Contrariamente al modelo centrado en las mutaciones, el cual asume que alteraciones en la función son consecuencia de mutaciones somáticas o heredadas en la secuencia del DNA, el modelo epigenético implica una carencia de regulación de uno o más genes. Un componente crítico del epigenoma son los patrones de distribución de las citosinas metiladas en secuencias de dinucleótidos CpG. Tal metilación marca los genes para su inactivación al interferir con la unión de factores de transcripción sensibles a DNA metilado o bien al reclutar proteínas que agrupan complejos correpresores y deacetilasas de histonas en torno a la cromatina. Estas marcas epigenéticas son propagadas luego mitótica y en algunos casos meióticamente, resultando en una herencia estable de estados regulatorios. Hoy se sabe que la dieta u otros factores ambientales son un punto de control para la regulación de la expresión génica y que durante periodos críticos de desarrollo, la cromatina sería particularmente sensible a modificaciones epigenómicas. De esta manera una explicación epigenómica del origen fetal de las enfermedades crónicas del adulto parece razonable. La presente revisión explica cómo la actividad/inactividad física de la madre o de la progenie en etapas tempranas, puede predisponer a Diabetes mellitus tipo 2 en la vida adulta a través de este mecanismo.

Palabras clave: diabetes; epigenética; inactividad física.

Abstract

Contrary to the model centered in the mutations, which assumes that alterations in the function are consequence of somatic or inherited mutations in the sequence of the DNA, the epigenetic model implies dysregulation of one or more genes. A critical component of epigenome is its distribution patterns of the methylated cytosines in CpG sequences. This methylation marks to genes for their inactivation interfering with the union of methylated DNA-sensible transcription factors or recruiting proteins that group corepressor complexes and histone deacetylases around of chromatin. These epigenetic marks are propagated soon mitotic and in some cases meioticaly, result in a stable inheritance of regulatory states. Today it is known that diet or other environmental factors are a control point for the regulation of the gene expression and that during critical periods of development, the chromatin would be particularly sensible to epigenomics modifications. This way, an epigenomic explanation of the fetal origin of adult´s chronic diseases seems reasonable. The present review explains how physical activity/inactivity of the mother or the lineage in early stages can ready to Diabetes mellitus type 2 in the adult life through this mechanism.

Key words: diabetes; epigenetic; physical inactivity.

doi:10.5232/ricyde2009.01601

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Referencias/references

Adair, L.S. & Prentice, A.M. (2004). A critical evaluation of the fetal origins hypothesis and its implications for developing countries. J Nutr, 134(1), 191-193.
PMid:14704317

Adamo, K.B.; Sigal, R.J.; Williams, K.; Kenny, G.; Prud'homme, D. & Tesson, F. (2005). Influence of Pro12Ala peroxisome proliferator-activated receptor gamma2 polymorphism on glucose response to exercise training in type 2 diabetes. Diabetologia, 48(8), 1503-1509.
doi:10.1007/s00125-005-1827-y
PMid:15986237

American Diabetes Association. (2004). Diagnosis and Classification Of Diabetes Mellitus. Diabetes Care, 27, S5-S10.
doi:10.2337/diacare.27.2007.S5

Baier, L.J.; Wiedrich, C.; Hanson, R.L.; Bogardus, C. (1998). Variant in the regulatory subunit of phosphatidylinositol 3-kinase (p85α): preliminary evidence indicates a potential role of this variant in the acute insulin response and type 2 diabetes in Pima women. Diabetes, 47: 973–975.
doi:10.2337/diabetes.47.6.973
PMid:9604878

Barker, D.J. (2004). The developmental origins of adult disease. J Am Coll Nutr, 23(6 Suppl), 588S-595S.
PMid:15640511

Barroso I. (2005). Genetics of Type 2 diabetes. Diabet Med, 22(5):517-35.
doi:10.1111/j.1464-5491.2005.01550.x
PMid:15842505

Bindon, J.; Baker, P. (1997). Bergmann’s Rule and the Thrifty Genotype. Am J Phys Anthropol, 104, 201-210.
doi:10.1002/(SICI)1096-8644(199710)104:2<201::AID-AJPA6>3.0.CO;2-0

Booth, F.; Chakravarthy, M.; Gordon, S. & Spangenburg, E. (2002). Waging War On physical inactivity: using modern molecular ammunition against an ancient enemy. J Appl Physiol, 93, 3–30.
PMid:12070181

Booth, F.; Gordon, S.; Carlson, C. & Hamilton, M. (2000). Waging war on modern chronic diseases: primary prevention through exercise biology. J. Appl. Physiol, 88, 774–787.
PMid:10658050

Booth, F.W. & Lees, S.J. (2007). Fundamental questions about genes, inactivity, and chronic diseases. Physiol Genomics, 28(2), 146-157.
doi:10.1152/physiolgenomics.00174.2006
PMid:17032813

Carulli, L.; Rondinella, S.; Lombardini, S.; Canedi, I; Loria, P. & Carulli, N. (2005). Diabetes, genetics and ethnicity. Aliment Pharmacol Ther, 22 (Suppl. 2), 16–19.
doi:10.1111/j.1365-2036.2005.02588.x

Chakravarthy, M. & Booth, F. (2004). Eating, exercise, and “thrifty” genotypes: connecting the dots toward an evolutionary understanding of modern chronic diseases. J Appl Physiol, 96, 3–10.
doi:10.1152/japplphysiol.00757.2003
PMid:14660491

Cooney, C.A.; Dave, A.A. & Wolff, G.L. (2002). Maternal methyl supplements in mice affect epigenetic variation and DNA methylation of offspring. J Nutr, 132(8 Suppl), 2393S-2400S.
PMid:12163699

Cordain, L.; Gotshall, R.W.; Eaton, S.B. & Eaton, S.B. III. (1998). Physical activity, energy expenditure and fitness: an evolutionary perspective. Int J Sports Med, 19, 328–335.
doi:10.1055/s-2007-971926
PMid:9721056

Cushing, B.S. & Kramer, K.M. (2005). Mechanisms underlying epigenetic effects of early social experience: the role of neuropeptides and steroids. Neurosci Biobehav Rev, 29(7), 1089-1105.
doi:10.1016/j.neubiorev.2005.04.001

Dabelea, D.; Hanson, R.L.; Lindsay, R.S.; Pettitt, D.J.; Imperatore, G.; Gabir, M.M.; Roumain, J.; Bennett, P.H. & Knowler, W.C. (2000). Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity. Diabetes, 49, 2208–2211.
doi:10.2337/diabetes.49.12.2208
PMid:11118027

Deeb, S.S.; Fajas, L.; Nemoto, M.; Pihlajamaki, J.; Mykkanen, L.; Kuusisto, J.; Laakso, M.; Fujimoto, W. and Auwerx, J. (1998) A Pro12Ala substitution in PPARgamma2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nat. Genet., 20, 284–287.
doi:10.1038/3099
PMid:9806549

Doherty, A.S.; Mann, M.R.; Tremblay, K.D.; Bartolomei, M.S. & Schultz, R.M. (2000). Differential effects of culture on imprinted H19 expression in the preimplantation mouse embryo. Biol Reprod, 62(6), 1526-1535.
doi:10.1095/biolreprod62.6.1526
PMid:10819752

Dolinoy, D.C.; Weidman, J.R. & Jirtle, R.L. (2007). Epigenetic gene regulation: Linking early developmental environment to adult disease. Reproductive Toxicology, 23, 297–307.
doi:10.1016/j.reprotox.2006.08.012
PMid:17046196

Eaton, S.B.; Strassman, B.I.; Nesse, R.M.; Neel, J.V.; Ewald, P.W.; Williams, G.C.; Weder, A.B.; Eaton, S.B. III; Lindeberg, S.; Konner, M.J.; Mysterud, I. & Cordain, L. (2002). Evolutionary health promotion. Prev Med, 34, 109–118.
doi:10.1006/pmed.2001.0876
PMid:11817903

Egeland, G.M.; Skjaerven, R. & Irgens, L.M. (2000). Birth characteristics of women who develop gestational diabetes: population based study. BMJ, 321(7260), 546-547.
PMid:11793024

Ek, J.; Andersen, G.; Urhammer, S.A.; Gaede, P.H.; Drivsholm, T.; Borch-Johnsen, K.; Hansen, T.; Pedersen, O. (2001). Mutation analysis of peroxisome proliferatoractivated receptor-gamma coactivator-1 (PGC-1) and relationships of identified amino acid polymorphisms to Type II diabetes mellitus. Diabetologia, 44: 2220–2226.
doi:10.1007/s001250100032
PMid:1778354

Eriksson, K.F. & Lindgärde, F. (1991). Prevention of type 2 (non-insulin-dependent) diabetes mellitus by diet and physical exercise. The 6-year Malmo feasibility study. Diabetologia, 34(12), 891-898.
doi:10.1007/BF00400196

Forcales, S. & Puri, P. (2005). Signaling to the chromatin during skeletal myogenesis: Novel targets for pharmacological modulation of gene expression. Semin Cell Dev Biol, 16596–16611.
PMid:10906831

Forsen, T.; Eriksson, J.; Tuomilehto, J.; Reunanen, A.; Osmond, C. & Barker, D. (2000). The fetal and childhood growth of persons who develop type 2 diabetes. Ann Intern Med, 133(3), 176-182.
PMid:15983188

Gallou-Kabani, C. & Junien, C. (2005). Nutricional epigenomics of metabolic syndrome. New perspective against the epidemic. Diabetes, 1899-1906.
doi:10.2337/diabetes.54.7.1899

Garant, M.J.; Kao, W.H.; Brancati, F.; Coresh, J.; Rami, T.M.; Hanis, C.L.; Boerwinkle, E.; Shuldiner, A.R. (2002). Atherosclerosis Risk in Communities Study. SNP43 of CAPN10 and the risk of type 2 diabetes in African-Americans: the Atherosclerosis Risk in Communities Study. Diabetes, 51: 231–237.
doi:10.2337/diabetes.51.1.231

Gloyn, A.L.; Weedon, M.N.; Owen, K.R.; Turner, M.J.; Knight, B.A.; Hitman, G.A.; Walker, M.; Levy, J.C.; Sampson, M.J.; Halford, S; McCarthy, M.I.; Hattersley, A.T.; Frayling, T.M. (2003) Large scale association studies of variants in genes encoding the pancreatic beta-cell K-ATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with increased risk of Type 2 Diabetes. Diabetes, 52, 568–572.
doi:10.2337/diabetes.52.2.568
PMid:8541847

Gough, S.C.; Saker, P.J.; Pritchard, L.E.; Merriman, T.R.; Merriman, M.E.; Rowe, B.R.; Kumar, S.; Aitman, T.; Barnett, A.H.; Turner, R.C. (1995). Mutation of the glucagon receptor gene and diabetes mellitus in the UK: association or founder effect? Hum Mol Genet, 4: 1609–1612.
doi:10.1093/hmg/4.9.1609
PMid:7773293

Hager, J.; Hansen, L.; Vaisse, C.; Vionnet, N.; Philippi, A.; Poller, W. (1995). A missense mutation in the glucagon receptor gene is associated with non-insulin-dependent diabetes mellitus. Nat Genet, 9: 299–304.
doi:10.1038/ng0395-299
PMid:12107756

Hara, K.; Tobe, K.; Okada, T.; Kadowaki, H.; Akanuma, Y.; Ito, C.; Kimura, S.; Kadowaki, T. (2002). A genetic variation in the PGC-1 gene could confer insulin resistance and susceptibility to Type II diabetes. Diabetologia, 45: 740–743.
doi:10.1007/s00125-002-0803-z
PMid:11017071

Horikawa, Y.; Oda, N.; Cox, N.J.; Li, X.; Orho-Melander, M.; Hara, M.; Hinokio, Y.; Lindner, T.H.; Mashima, H.; Schwarz, P.E.; del Bosque-Plata; L., Horikawa, Y.; Oda, Y.; Yoshiuchi, I.; Colilla, S.; Polonsky, K.S.; Wei, S.; Concannon, P.; Iwasaki, N.; Schulze, J.; Baier, L.J.; Bogardus, C.; Groop, L.; Boerwinkle, E.; Hanis, C.L.; Bell, G.I. (2000). Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nat Genet, 26: 163–175.
doi:10.1038/79876
PMid:10752264

Jaquet, D.; Gaboriau, A.; Czernichow, P. & Levy-Marchal, C. (2000). Insulin resistance early in adulthood in subjects born with intrauterine growth retardation. J Clin Endocrinol Metab, 85(4), 1401-1406.
doi:10.1210/jc.85.4.1401
PMid:12819898

Jellema, A.; Zeegers, M.P.; Feskens, E.J.; Dagnelie, P.C.; Mensink, R.P. (2003). Gly972Arg variant in the insulin receptor substrate-1 gene and association with Type 2 diabetes: a meta-analysis of 27 studies. Diabetologia, 46: 990–995.
doi:10.1007/s00125-003-1126-4
PMid:12424509

Kaur, J.; Singh, P. & Sowers, J. (2002). Diabetes and Cardiovascular Diseases. Am J Ther, 9, 510–515.
doi:10.1097/00045391-200211000-00009
PMid:15569624

Khan, A.U. & Krishnamurthy, S. (2005). Histone modifications as key regulators of transcription. Front Biosci, 1(10), 866-872.
doi:10.2741/1580
PMid:17434282

Kim, H.; Lee, S.H.; Kim, S.S.; Yoo, J.H. & Kim, C.J. (2007). The influence of maternal treadmill running during pregnancy on short-term memory and hippocampal cell survival in rat pups. Int J Dev Neurosci, 25(4), 243-249.
doi:10.1016/j.ijdevneu.2007.03.003
PMid:15562396

Kim, K.S.; Choi, S.M.; Shin, S.U.; Yang, H.S. & Yoon, Y. (2004). Effects of peroxisome proliferator-activated receptor-gamma 2 Pro12Ala polymorphism on body fat distribution in female Korean subjects. Metabolism, 53(12), 1538-1543.
doi:10.1016/j.metabol.2004.06.019
PMid:11832527    PMCid:1370926

Knowler, W.C.; Barrett-Connor, E.; Fowler, S.E.; Hamman, R.F.; Lachin, J.M.; Walker, E.A. & Nathan, D.M. (2002). Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med, 346(6), 393-403.
doi:10.1056/NEJMoa012512
PMid:15649575

Kosaka, K.; Noda, M. & Kuzuya, T. (2005). Prevention of type 2 diabetes by lifestyle intervention: a Japanese trial in IGT males. Diabetes Res Clin Pract, 67(2), 152-162.
doi:10.1016/j.diabres.2004.06.010
PMid:12882479

Kriska, A. (2003). Can a Physically active lifestyle prevent type 2 diabetes?. Exerc Sport Sci Rev, 31(3), 132-137.
doi:10.1097/00003677-200307000-00006
PMid:16368211

Lee, H.H.; Kim, H.; Lee, J.W.; Kim, Y.S.; Yang, H.Y.; Chang, H.K.; Lee, T.H.; Shin, M.C.; Lee, M.H.; Shin, M.S.; Park, S.; Baek, S. & Kim, C.J. (2006). Maternal swimming during pregnancy enhances short-term memory and neurogenesis in the hippocampus of rat pups. Brain Dev, 28(3), 147-154.
doi:10.1016/j.braindev.2005.05.007
PMid:12145174

Lindi, V.; Uusitupa, M.; Lindström, J.; Louheranta, A.; Erickson, J.; Valle, T.; Hämäläinem, H.; Ilanne-Parikka, P.; Keinänem-Kiukaanniemi, S.; Laakso, M. & Tuomiletho, J. for the Finnish Diabetes Prevention Study Group. (2002). Association Of The Pro12Ala Polymorphism In The PPAR-g2 Gene Whit 3-Year Incidence Of Type 2 Diabetes And Body Weight Change In The Finnish Diabetes Prevention Study. Diabetes, 51, 2581-2586.
doi:10.2337/diabetes.51.8.2581

Lindstrom, J.; Ilanne-Parikka, P.; Peltonen, M.; Aunola, S.; Eriksson, J.G.; Hemio, K.; Hamalainen, H.; Harkonen, P.; Keinanen-Kiukaanniemi, S.; Laakso, M.; Louheranta, A.; Mannelin, M.; Paturi, M.; Sundvall, J.; Valle, T.T.; Uusitupa, M. & Tuomilehto, J. (2006). Finnish Diabetes Prevention Study Group. Sustained reduction in the incidence of type 2 diabetes by lifestyle intervention: follow-up of the Finnish Diabetes Prevention Study. Lancet, 368(9548), 1673-1679.
doi:10.1016/S0140-6736(06)69701-8
PMid:16759313

Mager, U.; Lindi, V.; Lindstrom, J.; Eriksson, J.G.; Valle, T.T.; Hamalainen, H.; Ilanne-Parikka, P.; Keinanen-Kiukaanniemi, S.; Tuomilehto, J.; Laakso, M.; Pulkkinen, L. & Uusitupa, M. Finnish Diabetes Prevention Study Group. (2006). Association of the Leu72Met polymorphism of the ghrelin gene with the risk of Type 2 diabetes in subjects with impaired glucose tolerance in the Finnish Diabetes Prevention Study. Diabet Med, 23(6), 685-689.
doi:10.1111/j.1464-5491.2006.01870.x
PMid:12163708

Maier, S. & Olek, A. (2002). Diabetes: A Candidate Disease for Efficient DNA Methylation Profiling. J Nutr, 132, 2440S-2443S.
PMid:15955369

Malecki, M. (2005). Genetics of type 2 diabetes mellitus. Diabetes Res Clin Pract, 68(S1), S10-S21.
doi:10.1016/j.diabres.2005.03.003

Maynard Smith, J. (1990). Models of a dual inheritance system. J Theor Biol, 143(1), 41-53.
doi:10.1016/S0022-5193(05)80287-5
PMid:11854095

McCarthy, M. (2002). Susceptibility gene discovery for common metabolic and endocrine traits. J Mol Endocrinol, 28, 1-17.
doi:10.1677/jme.0.0280001
PMid:14722160

McCarthy, M. (2004). Progress in defining the molecular basis of type 2 diabetes mellitus through susceptibility-gene identification. Hum Mol Genet, 13(Spec N°1), R33-R41.
doi:10.1093/hmg/ddh057
PMid:16620308

McGee, S.L. (2006). Hargreaves M. Exercise and skeletal muscle glucose transporter 4 expression: molecular mechanisms. Clin Exp Pharmacol Physiol, 33(4), 395-399.
doi:10.1111/j.1440-1681.2006.04362.x
PMid:15180970

McKenzie, J.A.; Weiss, E.P.; Ghiu, I.A.; Kulaputana, O.; Phares, D.A.; Ferrell, R.E. & Hagberg, J.M. (2004). Influence of the interleukin-6 -174 G/C gene polymorphism on exercise training-induced changes in glucose tolerance indexes. J Appl Physiol, 97(4), 1338-1342.
doi:10.1152/japplphysiol.00199.2004

Neel, J.V. (1962). Diabetes mellitus a “thrifty” genotype rendered detrimental by “progress”? Am J Hum Genet, 14, 352-353.
PMid:10968815    PMCid:27469

Pan, X.R.; Li, G.W.; Hu, Y.H.; Wang, J.X.; Yang, W.Y.; An, Z.X.; Hu, Z.X.; Lin, J.; Xiao, J.Z.; Cao, H.B.; Liu, P.A.; Jiang, X.G.; Jiang, Y.Y.; Wang, J.P.; Zheng, H.; Zhang, H.; Bennett, P.H. & Howard, B.V. (1997). Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care, 20(4), 537-544.
doi:10.2337/diacare.20.4.537
PMid:9096977

Parnpiansil, P.; Jutapakdeegul, N.; Chentanez, T. & Kotchabhakdi, N. (2003). Exercise during pregnancy increases hippocampal brain-derived neurotrophic factor mRNA expression and spatial learning in neonatal rat pup. Neurosci Lett, 352(1), 45-48.
doi:10.1016/j.neulet.2003.08.023
PMid:14615046

Permutt, A.; Wasson, J. & Cox, N. (2005). Genetic epidemiology of diabetes. J Clin Invest, 115, 1431-1439.
doi:10.1172/JCI24758
PMid:15931378    PMCid:1137004

Poirier, L.A.; Brown, A.T.; Fink, L.M.; Wise, C.K. & Randolph, C.J. (2001). Delongchamp RR, Fonseca VA. Blood S-adenosylmethionine concentrations and lymphocyte methylenetetrahydrofolate reductase activity in diabetes mellitus and diabetic nephropathy. Metabolism, 50, 1014–1018.
doi:10.1053/meta.2001.25655
PMid:11555831

Ramachandran, A.; Snehalatha, C.; Mary, S.; Mukesh, B.; Bhaskar, A.D. & Vijay, V. (2006). Indian Diabetes Prevention Programme (IDPP). The Indian Diabetes Prevention Programme shows that lifestyle modification and metformin prevent type 2 diabetes in Asian Indian subjects with impaired glucose tolerance (IDPP-1). Diabetologia, 49(2), 289-297.
doi:10.1007/s00125-005-0097-z
PMid:16391903

Reik, W.; Römer, I.; Barton, S.C.; Surani, M.A.; Howlett, S.K. & Klose, J. (1993). Adult phenotype in the mouse can be affected by epigenetic events in the early embryo. Development, 119(3), 933-942.
PMid:8187648

Simmons, R. (2005). Developmental origins of adult metabolic disease: concepts and controversies. Trends Endocrinol Metab, 16(8), 390-394.
doi:10.1016/j.tem.2005.08.004
PMid:16118054

Sladek, R.; Rocheleau, G.; Rung, J.; Dina, C.; Shen, L.; Serre, D.; Boutin, P.; Vincent, D.; Belisle, A.; Hadjadj, S.; Balkau, B.; Heude, B.; Charpentier, G.; Hudson, T.J.; Montpetit, A.; Pshezhetsky, A.V.; Prentki, M.; Posner, B.I.; Balding, D.J.; Meyre, D.; Polychronakos, C. & Froguel, P. (2007). A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature, 445, 881-885.
doi:10.1038/nature05616
PMid:17293876

Sng, J.C.; Taniura, H. & Yoneda, Y. (2004). A Tale of Early Response Genes. Biol Pharm Bull, 27(5), 606-612.
doi:10.1248/bpb.27.606

Sreekumar, R.; Halvatsiotis, P.; Schimke, J.C. & Nair, K.S. (2002). Gene Expression Profile in Skeletal Muscle of Type 2 Diabetes and the Effect of Insulin Treatment. Diabetes, 51, 1913-1920.
doi:10.2337/diabetes.51.6.1913
PMid:12031981

Valdez, R.; Athens, M.A.; Thompson, G.H.; Bradshaw, B.S. & Stern, M.P. (1994). Birthweight and adult health outcomes in a biethnic population in the USA. Diabetologia, 37(6), 624-631.
doi:10.1007/BF00403383
PMid:7926349

Voight, B.F.; Kudaravalli, S.; Wen, X. & Pritchard, J.K. (2006). A map of recent positive selection in the human genome. PLoS Biol, 4,e72.
doi:10.1371/journal.pbio.0040072
PMid:16494531    PMCid:1382018

Waterland, R.A. & Jirtle, R.L. (2004). Early nutrition, epigenetic changes at transposons and imprinted genes, and enhanced susceptibility to adult chronic diseases. Nutrition, 20, 63-68.
doi:10.1016/j.nut.2003.09.011
PMid:14698016

Waterland, R.A.; Lin, J.R.; Smith, C.A. & Jirtle, R.L. (2006). Post-weaning diet affects genomic imprinting at the insulin-like growth factor 2 (Igf2) locus. Hum Mol Genet, 15(5), 705-716.
doi:10.1093/hmg/ddi484
PMid:16421170

Waterland, RA. (2006). Epigenetic mechanisms and gastrointestinal development. J Pediatr, 149, s137-s142.
doi:10.1016/j.jpeds.2006.06.064
PMid:17212956

Weaver, I.C.; Cervoni, N.; Champagne, F.A.; D'Alessio, A.C.; Sharma, S.; Seckl, J.R.; Dymov, S.; Szyf, M. & Meaney, M.J. (2004). Epigenetic programming by maternal behavior. Nat Neurosci, 7, 847-854.
doi:10.1038/nn1276
PMid:15220929

Wong, A.; Gottesman, I. & Petronis, A. (2005). Phenotypic differences in genetically identical organism: the epigenetic perspective. Human Molecular Genetics, 14, R11-R18.
doi:10.1093/hmg/ddi116
PMid:15809262

Wren, J. & Garner, H. (2005). Data-mining analysis suggests an epigenetic pathogenesis for type 2 diabetes. Journal of Biomedicine and Biotechnology, 2, 104-112.
doi:10.1155/JBB.2005.104
PMid:16046815    PMCid:1184044

Xu, M.; Li, X.; Wang, J.G.; Du, P.; Hong, J.; Gu, W.; Zhang, Y. & Ning, G. (2005). Glucose and lipid metabolism in relation to novel polymorphisms in the 5’-AMP-activated protein kinase γ gene in Chinese. Molecular Genetics and Metabolism, 86, 372-378.
doi:10.1016/j.ymgme.2005.06.012
PMid:16115789

Yamaoka, K. & Tango, T. (2005). Efficacy of lifestyle education to prevent type 2 diabetes: a meta-analysis of randomized controlled trials. Diabetes Care, 28(11), 2780-2786.
doi:10.2337/diacare.28.11.2780
PMid:16249558

Yokomori, N.; Tawata, M. & Onaya, T. (1999). DNA demethylation during the differentiation of 3T3–L1 cells affects the expression of the mouse GLUT4 gene. Diabetes, 48, 685-690.
doi:10.2337/diabetes.48.4.685
PMid:10102682

Zimmet, P.; Dowse, G. & Finch, C. (1990). The epidemiology and natural history of NIDDM—lessons from the South Pacific. Diabetes Metab Rev, 6, 91-124.
doi:10.1002/dmr.5610060203
PMid:2198152

Zimmet, P.; Faaisu, S.; Ainuu, J.; Whitehouse, S.; Milne. B. & DeBoer, W. (1981). The prevalence of diabetes in the rural and urban populations of Western Samoa. Diabetes, 30, 45-51.
doi:10.2337/diabetes.30.1.45
PMid:7227656

Zimmet, P.; Seluka, A.; Collins, J.; Currie, P.; Wicking, J. & DeBoer, W. (1977). Diabetes mellitus in an urbanized, isolated Polynesian population: The Funafuti survey. Diabetes, 26, 1101-1108.
doi:10.2337/diabetes.26.12.1101
PMid:590635

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