. et al. Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps. Nat. Genet. 50, 1505–1513 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Locke, A. E. et al. Genetic studies of body mass index yield new insights for obesity biology. Nature 518, 197–206 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Da Silva Xavier, G. The cells of the islets of Langerhans. J. Clin. Med. 7, 54 (2018).

    Article  PubMed Central  CAS  Google Scholar 

  7. Galicia-Garcia, U. et al. Pathophysiology of type 2 diabetes mellitus. Int. J. Mol. Sci. 21, 6275 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  8. Avrahami, D. et al. Aging-dependent demethylation of regulatory elements correlates with chromatin state and improved beta cell function. Cell Metab. 22, 619–632 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Bacos, K. et al. Blood-based biomarkers of age-associated epigenetic changes in human islets associate with insulin secretion and diabetes. Nat. Commun. 7, 11089 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Daneshpajooh, M. et al. HDAC7 is overexpressed in human diabetic islets and impairs insulin secretion in rat islets and clonal beta cells. Diabetologia 60, 116–125 (2017).

    Article  CAS  PubMed  Google Scholar 

  11. Daneshpajooh, M., Eliasson, L., Bacos, K. & Ling, C. MC1568 improves insulin secretion in islets from type 2 diabetes patients and rescues beta-cell dysfunction caused by Hdac7 upregulation. Acta Diabetol. 55, 1231–1235 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Dayeh, T. et al. Genome-wide DNA methylation analysis of human pancreatic islets from type 2 diabetic and non-diabetic donors identifies candidate genes that influence insulin secretion. PLoS Genet. 10, e1004160 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Dhawan, S. et al. DNA methylation directs functional maturation of pancreatic beta cells. J. Clin. Invest. 125, 2851–2860 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Hall, E. et al. DNA methylation of the glucagon-like peptide 1 receptor (GLP1R) in human pancreatic islets. BMC Med. Genet. 14, 76 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hall, E. et al. Glucolipotoxicity alters insulin secretion via epigenetic changes in human islets. Diabetes 68, 1965–1974 (2019).

    Article  CAS  PubMed  Google Scholar 

  16. Hall, E. et al. Sex differences in the genome-wide DNA methylation pattern and impact on gene expression, microRNA levels and insulin secretion in human pancreatic islets. Genome Biol. 15, 522 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Malmgren, S. et al. Coordinate changes in histone modifications, mRNA levels, and metabolite profiles in clonal INS-1 832/13 beta-cells accompany functional adaptations to lipotoxicity. J. Biol. Chem. 288, 11973–11987 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Olsson, A. H. et al. Genome-wide associations between genetic and epigenetic variation influence mRNA expression and insulin secretion in human pancreatic islets. PLoS Genet. 10, e1004735 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Yang, B. T. et al. Increased DNA methylation and decreased expression of PDX-1 in pancreatic islets from patients with type 2 diabetes. Mol. Endocrinol. 26, 1203–1212 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kameswaran, V. et al. Epigenetic regulation of the DLK1-MEG3 microRNA cluster in human type 2 diabetic islets. Cell. Metab. 19, 135–145 (2014).

    Article  CAS  PubMed  Google Scholar 

  21. Ling, C. et al. Epigenetic regulation of PPARGC1A in human type 2 diabetic islets and effect on insulin secretion. Diabetologia 51, 615–622 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Volkmar, M. et al. DNA methylation profiling identifies epigenetic dysregulation in pancreatic islets from type 2 diabetic patients. EMBO J. 31, 1405–1426 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yang, B. T. et al. Insulin promoter DNA methylation correlates negatively with insulin gene expression and positively with HbA(1c) levels in human pancreatic islets. Diabetologia 54, 360–367 (2011).

    Article  CAS  PubMed  Google Scholar 

  24. Kaneto, H. et al. PDX-1 functions as a master factor in the pancreas. Front. Biosci. 13, 6406–6420 (2008).

    Article  CAS  PubMed  Google Scholar 

  25. Lytrivi, M., Castell, A. L., Poitout, V. & Cnop, M. Recent insights into mechanisms of beta-cell lipo- and glucolipotoxicity in type 2 diabetes. J. Mol. Biol. 432, 1514–1534 (2020).

    Article  CAS  PubMed  Google Scholar 

  26. Hall, E. et al. The effects of high glucose exposure on global gene expression and DNA methylation in human pancreatic islets. Mol. Cell Endocrinol. 472, 57–67 (2018).

    Article  CAS  PubMed  Google Scholar 

  27. Hall, E. et al. Effects of palmitate on genome-wide mRNA expression and DNA methylation patterns in human pancreatic islets. BMC Med. 12, 103 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Carlsson, M., Wessman, Y., Almgren, P. & Groop, L. High levels of nonesterified fatty acids are associated with increased familial risk of cardiovascular disease. Arterioscler. Thromb. Vasc. Biol. 20, 1588–1594 (2000).

    Article  CAS  PubMed  Google Scholar 

  29. Tramunt, B. et al. Sex differences in metabolic regulation and diabetes susceptibility. Diabetologia 63, 453–461 (2020).

    Article  PubMed  Google Scholar 

  30. Pasquali, L. et al. Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants. Nat. Genet. 46, 136–143 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bhandare, R. et al. Genome-wide analysis of histone modifications in human pancreatic islets. Genome Res. 20, 428–433 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Parker, S. C. et al. Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants. Proc. Natl Acad. Sci. USA 110, 17921–17926 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Khetan, S. et al. Type 2 diabetes-associated genetic variants regulate chromatin accessibility in human islets. Diabetes 67, 2466–2477 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Varshney, A. et al. Genetic regulatory signatures underlying islet gene expression and type 2 diabetes. Proc. Natl Acad. Sci. USA 114, 2301–2306 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Bysani, M. et al. ATAC-seq reveals alterations in open chromatin in pancreatic islets from subjects with type 2 diabetes. Sci. Rep. 9, 7785 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Khalid, M., Alkaabi, J., Khan, M. A. B. & Adem, A. Insulin signal transduction perturbations in insulin resistance. Int. J. Mol. Sci. 22, 8590 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Lillioja, S. et al. Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus. Prospective studies of Pima Indians. N. Engl. J. Med. 329, 1988–1992 (1993).

    Article  CAS  PubMed  Google Scholar 

  38. James, D. E., Stockli, J. & Birnbaum, M. J. The aetiology and molecular landscape of insulin resistance. Nat. Rev. Mol. Cell Biol. 22, 751–771 (2021).

    Article  CAS  PubMed  Google Scholar 

  39. Petersen, M. C. & Shulman, G. I. Mechanisms of insulin action and insulin resistance. Physiol. Rev. 98, 2133–2223 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ryall, J. G. et al. The NAD+-dependent SIRT1 deacetylase translates a metabolic switch into regulatory epigenetics in skeletal muscle stem cells. Cell Stem Cell 16, 171–183 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Das, S. et al. ATP citrate lyase regulates myofiber differentiation and increases regeneration by altering histone acetylation. Cell Rep. 21, 3003–3011 (2017).

    Article  CAS  PubMed  Google Scholar 

  42. Davegardh, C. et al. VPS39-deficiency observed in type 2 diabetes impairs muscle stem cell differentiation via altered autophagy and epigenetics. Nat. Commun. 12, 2431 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Barres, R. et al. Non-CpG methylation of the PGC-1alpha promoter through DNMT3B controls mitochondrial density. Cell Metab. 10, 189–198 (2009).

    Article  CAS  PubMed  Google Scholar 

  44. Brons, C. et al. Deoxyribonucleic acid methylation and gene expression of PPARGC1A in human muscle is influenced by high-fat overfeeding in a birth-weight-dependent manner. J. Clin. Endocrinol. Metab. 95, 3048–3056 (2010).

    Article  PubMed  CAS  Google Scholar 

  45. Bysani, M. et al. Epigenetic alterations in blood mirror age-associated DNA methylation and gene expression changes in human liver. Epigenomics 9, 105–122 (2017).

    Article  CAS  PubMed  Google Scholar 

  46. Davegårdh, C. et al. Abnormal epigenetic changes during differentiation of human skeletal muscle stem cells from obese subjects. BMC Med. 15, 39–39 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Dayeh, T. et al. DNA methylation of loci within ABCG1 and PHOSPHO1 in blood DNA is associated with future type 2 diabetes risk. Epigenetics 11, 482–488 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Gillberg, L. et al. Adipose tissue transcriptomics and epigenomics in low birthweight men and controls: role of high-fat overfeeding. Diabetologia 59, 799–812 (2016).

    Article  CAS  PubMed  Google Scholar 

  49. Jacobsen, S. C. et al. Young men with low birthweight exhibit decreased plasticity of genome-wide muscle DNA methylation by high-fat overfeeding. Diabetologia 57, 1154–1158 (2014).

    Article  CAS  PubMed  Google Scholar 

  50. Ling, C. et al. Genetic and epigenetic factors are associated with expression of respiratory chain component NDUFB6 in human skeletal muscle. J. Clin. Invest. 117, 3427–3435 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Mudry, J. M. et al. Insulin and glucose alter death-associated protein kinase 3 (DAPK3) DNA methylation in human skeletal muscle. Diabetes 66, 651–662 (2017).

    Article  CAS  PubMed  Google Scholar 

  52. Nilsson, E. et al. Altered DNA methylation and differential expression of genes influencing metabolism and inflammation in adipose tissue from subjects with type 2 diabetes. Diabetes 63, 2962–2976 (2014).

    Article  PubMed  Google Scholar 

  53. Nilsson, E. et al. Epigenetic alterations in human liver from subjects with type 2 diabetes in parallel with reduced folate levels. J. Clin. Endocrinol. Metab. 100, E1491–E1501 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Nilsson, E. et al. Differential DNA methylation and expression of micrornas in adipose tissue from twin pairs discordant for type 2. Diabetes 70, 2402–2418 (2021).

    Article  PubMed  Google Scholar 

  55. Nitert, M. D. et al. Impact of an exercise intervention on DNA methylation in skeletal muscle from first-degree relatives of patients with type 2 diabetes. Diabetes 61, 3322–3332 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Ribel-Madsen, R. et al. Genome-wide analysis of DNA methylation differences in muscle and fat from monozygotic twins discordant for type 2 diabetes. PLoS ONE 7, e51302 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Ronn, T. et al. Age influences DNA methylation and gene expression of COX7A1 in human skeletal muscle. Diabetologia 51, 1159–1168 (2008).

    Article  CAS  PubMed  Google Scholar 

  58. Ronn, T. et al. Impact of age, BMI and HbA1c levels on the genome-wide DNA methylation and mRNA expression patterns in human adipose tissue and identification of epigenetic biomarkers in blood. Hum. Mol. Genet. 24, 3792–3813 (2015).

    PubMed  Google Scholar 

  59. Mootha, V. K. et al. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat. Genet. 34, 267–273 (2003).

    Article  CAS  PubMed  Google Scholar 

  60. Taylor, D. L. et al. Integrative analysis of gene expression, DNA methylation, physiological traits, and genetic variation in human skeletal muscle. Proc. Natl Acad. Sci. USA 116, 10883–10888 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Chambers, J. C. et al. Epigenome-wide association of DNA methylation markers in peripheral blood from Indian Asians and Europeans with incident type 2 diabetes: a nested case-control study. Lancet Diabetes Endocrinol. 3, 526–534 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Peng, Y. et al. Phosphatase orphan 1 inhibits myoblast proliferation and promotes myogenic differentiation. FASEB J. 35, e21154 (2021).

    Article  CAS  PubMed  Google Scholar 

  63. Green, C. J., Pedersen, M., Pedersen, B. K. & Scheele, C. Elevated NF-kappaB activation is conserved in human myocytes cultured from obese type 2 diabetic patients and attenuated by AMP-activated protein kinase. Diabetes 60, 2810–2819 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Broholm, C. et al. Epigenetic programming of adipose-derived stem cells in low birthweight individuals. Diabetologia 59, 2664–2673 (2016).

    Article  PubMed  Google Scholar 

  65. Broholm, C. et al. Human adipogenesis is associated with genome-wide DNA methylation and gene-expression changes. Epigenomics 8, 1601–1617 (2016).

    Article  CAS  PubMed  Google Scholar 

  66. Keller, M. et al. Genome-wide DNA promoter methylation and transcriptome analysis in human adipose tissue unravels novel candidate genes for obesity. Mol. Metab. 6, 86–100 (2017).

    Article  CAS  PubMed  Google Scholar 

  67. You, D. et al. Dnmt3a is an epigenetic mediator of adipose insulin resistance. eLife 6, e30766 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Andersen, E. et al. Preadipocytes from obese humans with type 2 diabetes are epigenetically reprogrammed at genes controlling adipose tissue function. Int. J. Obes. 43, 306–318 (2019).

    Article  CAS  Google Scholar 

  69. Hotamisligil, G. S. Inflammation and metabolic disorders. Nature 444, 860–867 (2006).

    Article  CAS  PubMed  Google Scholar 

  70. Guenard, F. et al. Differential methylation in visceral adipose tissue of obese men discordant for metabolic disturbances. Physiol. Genomics 46, 216–222 (2014).

    Article  PubMed  CAS  Google Scholar 

  71. Castellano-Castillo, D. et al. Altered adipose tissue DNA methylation status in metabolic syndrome: relationships between global DNA methylation and specific methylation at adipogenic, lipid metabolism and inflammatory candidate genes and metabolic variables. J. Clin. Med. 8, 87 (2019).

    Article  CAS  PubMed Central  Google Scholar 

  72. Whincup, P. H. et al. Birth weight and risk of type 2 diabetes: a systematic review. JAMA 300, 2886–2897 (2008).

    Article  CAS  PubMed  Google Scholar 

  73. Hjort, L. et al. 36 h fasting of young men influences adipose tissue DNA methylation of LEP and ADIPOQ in a birth weight-dependent manner. Clin. Epigenetics 9, 40 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Arner, P. et al. The epigenetic signature of systemic insulin resistance in obese women. Diabetologia 59, 2393–2405 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Rodriguez-Rodero, S. et al. Altered intragenic DNA methylation of HOOK2 gene in adipose tissue from individuals with obesity and type 2 diabetes. PLoS ONE 12, e0189153 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Crujeiras, A. B. et al. Genome-wide DNA methylation pattern in visceral adipose tissue differentiates insulin-resistant from insulin-sensitive obese subjects. Transl. Res. 178, 13–24 (2016).

    Article  CAS  PubMed  Google Scholar 

  77. Sievert, H. et al. Epigenetic downregulation of FASN in visceral adipose tissue of insulin resistant subjects. Exp. Clin. Endocrinol. Diabetes 129, 674–682 (2021).

    Article  CAS  PubMed  Google Scholar 

  78. Nadiger, N. et al. Protocol for a prospective, observational, deep phenotyping study on adipose epigenetic and lipidomic determinants of metabolic homoeostasis in South Asian Indians: the Indian Diabetes and Metabolic Health (InDiMeT) study. BMJ Open 11, e043644 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Sharma, N. K. et al. Integrative analysis of glucometabolic traits, adipose tissue DNA methylation, and gene expression identifies epigenetic regulatory mechanisms of insulin resistance and obesity in African Americans. Diabetes 69, 2779–2793 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Wewer Albrechtsen, N. J. et al. The liver-alpha-cell axis and type 2 diabetes. Endocr. Rev. 40, 1353–1366 (2019).

    Article  PubMed  Google Scholar 

  81. Abderrahmani, A. et al. Increased Hepatic PDGF-AA signaling mediates liver insulin resistance in obesity-associated type 2 diabetes. Diabetes 67, 1310–1321 (2018).

    Article  CAS  PubMed  Google Scholar 

  82. Krause, C. et al. Multi-layered epigenetic regulation of IRS2 expression in the liver of obese individuals with type 2 diabetes. Diabetologia 63, 2182–2193 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Kirchner, H. et al. Altered DNA methylation of glycolytic and lipogenic genes in liver from obese and type 2 diabetic patients. Mol. Metab. 5, 171–183 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Prokopenko, I. et al. A central role for GRB10 in regulation of islet function in man. PLoS Genet. 10, e1004235 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Zhang, N. et al. Elevated hepatic expression of H19 long noncoding RNA contributes to diabetic hyperglycemia. JCI Insight 3, e120304 (2018).

    Article  PubMed Central  Google Scholar 

  86. Baumeier, C. et al. Hepatic DPP4 DNA methylation associates with fatty liver. Diabetes 66, 25–35 (2017).

    Article  CAS  PubMed  Google Scholar 

  87. Rusu, V. et al. Type 2 diabetes variants disrupt function of SLC16A11 through two distinct mechanisms. Cell 170, 199–212 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Lopez Rodriguez, M. et al. Identification and characterization of a FOXA2-regulated transcriptional enhancer at a type 2 diabetes intronic locus that controls GCKR expression in liver cells. Genome Med. 9, 63 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Knowler, W. C. et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N. Engl. J. Med. 346, 393–403 (2002).

    Article  CAS  PubMed  Google Scholar 

  90. Ronn, T. et al. A six months exercise intervention influences the genome-wide DNA methylation pattern in human adipose tissue. PLoS Genet. 9, e1003572 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Lindholm, M. E. et al. An integrative analysis reveals coordinated reprogramming of the epigenome and the transcriptome in human skeletal muscle after training. Epigenetics 9, 1557–1569 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Robinson, M. M. et al. Enhanced protein translation underlies improved metabolic and physical adaptations to different exercise training modes in young and old humans. Cell Metab. 25, 581–592 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Sailani, M. R. et al. Lifelong physical activity is associated with promoter hypomethylation of genes involved in metabolism, myogenesis, contractile properties and oxidative stress resistance in aged human skeletal muscle. Sci. Rep. 9, 3272 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Barres, R. et al. Acute exercise remodels promoter methylation in human skeletal muscle. Cell Metab. 15, 405–411 (2012).

    Article  CAS  PubMed  Google Scholar 

  95. Fabre, O. et al. Exercise training alters the genomic response to acute exercise in human adipose tissue. Epigenomics 10, 1033–1050 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Bajpeyi, S. et al. Skeletal muscle PGC1alpha -1 nucleosome position and -260 nt DNA methylation determine exercise response and prevent ectopic lipid accumulation in men. Endocrinology 158, 2190–2199 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Ruple, B. A. et al. Resistance training rejuvenates the mitochondrial methylome in aged human skeletal muscle. FASEB J. 35, e21864 (2021).

    Article  CAS  PubMed  Google Scholar 

  98. Rowlands, D. S. et al. Multi-omic integrated networks connect DNA methylation and miRNA with skeletal muscle plasticity to chronic exercise in type 2 diabetic obesity. Physiol. Genomics 46, 747–765 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Stephens, N. A. et al. Exercise response variations in skeletal muscle PCr recovery rate and insulin sensitivity relate to muscle epigenomic profiles in individuals with type 2 diabetes. Diabetes Care 41, 2245–2254 (2018).

    Article  CAS  PubMed  Google Scholar 

  100. Denham, J., O’Brien, B. J., Marques, F. Z. & Charchar, F. J. Changes in the leukocyte methylome and its effect on cardiovascular-related genes after exercise. J. Appl. Physiol. 118, 475–488 (2015).

    Article  CAS  PubMed  Google Scholar 

  101. Fernandez-Sanles, A. et al. Physical activity and genome-wide DNA methylation: the REgistre GIroni del COR study. Med. Sci. Sports Exerc. 52, 589–597 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Hunter, D. J. et al. Impact of aerobic exercise and fatty acid supplementation on global and gene-specific DNA methylation. Epigenetics 14, 294–309 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Kankaanpaa, A. et al. Leisure-time and occupational physical activity associates differently with epigenetic aging. Med. Sci. Sports Exerc. 53, 487–495 (2021).

    Article  PubMed  CAS  Google Scholar 

  104. Kresovich, J. K. et al. Associations of body composition and physical activity level with multiple measures of epigenetic age acceleration. Am. J. Epidemiol. 190, 984–993 (2021).

    Article  PubMed  Google Scholar 

  105. Lu, A. T. et al. DNA methylation GrimAge strongly predicts lifespan and healthspan. Aging 11, 303–327 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. White, A. J. et al. Recreational and household physical activity at different time points and DNA global methylation. Eur. J. Cancer 49, 2199–2206 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Nakajima, K. et al. Exercise effects on methylation of ASC gene. Int. J. Sports Med. 31, 671–675 (2010).

    Article  CAS  PubMed  Google Scholar 

  108. Denham, J., O’Brien, B. J., Harvey, J. T. & Charchar, F. J. Genome-wide sperm DNA methylation changes after 3 months of exercise training in humans. Epigenomics 7, 717–731 (2015).

    Article  CAS  PubMed  Google Scholar 

  109. Ingerslev, L. R. et al. Endurance training remodels sperm-borne small RNA expression and methylation at neurological gene hotspots. Clin. Epigenetics 10, 12 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Jonsson, J. et al. Lifestyle intervention in pregnant women with obesity impacts cord blood DNA methylation, which associates with body composition in the offspring. Diabetes 70, 854–866 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Antoun, E. et al. Maternal dysglycaemia, changes in the infant’s epigenome modified with a diet and physical activity intervention in pregnancy: secondary analysis of a randomised control trial. PLoS Med. 17, e1003229 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Jacobsen, S. C. et al. Effects of short-term high-fat overfeeding on genome-wide DNA methylation in the skeletal muscle of healthy young men. Diabetologia 55, 3341–3349 (2012).

    Article  CAS  PubMed  Google Scholar 

  113. Laker, R. C. et al. Transcriptomic and epigenetic responses to short-term nutrient-exercise stress in humans. Sci. Rep. 7, 15134 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Jorgensen, S. W. et al. Metabolic response to 36 hours of fasting in young men born small vs appropriate for gestational age. Diabetologia 58, 178–187 (2015).

    Article  PubMed  CAS  Google Scholar 

  115. Di Francesco, A., Di Germanio, C., Bernier, M. & de Cabo, R. A time to fast. Science 362, 770–775 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Gillberg, L. et al. Fasting unmasks differential fat and muscle transcriptional regulation of metabolic gene sets in low versus normal birth weight men. eBioMedicine 47, 341–351 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Fitzgerald, K. N. et al. Potential reversal of epigenetic age using a diet and lifestyle intervention: a pilot randomized clinical trial. Aging 13, 9419–9432 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Quach, A. et al. Epigenetic clock analysis of diet, exercise, education, and lifestyle factors. Aging 9, 419–446 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Sun, D. et al. Genetic, epigenetic and transcriptional variations at NFATC2IP locus with weight loss in response to diet interventions: the POUNDS Lost trial. Diabetes Obes. Metab. 20, 2298–2303 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Rosqvist, F. et al. Overfeeding polyunsaturated and saturated fat causes distinct effects on liver and visceral fat accumulation in humans. Diabetes 63, 2356–2368 (2014).

    Article  PubMed  Google Scholar 

  121. Bjermo, H. et al. Effects of n-6 PUFAs compared with SFAs on liver fat, lipoproteins, and inflammation in abdominal obesity: a randomized controlled trial. Am. J. Clin. Nutr. 95, 1003–1012 (2012).

    Article  CAS  PubMed  Google Scholar 

  122. Perfilyev, A. et al. Impact of polyunsaturated and saturated fat overfeeding on the DNA-methylation pattern in human adipose tissue: a randomized controlled trial. Am. J. Clin. Nutr. 105, 991–1000 (2017).

    Article  CAS  PubMed  Google Scholar 

  123. Arpon, A. et al. Impact of consuming extra-virgin olive oil or nuts within a mediterranean diet on DNA methylation in peripheral white blood cells within the PREDIMED-navarra randomized controlled trial: a role for dietary lipids. Nutrients 10, 15 (2017).

    Article  PubMed Central  CAS  Google Scholar 

  124. Corella, D., Coltell, O., Macian, F. & Ordovas, J. M. Advances in understanding the molecular basis of the mediterranean diet effect. Annu. Rev. Food Sci. Technol. 9, 227–249 (2018).

    Article  CAS  PubMed  Google Scholar 

  125. Ma, J. et al. Whole blood DNA methylation signatures of diet are associated with cardiovascular disease risk factors and all-cause mortality. Circ. Genom. Precis. Med. 13, e002766 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Phang, M. et al. Epigenetic aging in newborns: role of maternal diet. Am. J. Clin. Nutr. 111, 555–561 (2020).

    Article  PubMed  Google Scholar 

  127. Lai, C. Q. et al. Carbohydrate and fat intake associated with risk of metabolic diseases through epigenetics of CPT1A. Am. J. Clin. Nutr. 112, 1200–1211 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  128. Voisin, S. et al. Meta-analysis of genome-wide DNA methylation and integrative omics of age in human skeletal muscle. J. Cachexia Sarcopenia Muscle 12, 1064–1078 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Zhou, J. et al. Elevated H3K27ac in aged skeletal muscle leads to increase in extracellular matrix and fibrogenic conversion of muscle satellite cells. Aging Cell 18, e12996 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Bigot, A. et al. Age-associated methylation suppresses SPRY1, leading to a failure of re-quiescence and loss of the reserve stem cell pool in elderly muscle. Cell Rep. 13, 1172–1182 (2015).

    Article  CAS  PubMed  Google Scholar 

  131. Blocquiaux, S. et al. Recurrent training rejuvenates and enhances transcriptome and methylome responses in young and older human muscle. JCSM Rapid Commun. 5, 10–32 (2022).

    Article  Google Scholar 

  132. Horvath, S. et al. Obesity accelerates epigenetic aging of human liver. Proc. Natl Acad. Sci. USA 111, 15538–15543 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. de Toro-Martin, J. et al. Body mass index is associated with epigenetic age acceleration in the visceral adipose tissue of subjects with severe obesity. Clin. Epigenetics 11, 172 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  134. Loos, R. J. F. & Janssens, A. Predicting polygenic obesity using genetic information. Cell Metab. 25, 535–543 (2017).

    Article  CAS  PubMed  Google Scholar 

  135. Langenberg, C. & Lotta, L. A. Genomic insights into the causes of type 2 diabetes. Lancet 391, 2463–2474 (2018).

    Article  CAS  PubMed  Google Scholar 

  136. Volkov, P. et al. A genome-wide mQTL analysis in human adipose tissue identifies genetic variants associated with DNA methylation, gene expression and metabolic traits. PLoS ONE 11, e0157776 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. Drong, A. W. et al. The presence of methylation quantitative trait loci indicates a direct genetic influence on the level of DNA methylation in adipose tissue. PLoS ONE 8, e55923 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Dayeh, T. A. et al. Identification of CpG-SNPs associated with type 2 diabetes and differential DNA methylation in human pancreatic islets. Diabetologia 56, 1036–1046 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Almen, M. S. et al. Genome wide analysis reveals association of a FTO gene variant with epigenetic changes. Genomics 99, 132–137 (2012).

    Article  CAS  PubMed  Google Scholar 

  140. Zhou, D. et al. Polymorphisms involving gain or loss of CpG sites are significantly enriched in trait-associated SNPs. Oncotarget 6, 39995–40004 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Shah, U. J. et al. Differential methylation of the type 2 diabetes susceptibility locus KCNQ1 is associated with insulin sensitivity and is predicted by CpG site specific genetic variation. Diabetes Res. Clin. Pract. 148, 189–199 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Wahl, S. et al. Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity. Nature 541, 81–86 (2017).

    Article  CAS  PubMed  Google Scholar 

  143. Cardona, A. et al. Epigenome-wide association study of incident type 2 diabetes in a British population: EPIC-Norfolk study. Diabetes 68, 2315–2326 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Ouni, M. et al. Epigenetic changes in islets of Langerhans preceding the onset of diabetes. Diabetes 69, 2503–2517 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Agardh, E. et al. Genome-wide analysis of DNA methylation in subjects with type 1 diabetes identifies epigenetic modifications associated with proliferative diabetic retinopathy. BMC Med. 13, 182 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  146. Juvinao-Quintero, D. L. et al. DNA methylation of blood cells is associated with prevalent type 2 diabetes in a meta-analysis of four European cohorts. Clin. Epigenetics 13, 40 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Galmozzi, A. et al. Inhibition of class I histone deacetylases unveils a mitochondrial signature and enhances oxidative metabolism in skeletal muscle and adipose tissue. Diabetes 62, 732–742 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Gao, Z. et al. Butyrate improves insulin sensitivity and increases energy expenditure in mice. Diabetes 58, 1509–1517 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Lundh, M., Galbo, T., Poulsen, S. S. & Mandrup-Poulsen, T. Histone deacetylase 3 inhibition improves glycaemia and insulin secretion in obese diabetic rats. Diabetes Obes. Metab. 17, 703–707 (2015).

    Article  CAS  PubMed  Google Scholar 

  150. Wagner, F. F. et al. An isochemogenic set of inhibitors to define the therapeutic potential of histone deacetylases in beta-cell protection. ACS Chem. Biol. 11, 363–374 (2016).

    Article  CAS  PubMed  Google Scholar 

  151. Kameswaran, V. et al. The dysregulation of the DLK1-MEG3 locus in islets from patients with type 2 diabetes is mimicked by targeted epimutation of its promoter with TALE-DNMT constructs. Diabetes 67, 1807–1815 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Liu, X. S. et al. Editing DNA methylation in the mammalian genome. Cell 167, 233–247 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Ou, K. et al. Targeted demethylation at the CDKN1C/p57 locus induces human beta cell replication. J. Clin. Invest. 129, 209–214 (2019).

    Article  PubMed  Google Scholar 

  154. Diabetes Prevention Program Research Group. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet 374, 1677–1686 (2009).

    Article  PubMed Central  Google Scholar 

  155. Soriano-Tarraga, C. et al. Epigenome-wide association study identifies TXNIP gene associated with type 2 diabetes mellitus and sustained hyperglycemia. Hum. Mol. Genet 25, 609–619 (2016).

    Article  CAS  PubMed  Google Scholar 

  156. Qie, R. et al. Association of ABCG1 gene methylation and its dynamic change status with incident type 2 diabetes mellitus: the Rural Chinese Cohort Study. J. Hum. Genet. 66, 347–357 (2021).

    Article  CAS  PubMed  Google Scholar 

  157. Kulkarni, H. et al. Novel epigenetic determinants of type 2 diabetes in Mexican-American families. Hum. Mol. Genet. 24, 5330–5344 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Kim, K. et al. DNA methylation grimage and incident diabetes: the coronary artery risk development in young adults (CARDIA) study. Diabetes 70, 1404–1413 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Feinberg, A. P. et al. Personalized epigenomic signatures that are stable over time and covary with body mass index. Sci. Transl. Med. 2, 49ra67 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  160. Wang, X. et al. Obesity related methylation changes in DNA of peripheral blood leukocytes. BMC Med. 8, 87 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  161. Dick, K. J. et al. DNA methylation and body-mass index: a genome-wide analysis. Lancet 383, 1990–1998 (2014).

    Article  CAS  PubMed  Google Scholar 

  162. Agha, G. et al. Adiposity is associated with DNA methylation profile in adipose tissue. Int. J. Epidemiol. 44, 1277–1287 (2015).

    Article  PubMed  Google Scholar 

  163. Demerath, E. W. et al. Epigenome-wide association study (EWAS) of BMI, BMI change and waist circumference in African American adults identifies multiple replicated loci. Hum. Mol. Genet. 24, 4464–4479 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Pan, H. et al. HIF3A association with adiposity: the story begins before birth. Epigenomics 7, 937–950 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Wang, S. et al. HIF3A DNA methylation is associated with childhood obesity and ALT. PLoS ONE 10, e0145944 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  166. Richmond, R. C. et al. DNA methylation and BMI: investigating identified methylation sites at HIF3A in a causal framework. Diabetes 65, 1231–1244 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Mendelson, M. M. et al. Association of body mass index with DNA methylation and gene expression in blood cells and relations to cardiometabolic disease: a Mendelian randomization approach. PLoS Med. 14, e1002215 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  168. Do, W. L. et al. Examining the association between adiposity and DNA methylation: a systematic review and meta-analysis. Obes. Rev. 22, e13319 (2021).

    Article  CAS  PubMed  Google Scholar 

  169. Godfrey, K. M. et al. Epigenetic gene promoter methylation at birth is associated with child’s later adiposity. Diabetes 60, 1528–1534 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Relton, C. L. et al. DNA methylation patterns in cord blood DNA and body size in childhood. PLoS ONE 7, e31821 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. van Dijk, S. J. et al. DNA methylation in blood from neonatal screening cards and the association with BMI and insulin sensitivity in early childhood. Int. J. Obes. 42, 28–35 (2018).

    Article  CAS  Google Scholar 

  172. Vehmeijer, F. O. L. et al. DNA methylation and body mass index from birth to adolescence: meta-analyses of epigenome-wide association studies. Genome Med. 12, 105 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Robinson, N. et al. Childhood DNA methylation as a marker of early life rapid weight gain and subsequent overweight. Clin. Epigenetics 13, 8 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Gutierrez-Repiso, C. et al. Epigenetic biomarkers of transition from metabolically healthy obesity to metabolically unhealthy obesity phenotype: a prospective study. Int. J. Mol. Sci. 22, 10417 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Esposito, K. et al. Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: role of oxidative stress. Circulation 106, 2067–2072 (2002).

    Article  CAS  PubMed  Google Scholar 

  176. van Greevenbroek, M. M., Schalkwijk, C. G. & Stehouwer, C. D. Obesity-associated low-grade inflammation in type 2 diabetes mellitus: causes and consequences. Neth. J. Med. 71, 174–187 (2013).

    PubMed  Google Scholar 

  177. Chung, W. K. et al. Precision medicine in diabetes: a Consensus Report from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 63, 1671–1693 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  178. Cook, M. N., Girman, C. J., Stein, P. P. & Alexander, C. M. Initial monotherapy with either metformin or sulphonylureas often fails to achieve or maintain current glycaemic goals in patients with type 2 diabetes in UK primary care. Diabet. Med. 24, 350–358 (2007).

    Article  CAS  PubMed  Google Scholar 

  179. Garcia-Calzon, S. et al. Epigenetic markers associated with metformin response and intolerance in drug-naive patients with type 2 diabetes. Sci. Transl. Med. 12, eaaz1803 (2020).

    Article  CAS  PubMed  Google Scholar 

  180. Lin, C. H., Lee, Y. S., Huang, Y. Y. & Tsai, C. N. Methylation status of vault RNA 2-1 promoter is a predictor of glycemic response to glucagon-like peptide-1 analog therapy in type 2 diabetes mellitus. BMJ Open Diabetes Res. Care 9, e001416 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  181. Brown, A. et al. Dietary strategies for remission of type 2 diabetes: a narrative review. J. Hum. Nutr. Diet. 35, 165–178 (2022).

    Article  PubMed  Google Scholar 

  182. Cordero, P. et al. Leptin and TNF-alpha promoter methylation levels measured by MSP could predict the response to a low-calorie diet. J. Physiol. Biochem. 67, 463–470 (2011).

    Article  CAS  PubMed  Google Scholar 

  183. Stone, N. J. et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J. Am. Coll. Cardiol. 63, 2889–2934 (2014).

    Article  PubMed  Google Scholar 

  184. Schrader, S., Perfilyev, A., Martinell, M., Garcia-Calzon, S. & Ling, C. Statin therapy is associated with epigenetic modifications in individuals with type 2 diabetes. Epigenomics 13, 919–925 (2021).

    Article  CAS  PubMed  Google Scholar 

  185. Ochoa-Rosales, C. et al. Epigenetic link between statin therapy and type 2 diabetes. Diabetes Care 43, 875–884 (2020).

    Article  CAS  PubMed  Google Scholar 

  186. Liu, Y. et al. Statin use associates with risk of type 2 diabetes via epigenetic patterns at ABCG1. Front. Genet. 11, 622 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Natarajan, R. Epigenetic mechanisms in diabetic vascular complications and metabolic memory: the 2020 Edwin Bierman Award Lecture. Diabetes 70, 328–337 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Qiu, C. et al. Cytosine methylation predicts renal function decline in American Indians. Kidney Int. 93, 1417–1431 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. VanderJagt, T. A., Neugebauer, M. H., Morgan, M., Bowden, D. W. & Shah, V. O. Epigenetic profiles of pre-diabetes transitioning to type 2 diabetes and nephropathy. World J. Diabetes 6, 1113–1121 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  190. Roshandel, D. et al. DNA methylation age calculators reveal association with diabetic neuropathy in type 1 diabetes. Clin. Epigenetics 12, 52 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Maghbooli, Z., Hossein-nezhad, A., Larijani, B., Amini, M. & Keshtkar, A. Global DNA methylation as a possible biomarker for diabetic retinopathy. Diabetes Metab. Res. Rev. 31, 183–189 (2015).

    Article  CAS  PubMed  Google Scholar 

  192. Allen, S. C. & Mamotte, C. D. S. Pleiotropic and adverse effects of statins — do epigenetics play a role? J. Pharmacol. Exp. Ther. 362, 319–326 (2017).

    Article  CAS  PubMed  Google Scholar 

  193. Bridgeman, S. C., Ellison, G. C., Melton, P. E., Newsholme, P. & Mamotte, C. D. S. Epigenetic effects of metformin: from molecular mechanisms to clinical implications. Diabetes Obes. Metab. 20, 1553–1562 (2018).

    Article  PubMed  Google Scholar 

  194. Garcia-Calzon, S. et al. Diabetes medication associates with DNA methylation of metformin transporter genes in the human liver. Clin. Epigenetics 9, 102 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  195. Caton, P. W. et al. Metformin suppresses hepatic gluconeogenesis through induction of SIRT1 and GCN5. J. Endocrinol. 205, 97–106 (2010).

    Article  CAS  PubMed  Google Scholar 

  196. Khamis, A. et al. Histone deacetylase 9 promoter hypomethylation associated with adipocyte dysfunction is a statin-related metabolic effect. Clin. Epigenetics 12, 68 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Vallois, D. et al. Gluco-incretins regulate beta-cell glucose competence by epigenetic silencing of Fxyd3 expression. PLoS ONE 9, e103277 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  198. Pinney, S. E., Jaeckle Santos, L. J., Han, Y., Stoffers, D. A. & Simmons, R. A. Exendin-4 increases histone acetylase activity and reverses epigenetic modifications that silence Pdx1 in the intrauterine growth retarded rat. Diabetologia 54, 2606–2614 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Cheng, Y. et al. Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials. Signal. Transduct. Target. Ther. 4, 62 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  200. Remsberg, J. R. et al. Deletion of histone deacetylase 3 in adult beta cells improves glucose tolerance via increased insulin secretion. Mol. Metab. 6, 30–37 (2017).

    Article  CAS  PubMed  Google Scholar 

  201. Hong, S. et al. Dissociation of muscle insulin sensitivity from exercise endurance in mice by HDAC3 depletion. Nat. Med. 23, 223–234 (2017).

    Article  CAS  PubMed  Google Scholar 

  202. Sun, Z. et al. Diet-induced lethality due to deletion of the Hdac3 gene in heart and skeletal muscle. J. Biol. Chem. 286, 33301–33309 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Zhao, Z., Ukidve, A., Kim, J. & Mitragotri, S. Targeting strategies for tissue-specific drug delivery. Cell 181, 151–167 (2020).

    Article  CAS  PubMed  Google Scholar 

  204. Ling, C. & Ronn, T. Epigenetics in human obesity and type 2 diabetes. Cell Metab. 29, 1028–1044 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors’ research is supported by grants from the Swedish research council, Exodiab (2009-1039), Swedish Foundation for Strategic Research for IRC15-0067, the Diabetes Foundation, the European Foundation for the Study of Diabetes, the European Research Council (Paintbox), Region Skåne (ALF), the Novo Nordisk foundation, Påhlsson foundation, the EFSD/NNF and the Crafoord foundation.

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  1. Epigenetics and Diabetes Unit, Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Scania University Hospital, Malmö, Sweden

    Charlotte Ling, Karl Bacos & Tina Rönn

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C.L., K.B. and T.R. contributed equally to all aspects of the article.

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Ling, C., Bacos, K. & Rönn, T. Epigenetics of type 2 diabetes mellitus and weight change — a tool for precision medicine?. Nat Rev Endocrinol 18, 433–448 (2022). https://doi.org/10.1038/s41574-022-00671-w

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