DNA methylation as a diagnostic and therapeutic target in the battle against Type 2 diabetes.

Type 2 diabetes (T2D) develops due to insulin resistance and impaired insulin secretion, predominantly in genetically predisposed subjects exposed to nongenetic risk factors like obesity, physical inactivity and ageing. Emerging data suggest that epigenetics also play a key role in the pathogenesis of T2D. Genome-wide studies have identified altered DNA methylation patterns in pancreatic islets, skeletal muscle and adipose tissue from subjects with T2D compared with nondiabetic controls. Environmental factors known to affect T2D, including obesity, exercise and diet, have also been found to alter the human epigenome. Additionally, ageing and the intrauterine environment are associated with differential DNA methylation. Together, these data highlight a key role for epigenetics and particularly DNA methylation in the growing incidence of T2D.

[1]  Fafa Nadira,et al.  Type 2 diabetes and obesity , 2016 .

[2]  C. Ling,et al.  Genome-Wide Associations between Genetic and Epigenetic Variation Influence mRNA Expression and Insulin Secretion in Human Pancreatic Islets , 2014, PLoS genetics.

[3]  Yoshimasa Tanaka,et al.  Risk Factors Contributing to Type 2 Diabetes and Recent Advances in the Treatment and Prevention , 2014, International journal of medical sciences.

[4]  L. Hesson,et al.  DNA methylation is altered in B and NK lymphocytes in obese and type 2 diabetic human. , 2014, Metabolism: clinical and experimental.

[5]  C. Ling,et al.  Effects of palmitate on genome-wide mRNA expression and DNA methylation patterns in human pancreatic islets , 2014, BMC Medicine.

[6]  R. Gomis,et al.  Differential Methylation of TCF7L2 Promoter in Peripheral Blood DNA in Newly Diagnosed, Drug-Naïve Patients with Type 2 Diabetes , 2014, PloS one.

[7]  C. Ling,et al.  Altered DNA Methylation and Differential Expression of Genes Influencing Metabolism and Inflammation in Adipose Tissue From Subjects With Type 2 Diabetes , 2014, Diabetes.

[8]  C. Bogardus,et al.  Potential epigenetic dysregulation of genes associated with MODY and type 2 diabetes in humans exposed to a diabetic intrauterine environment: an analysis of genome-wide DNA methylation. , 2014, Metabolism: clinical and experimental.

[9]  K. Eriksson,et al.  Extensive changes in the transcriptional profile of human adipose tissue including genes involved in oxidative phosphorylation after a 6‐month exercise intervention , 2014, Acta physiologica.

[10]  C. Ling,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 , 2014, PLoS genetics.

[11]  Jonathan Schug,et al.  Epigenetic regulation of the DLK1-MEG3 microRNA cluster in human type 2 diabetic islets. , 2014, Cell metabolism.

[12]  C. Östenson,et al.  Increased DNA methylation levels of the insulin-like growth factor binding protein 1 gene are associated with type 2 diabetes in Swedish men , 2013, Clinical Epigenetics.

[13]  T. Spector,et al.  Global analysis of DNA methylation variation in adipose tissue from twins reveals links to disease-associated variants in distal regulatory elements. , 2013, American journal of human genetics.

[14]  C. Östenson,et al.  Evaluation of IGFBP-7 DNA methylation changes and serum protein variation in Swedish subjects with and without type 2 diabetes , 2013, Clinical Epigenetics.

[15]  C. Ling,et al.  DNA methylation of the glucagon-like peptide 1 receptor (GLP1R) in human pancreatic islets , 2013, BMC Medical Genetics.

[16]  Leif Groop,et al.  A Six Months Exercise Intervention Influences the Genome-wide DNA Methylation Pattern in Human Adipose Tissue , 2013, PLoS genetics.

[17]  C. Julier,et al.  GLIS3, a Susceptibility Gene for Type 1 and Type 2 Diabetes, Modulates Pancreatic Beta Cell Apoptosis via Regulation of a Splice Variant of the BH3-Only Protein Bim , 2013, PLoS genetics.

[18]  T. Rönn,et al.  Identification of CpG-SNPs associated with type 2 diabetes and differential DNA methylation in human pancreatic islets , 2013, Diabetologia.

[19]  Chengyang Liu,et al.  MicroRNA-7 Regulates the mTOR Pathway and Proliferation in Adult Pancreatic β-Cells , 2013, Diabetes.

[20]  M. McCarthy,et al.  Insights Into the Molecular Mechanism for Type 2 Diabetes Susceptibility at the KCNQ1 Locus From Temporal Changes in Imprinting Status in Human Islets , 2013, Diabetes.

[21]  M. Fraga,et al.  Genome-Wide Analysis of DNA Methylation Differences in Muscle and Fat from Monozygotic Twins Discordant for Type 2 Diabetes , 2012, PloS one.

[22]  K. Eriksson,et al.  Impact of an Exercise Intervention on DNA Methylation in Skeletal Muscle From First-Degree Relatives of Patients With Type 2 Diabetes , 2012, Diabetes.

[23]  M. Fraga,et al.  Effects of short-term high-fat overfeeding on genome-wide DNA methylation in the skeletal muscle of healthy young men , 2012, Diabetologia.

[24]  I. Rigoutsos,et al.  The microRNAs within the DLK1-DIO3 genomic region: involvement in disease pathogenesis , 2012, Cellular and Molecular Life Sciences.

[25]  H. Putter,et al.  Prenatal Famine and Genetic Variation Are Independently and Additively Associated with DNA Methylation at Regulatory Loci within IGF2/H19 , 2012, PloS one.

[26]  Peter A. Jones.  Functions of DNA methylation: islands, start sites, gene bodies and beyond , 2012, Nature Reviews Genetics.

[27]  D. O'Gorman,et al.  Acute exercise remodels promoter methylation in human skeletal muscle. , 2012, Cell metabolism.

[28]  Matthieu Defrance,et al.  DNA methylation profiling identifies epigenetic dysregulation in pancreatic islets from type 2 diabetic patients , 2012, The EMBO journal.

[29]  Dvir Aran,et al.  Genome-wide survey reveals predisposing diabetes type 2-related DNA methylation variations in human peripheral blood. , 2012, Human molecular genetics.

[30]  R. Vatsyayan,et al.  RLIP76, a Glutathione-Conjugate Transporter, Plays a Major Role in the Pathogenesis of Metabolic Syndrome , 2011, PloS one.

[31]  M. McCarthy.  Genomics, type 2 diabetes, and obesity. , 2010, The New England journal of medicine.

[32]  L. Groop,et al.  Insulin promoter DNA methylation correlates negatively with insulin gene expression and positively with HbA1c levels in human pancreatic islets , 2010, Diabetologia.

[33]  P. Deloukas,et al.  Integrated Genetic and Epigenetic Analysis Identifies Haplotype-Specific Methylation in the FTO Type 2 Diabetes and Obesity Susceptibility Locus , 2010, PloS one.

[34]  Xiaodong Cheng,et al.  Molecular coupling of DNA methylation and histone methylation. , 2010, Epigenomics.

[35]  L. Groop,et al.  A family history of diabetes is associated with reduced physical fitness in the Prevalence, Prediction and Prevention of Diabetes (PPP)–Botnia study , 2010, Diabetologia.

[36]  S. Sookoian,et al.  Methylation of TFAM gene promoter in peripheral white blood cells is associated with insulin resistance in adolescents. , 2010, Molecular genetics and metabolism.

[37]  R. Blumenthal,et al.  Coordinated chromatin control: structural and functional linkage of DNA and histone methylation. , 2010, Biochemistry.

[38]  Jonathan Schug,et al.  Genome-wide analysis of histone modifications in human pancreatic islets. , 2010, Genome research.

[39]  P. Laird.  Principles and challenges of genome-wide DNA methylation analysis , 2010, Nature Reviews Genetics.

[40]  L. Groop,et al.  Epigenetics: A Molecular Link Between Environmental Factors and Type 2 Diabetes , 2009, Diabetes.

[41]  T. Rauch,et al.  Insulin Gene Expression Is Regulated by DNA Methylation , 2009, PloS one.

[42]  J. Zierath,et al.  Non-CpG methylation of the PGC-1alpha promoter through DNMT3B controls mitochondrial density. , 2009, Cell metabolism.

[43]  L. Groop,et al.  A Variant in the KCNQ1 Gene Predicts Future Type 2 Diabetes and Mediates Impaired Insulin Secretion , 2009, Diabetes.

[44]  P. Nilsson,et al.  Low levels of insulin-like growth-factor-binding protein-1 (IGFBP-1) are prospectively associated with the incidence of type 2 diabetes and impaired glucose tolerance (IGT): the Söderåkra Cardiovascular Risk Factor Study. , 2009, Diabetes & metabolism.

[45]  C. Ricordi,et al.  MicroRNA miR-7 is preferentially expressed in endocrine cells of the developing and adult human pancreas. , 2009, Gene expression patterns : GEP.

[46]  Nathaniel D. Heintzman,et al.  Histone modifications at human enhancers reflect global cell-type-specific gene expression , 2009, Nature.

[47]  H. Holthofer,et al.  Epigenetic and microRNA-mediated regulation in diabetes , 2008, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[48]  T. Hansen,et al.  SNPs in KCNQ1 are associated with susceptibility to type 2 diabetes in East Asian and European populations , 2008, Nature Genetics.

[49]  J. Rømer,et al.  Expression of the GLP-1 Receptor in Mouse, Rat, and Human Pancreas , 2008, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[50]  L. Groop,et al.  Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus , 2008, Nature Genetics.

[51]  L. Groop,et al.  Age influences DNA methylation and gene expression of COX7A1 in human skeletal muscle , 2008, Diabetologia.

[52]  Yoshimitsu Yamasaki,et al.  PDX-1 and MafA Play a Crucial Role in Pancreatic β-Cell Differentiation and Maintenance of Mature β-Cell Function , 2008 .

[53]  J. Sowers,et al.  Role of mitochondrial dysfunction in insulin resistance. , 2008, Circulation research.

[54]  L. Groop,et al.  Epigenetic regulation of PPARGC1A in human type 2 diabetic islets and effect on insulin secretion , 2008, Diabetologia.

[55]  L. Groop,et al.  Genetic and epigenetic factors are associated with expression of respiratory chain component NDUFB6 in human skeletal muscle. , 2007, The Journal of clinical investigation.

[56]  Qian Wang,et al.  Activation of RalA is required for insulin-stimulated Glut4 trafficking to the plasma membrane via the exocyst and the motor protein Myo1c. , 2007, Developmental cell.

[57]  D. Drucker.  The biology of incretin hormones. , 2006, Cell metabolism.

[58]  H. Stefánsson,et al.  Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes , 2006, Nature Genetics.

[59]  Christoph Handschin,et al.  Metabolic control through the PGC-1 family of transcription coactivators. , 2005, Cell metabolism.

[60]  E. Mannarino,et al.  The endocrine function of adipose tissue: an update , 2005, Clinical endocrinology.

[61]  M. Daly,et al.  PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes , 2003, Nature Genetics.

[62]  J. Eriksson,et al.  Effects of size at birth and childhood growth on the insulin resistance syndrome in elderly individuals , 2002, Diabetologia.

[63]  Paul Zimmet,et al.  Type 2 diabetes and obesity. , 2002 .

[64]  P. McKeigue,et al.  Relation of size at birth to non-insulin dependent diabetes and insulin concentrations in men aged 50-60 years , 1996, BMJ.

[65]  C. Hales,et al.  Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis , 1992, Diabetologia.

[66]  C Osmond,et al.  Fetal and infant growth and impaired glucose tolerance at age 64. , 1991, BMJ.

[67]  C. Ling,et al.  Increased DNA Methylation and Decreased Expression of PDX-1 in Pancreatic Islets from Patients with Type 2 Diabetes. , 2012 .

[68]  V. Mohan,et al.  Circulating levels of insulin-like growth factor binding protein-1 in relation to insulin resistance, type 2 diabetes mellitus, and metabolic syndrome (Chennai Urban Rural Epidemiology Study 118). , 2012, Metabolism: clinical and experimental.

[69]  Yoshimitsu Yamasaki,et al.  PDX-1 and MafA play a crucial role in pancreatic beta-cell differentiation and maintenance of mature beta-cell function. , 2008, Endocrine journal.

[70]  C. Osmond,et al.  Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth , 2004, Diabetologia.

[71]  V. Vaccarino,et al.  Global DNA Methylation Is Associated With Insulin Resistance A Monozygotic Twin Study , 2022 .

[72]  M. Jarvelin,et al.  References and Notes Supporting Online Material Materials and Methods Som Text Figs. S1 to S7 References a Common Variant in the Fto Gene Is Associated with Body Mass Index and Predisposes to Childhood and Adult Obesity , 2022 .