Diabetes Mellitus ve Epigenetik Mekanizmalar

Diabetes Mellitus (DM), insülin eksikliği veya insülin reseptör direnci kaynaklı ve hiperglisemi ile karakterize önemli bir metabolik bozukluktur. Dünya çapında görülme sıklığı giderek artmakta olan DM, sebep olduğu komplikasyonlar ile yaşam kalitesini olumsuz etkilemektedir. Bunun yanında yüksek tedavi maliyetleriyle ülkelere ciddi ekonomik yükler getirmektedir. Epigenetik, geri dönüşümlü çeşitli modifikasyonlar sayesinde DNA dizisi değişmeden gen ifadesinin değişikliğe uğramasını ifade eder. Çevresel faktörlerden kolaylıkla etkilenebilen bu epigenetik modifikasyonlardaki anormal değişimler başta kanser ve nörodejeneratif bozukluklar olmak üzere birçok hastalıkla ilişkilendirilmiştir. Bu derlemede, epigenetik modifikasyonların en önemlilerinden olan DNA ve RNA metilasyonunun DM ve komplikasyonları ile ilişkisi özetlenecektir.

Diabetes Mellitus and Epigenetic Mechanisms

Diabetes Mellitus (DM) is an important disease caused by insulin deficiency or insulin receptor resistance and characterized by hyperglycemia. The prevalence rate of DM is increasing rapidly worldwide and its associated complications affect the quality of life of patients adversely. In addition, high medical costs for its treatment bring significant economic load on countries. Epigenetics is the reversible modifications on the genome, which lead to changes in gene expression without any alteration in the DNA sequence. Epigenetic modifications can easily be affected by environmental factors and abnormalities in these modifications have been linked to many diseases including cancer and neurodegenerative disorders. In this review, we will summarize the relationship of DM and its complications with DNA and RNA methylation, which are among the most important modifications.

___

  • 1. International Diabetes Federation: IDF Diabetes Atlas. Brussels, Belgium 2013. Ulaşılabileceği adres: https://www.idf. org/sites/default/files/EN_6E_Atlas_Full_0.pdf
  • 2. Satman I, ve TURDEP-II çalışma grubu. TURDEP-II Sonuç- larıç Türk Endokronoloji ve Metabolizma Derneği Resmi Web Sayfası 2011; Ulaşılabileceği adres: http://www.turkendokrin.org/files/file/TURDEP_ II_2011.pdf
  • 3. Tanrıverdi MH, Çelepkolu T, Aslanhan H. Diabetes mellitus and primary healthcare. J Clin Exp Invest 2013;4:562-567.
  • 4. Yazgan ÜC, Taşdemir E, Bilgin HM, et al. Comparison of the anti-diabetic effects of resveratrol, gliclazide and losartan in streptozotocin-induced experimental diabetes. Arch Physiol Biochem 2015;121:157-161.
  • 5. Şahpaz F, Ulutaş KT. Assessment of mean platelet volume in type 2 diabetics receiving insulin or oral antidiabetic agents. Dicle Med J 2015;42:399-403.
  • 6. Yenigün EC, Okyay GU, Pirpir A, et al. Increased mean platelet volume in type 2 diabetes mellitus. Dicle Med J 2014;41:17-22.
  • 7. Portela A, Esteller M. Epigenetic modifications and human disease. Nat biotechnol 2010;28:1057-1068.
  • 8. Fu Y, Dominissini D, Rechavi G, He C. Gene expression regulation mediated through reversible m(6)A RNA methylation. Nat Rev Genet 2014;15:293-306.
  • 9. Wu H, Zhang Y. Reversing DNA methylation: mechanisms, genomics, and biological functions. Cell 2014;156:45-68.
  • 10. Liu N, Pan T. RNA epigenetics. Transl Res 2015;165:28-35.
  • 11. İzmirli M, Tufan T, Alptekin D. DNA metilasyonu. Arşiv Kaynak Tarama Dergisi 2012;21:274-282.
  • 12. Klose RJ, Bird AP. Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci 2006;31:89-97.
  • 13. Shen L, Song CX, He C, Zhang Y. Mechanism and function of oxidative reversal of DNA and RNA methylation. Annu Rev Biochem 2014;83:585-614.
  • 14. Tahiliani M, Koh KP, Shen Y, et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 2009;324:930-935.
  • 15. Kohli RM, Zhang Y. TET enzymes, TDG and the dynamics of DNA demethylation. Nature 2013;502:472-479.
  • 16. Piccolo FM, Fisher AG. Getting rid of DNA methylation. Trends Cell Biol 2014;24:136-143.
  • 17. Jones PA, Baylin SB. The epigenomics of cancer. Cell 2007;128:683-692.
  • 18. Akhavan-Niaki H, Samadani AA. DNA methylation and cancer development: molecular mechanism. Cell Biochem Biophys 2013;67:501-513.
  • 19. Yang M, Park JY. DNA methylation in promoter region as biomarkers in prostate cancer. Methods Mol Biol 2012;863:67-109.
  • 20. Scourzic L, Mouly E, Bernard OA. TET proteins and the control of cytosine demethylation in cancer. Genome Med 2015;7:9.
  • 21. Tan L, Shi YG. Tet family proteins and 5-hydroxymethylcytosine in development and disease. Development 2012;139:1895-1902.
  • 22. Shen F, Huang W, Huang JT, et al. Decreased N(6)-methyladenosine in peripheral blood RNA from diabetic patients is associated with FTO expression rather than ALKBH5. J Clin Endocrinol Metab 2015;100:E148-154.
  • 23. Xu C, Liu K, Tempel W, et al. Structures of human ALKBH5 demethylase reveal a unique binding mode for specific single-stranded N6-methyladenosine RNA demethylation. J Biol Chem 2014;289:17299-17311.
  • 24. Dominissini D. Genomics and Proteomics. Roadmap to the epitranscriptome. Science 2014;346:1192.
  • 25. Ben-Haim MS, Moshitch-Moshkovitz S, Rechavi G. FTO: linking m6A demethylation to adipogenesis. Cell Res 2015;25:3-4.
  • 26. Yılmaz A, Akan Z, Yılmaz H. Prevalence of diabetes mellitus and affecting factors of diabetes mellitus in adult age group in Van province. J Clin Exp Invest 2011;2:392-399.
  • 27. Ravelli GP, Stein ZA, Susser MW. Obesity in young men after famine exposure in utero and early infancy. N Engl J Med 1976;295:349-353.
  • 28. Ravelli AC, van Der Meulen JH, Osmond C, et al. Obesity at the age of 50 y in men and women exposed to famine prenatally. Am J Clin Nutr 1999;70:811-816.
  • 29. Ding GL, Huang HF. Role for tet in hyperglycemia-induced demethylation: a novel mechanism of diabetic metabolic memory. Diabetes 2014;63:2906-2908.
  • 30. Ong TP, Ozanne SE. Developmental programming of type 2 diabetes: early nutrition and epigenetic mechanisms. Curr Opin Clin Nutr Metab Care 2015;18:354-360.
  • 31. Yang BT, Dayeh TA, Volkov PA, et al. Increased DNA methylation and decreased expression of PDX-1 in pancreatic islets from patients with type 2 diabetes. Mol Endocrinol 2012;26:1203-1212
  • 32. Volkmar M, Dedeurwaerder S, Cunha DA, et al. DNA methylation profiling identifies epigenetic dysregulation in pancreatic islets from type 2 diabetic patients. EMBO J 2012;31:1405-1426.
  • 33. Dorner G, Mohnike A. Further evidence for a predominantly maternal transmission of maturity-onset type diabetes. Endokrinologie 1976;68:121-124.
  • 34. Dorner G, Mohnike A, Steindel E. On possible genetic and epigenetic modes of diabetes transmission. Endokrinologie 1975;66:225-227.
  • 35. Silverman BL, Metzger BE, Cho NH, Loeb CA. Impaired glucose tolerance in adolescent offspring of diabetic mothers. Relationship to fetal hyperinsulinism. Diabetes Care 1995;18:611-617.
  • 36. Pettitt DJ, Knowler WC, Bennett PH, et al. Obesity in offspring of diabetic Pima Indian women despite normal birth weight. Diabetes Care 1987;10:76-80.
  • 37. Dabelea D, Hanson RL, Lindsay RS, et al. Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity: a study of discordant sibships. Diabetes 2000;49:2208-2211.
  • 38. Maier S, Olek A. Diabetes: a candidate disease for efficient DNA methylation profiling. J Nutr 2002;132:2440S-2443S.
  • 39. Stefan M, Zhang W, Concepcion E, et al. DNA methylation profiles in type 1 diabetes twins point to strong epigenetic effects on etiology. J Autoimmun 2014;50:33-37.
  • 40. Seisenberger S, Andrews S, Krueger F, et al. The dynamics of genome-wide DNA methylation reprogramming in mouse primordial germ cells. Mol Cell 2012;48:849-862.
  • 41. Phillips DI, Barker DJ, Hales CN, et al. Thinness at birth and insulin resistance in adult life. Diabetologia 1994;37:150- 154.
  • 42. Martyn CN, Barker DJ, Jespersen S, et al. Growth in utero, adult blood pressure, and arterial compliance. Brit Heart J 1995;73:116-121.
  • 43. Sullivan EL, Nousen EK, Chamlou KA. Maternal high fat diet consumption during the perinatal period programs offspring behavior. Physiol Behav 2014;123:236-242.
  • 44. Duque-Guimaraes DE, Ozanne SE. Nutritional programming of insulin resistance: causes and consequences. Trends Endocrinol Metab 2013;24:525-535.
  • 45. Sinclair KD, Allegrucci C, Singh R, et al. DNA methylation, insulin resistance, and blood pressure in offspring determined by maternal periconceptional B vitamin and methionine status. Proc Natl Acad Sci USA 2007;104:19351- 19356.
  • 46. Huypens P, Sass S, Wu M, et al. Epigenetic germline inheritance of diet-induced obesity and insulin resistance. Nat Genet 2016; doi:10.1038/ng.3527.
  • 47. Ng SF, Lin RC, Laybutt DR, et al. Chronic high-fat diet in fathers programs beta-cell dysfunction in female rat offspring. Nature 2010;467:963-966.
  • 48. Souness JE, Stouffer JE, Chagoya de Sanchez V. Effect of N6-methyladenosine on fat-cell glucose metabolism. Evidence for two modes of action. Biochem Pharmacol 1982;31:3961-3971.
  • 49. Ceriello A, Ihnat MA, Thorpe JE. Clinical review 2: The "metabolic memory": is more than just tight glucose control necessary to prevent diabetic complications? J Clin Endocrinol Metab 2009;94:410-415.
  • 50. Olsen AS, Sarras MP, Jr., Leontovich A, Intine RV. Heritable transmission of diabetic metabolic memory in zebrafish correlates with DNA hypomethylation and aberrant gene expression. Diabetes 2012;61:485-491.
  • 51. Dhliwayo N, Sarras MP, Jr., Luczkowski E, et al. Parp inhibition prevents ten-eleven translocase enzyme activation and hyperglycemia-induced DNA demethylation. Diabetes 2014;63:3069-3076.
Dicle Tıp Dergisi-Cover
  • ISSN: 1300-2945
  • Yayın Aralığı: Yılda 4 Sayı
  • Başlangıç: 1963
  • Yayıncı: Cahfer GÜLOĞLU
Sayıdaki Diğer Makaleler

Romatoid Artritte Nötrofil/ Lenfosit ve Platelet/ Lenfosit Oranlarının Değerlendirilmesi

Elif KILIÇ, Aylin REZVANİ, Aybala Erek TOPRAK, Hayriye ERMAN, Siddika Kesgin AYHAN, Emine POYRAZ, Nihal ÖZARAS

Üriner Sistem Taşlarının Mikrofokus Bilgisayarlı Tomografi ile Ultrastrüktürel Yapısının Analizi ve Kimyasal Analizle Karşılaştırılması

Tolga KARAKAN, Emre HURİ, İlkan TATAR, HAKAN HAMDİ ÇELİK, MEHMET AKİF DİRİ, MURAT BAĞCIOĞLU, Cankon GERMİYANOĞLU

Tıp Fakültesi Öğrencilerinin Tüberküloz Hastalığı Hakkındaki Bilgi Düzeyleri

MELİKE DEMİR, Emel ASLAN, MAHŞUK TAYLAN, SÜREYYA YILMAZ, PAKİZE GAMZE ERTEN BUCAKTEPE, Nurefşan AYDENİZ, Esra Nur SİZER, MEHMET RECEP IŞIK

Pediatrik Hastalarda Femur Diafiz Kırıklarının Elastik Titanyum Çiviler ile Tedavisi

Yunus GÜZEL, Kenan GÜVENÇ, Onur BİLGE, Serdar TOKER, Mustafa YEL

Klinik Örneklerden İzole Edilen Stenotrophomonas maltophilia Suşlarının Dağılımı ve Antimikrobiyal Duyarlılıkları

İdris KANDEMİR, NİDA ÖZCAN, Ümit ALANBAYI, Hasan BOZDAĞ, NEZAHAT AKPOLAT, Kadri GÜL

Lateral Transperitoneal Laparoskopik Adrenalektomi: Tek Merkez Deneyimi

Ömer KURT, Cenk Murat YAZICI, Cüneyt TURAN

Diyareli Hastalarda Patojenik E. coli Serogruplarının Araştırılması

Zakir Zeki CALİK, MURAT KARAMEŞE, OSMAN AKTAŞ

Birinci Basamak Sağlık Çalışanlarında İş Doyumu ve Etkileyen Faktörler

FERİT KAYA, AYŞE FERDANE OĞUZÖNCÜL

Travma Sonrası Süreğen Şiddetli Başağrısı: Postkonküzyon Sendromlu Bir Ergen

Mustafa Yasin IRMAK, Ayşe Rodopman ARMAN, Dilşad TÜRKDOĞAN, Gülten THOMAS

Prematür Ejakülasyon Olgularında Cinsel Mitlere İnanma Düzeyi

MEHMET GÜNEŞ, Hasan AKÇALI, ONUR DEDE, Aslihan OKAN, Mahmut BULUT, Süleyman DEMİR, Abdullah ATLI, Aytekin SIR