Hürmet KÜÇÜKKATIRCI, Zeynep CAFEROĞLU, Nihal HATİPOĞLU

Diabetes Mellitusta Metabolik Hafızanın Rolü

Diabetes Mellitus, morbidite ve mortalitenin artmasına neden olan, önemli bir halk sağlığı problemidir. Diyabete spesifik hiperglisemi, çeşitli ilaçlar veya ekzojen insülin uygulaması yolu ile klinik olarak kontrol edilmeye çalışılmaktadır fakat gerek tedavi gerekse takipteki gelişmelere rağmen diyabetli birçok hastada vasküler komplikasyon gelişme durumunun önüne hâlen tam anlamı ile geçilememiştir. Çeşitli epidemiyolojik ve geniş kapsamlı çalışmalar, erken ve yoğun hiperglisemi kontrolünün diyabet ile ilişkili komplikasyon riskini azalttığını göstermiştir ve ilgili çalışmaların tamamı, erken glisemik kontrolün gerekliliğini vurgulamaktadır. Erken dönemdeki hiperglisemi kontrolü yakın zamanda “metabolik hafıza” olarak tanımlanmıştır. Mitokondri ve endotel hücrelerinde serbest oksijen radikallerinin aşırı üretimi, mitokondriyal deoksiribonükleik asit (DNA) hasarı, protein kinaz C aktivasyonu, poliol ve hekzoamin yolağı aktivasyonu, ileri glikozilasyon son ürünlerinin ve reseptörlerinin artışı gibi birçok mekanizma metabolik hafıza patogenezinde önemli rol oynamaktadır. Bu mekanizmalar, gen ekspresyonunu kalıcı olarak indükleyerek epigenetik değişikliklere neden olmaktadır. Metabolik hafıza; histon modifikasyonu, DNA metilasyonu ve mikro-ribonükleik asit (RNA) ile ilişkili mekanizmalar gibi epigenetik değişiklikler ile gerçekleşir. Klinik açıdan değerlendirildiğinde ise metabolik hafıza teorisi, metabolik kontrolü en kısa sürede sağlamak için erken ve yoğun tedavi rejiminin gerekliliğini vurgulamaktadır. Uzun süreli diyabetik komplikasyonları en aza indirgemek amacıyla erken ve yoğun hiperglisemi kontrolünün yanı sıra, reaktif oksijen türleri ve glikozilasyonu azaltabilen terapötik ajanlardan ve/veya epigenetik tedaviden de yararlanılabilir. Bu derlemede; metabolik hafıza teorisine, metabolik hafızanın tanımı ve patogenezine, epigenetik mekanizmalara ve terapötik yaklaşımlara yer verilmiştir.

Anahtar Kelimeler:

Diabetes Mellitus, Diyabetik komplikasyonlar, Epigenetik, Metabolik hafıza

The Role of Metabolic Memory in Diabetes Mellitus

Diabetes Mellitus, is an important public health problem that causes increased morbidity and mortality. Hyperglycemia, specific sign of diabetes; tried to be controlled clinically exogenous insulin administration or various drugs however, despite developments treatment and follow-up, development of vascular complications hasn’t been completely prevented in many diabetic patients. Several epidemiological, comprehensive studies have shown that early-intensive control of hyperglycemia reduces risk of diabetes-related complications. These studies emphasize need for early glycemic control. Early control of hyperglycemia has recently been defined as "metabolic memory". Different mechanisms, such as overproduction of free oxygen radicals in mitochondria and endothelial cells, mitochondrial deoxyribonucleic acid (DNA) damage, protein kinase C activation, polyol-hexosamine pathway activation, increased production of advanced glycation end products (AGEs) and AGE receptor overexpression play an important role in metabolic memory pathogenesis. These mechanisms induce gene expression permanently and causing epigenetic changes. Metabolic memory occurs through epigenetic changes such as histone modification, DNA methylation and micro-ribonucleic acid (RNA)-related mechanisms. From a clinical point of view, metabolic memory theory emphasizes necessity of an early-intensive treatment regimen to achieve metabolic control as soon as possible. In addition to early intensive hyperglycemia control, therapeutic agents or epigenetic therapy can reduce reactive oxygen species and glycosylation also be used in order to minimize long-term diabetic complications. In this review, metabolic memory theory, definition and pathogenesis of metabolic memory, epigenetic mechanisms and therapeutic approaches are evaluated.

Keywords:

Diabetes Mellitus, Diabetic complications, Epigenetics, Metabolic memory,

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1) Ceriello, A. (2012). “The Emerging Challenge in Diabetes: The "Metabolic Memory”. Vascular Pharmacology, 57 (5-6), 133-138. doi: 10.1016/j.vph.2012.05.005.
2) Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. (2002). “Effect of Intensive Therapy on The Microvascular Complications of Type 1 Diabetes Mellitus”. The Journal of the American Medical Association, 287, 563–2569. doi: 10.1001/jama.287.19.2563.
3) Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. (2003). “Sustained Effect of Intensive Treatment of Type 1 Diabetes Mellitus on Development and Progression of Diabetic Nephropathy: The Epidemiology of Diabetes Interventions and Complications (EDIC) study”. The Journal of the American Medical Association, 290, 2159–2167. doi: 10.1001/jama.290.16.2159.
4) Testa, R, Bonfigli, A.R, Prattichizzo, F, Sala, L.L, Nigris, V.D. and Ceriello, A. (2017). “The "Metabolic Memory" Theory and The Early Treatment of Hyperglycemia in Prevent of Diabetic Complications”. Nutrients, 9 (5), pii: E437. doi: 10.3390/nu9050437.
5) Holman, R.R, Paul, S.K, Bethel, M.A, Matthews, D.R. and Neil, H.A. (2008). “Long-Term Follow-Up After Tight Control of Blood Pressure in Type 2 Diabetes”. The New England Journal of Medicine, 359, 1565–1576. doi: 10.1056/NEJMoa0806359.
6) Holman, R.R, Paul, S.K, Bethel, M.A, Matthews, D.R. and Neil, H.A. (2008). “10-Year Follow-up of Intensive Glucose Control in Type 2 Diabetes”. The New England Journal of Medicine, 359, 1577–1589. doi: 10.1056/NEJMoa0806470.
7) Aschner, P.J. and Ruiz, A.J. (2012). “Metabolic Memory for Vascular Disease in Diabetes”. Diabetes Technology & Therapeutics, 14 (1), 68-74. doi: 10.1089/dia.2012.0012.
8) Gaede, P, Lund-Andersen, H, Parving, H.H. and Pedersen, O. (2008). “Effect of a Multifactorial Intervention on Mortality in Type 2 Diabetes”. The New England Journal of Medicine, 358, 580–591. doi: 10.1056/NEJMoa0706245.
9) Duckworth, W, Abraira, C, Moritz, T, Reda, D, Emanuele, N, Reaven, P.D, Zieve, F.J, Marks, J, Davis, S.N, Hayvard, R, Warren, S.R, Goldman, S, McCarren M, Vitek M.E, Henderson, W.G, Huang, G.D, and VADT İnvestigators. (2009). “Glucose Control and Vascular Complications in Veterans With Type 2 Diabetes”. The New England Journal of Medicine, 360, 129–139. doi: 10.1056/NEJMoa0808431.
10) Berezin, A. (2016). “Metabolic Memory Phenomenon in Diabetes Mellitus: Achieving and Perspectives”. Diabetes & Metabolic Syndrome, 10 (2 Suppl 1), 176-183. doi: 10.1016/j.dsx.2016.03.016.
11) Drzewoski, J, Kasznicki, J, and Trojanowski, Z. (2009). “The Role of "Metabolic Memory" in The Natural History of Diabetes Mellitus”. Polish Archives of Internal Medicine, 119 (7-8), 493-500.
12) Brownlee, M. (2001). “Biochemistry and Molecular Cell Biology of Diabetic Complications”. Nature, 414, 813‑820. doi: 10.1038/414813a.
13) Ihnat, M.A, Thorpe, J.E, Kamat, C.D, Szabo, C, Green, D.E, Warnke, L.A, Lacza, Z, Cselenyak, A, Ross, K, Shakir, S, Piconi, L, Kaltreider, R.C, and Ceriello, A. (2007). “Reactive Oxygen Species Mediate a Cellular ‘Memory’ of High Glucose Stress Signalling”. Diabetologia, 50, 1523‑1531. doi: 10.1007/s00125-007-0684-2.
14) Ceriello, A, Ihnat, M.A. and Thorpe, J.E. (2009). “Clinical Review 2: The “Metabolic Memory”: Is More Than Just Tight Glucose Control Necessary to Prevent Diabetic Complications?” The Journal of Clinical Endocrinology & Metabolism, 94 (2), 410‑415. doi: 10.1210/jc.2008-1824.
15) Kowluru, R.A. (2017). “Diabetic Retinopathy, Metabolic Memory and Epigenetic Modifications”. Vision Research, 139, 30-38. doi: 10.1016/j.visres.2017.02.011.
16) Portela, A. and Esteller, M. (2010). “Epigenetic Modifications and Human Disease”. Nature Biotechnology, 28, 1057-1068.
17) Fu, Y, Dominissini, D, Rechavi, G. and He, C. (2014). “Gene Expression Regulation Mediated Through Reversible m(6)A RNA Methylation”. Nature Reviews Genetics, 15, 293-306. doi: 10.1038/nrg3724.
18) Reddy, M.A, Zhang, E. and Natarajan, R. (2015). “Epigenetic Mechanisms in Diabetic Complications and Metabolic Memory”. Diabetelogia, 58 (3), 443-455. doi: 10.1007/s00 125-014-3462-y.
19) Ahmed, S.M, Johar, D, Ali, M.M. and El-Badri, N. (2019). “Insights Into The Role of DNA Methylation and Protein Misfolding in Diabetes Mellitus”. Endocrine, Metabolic & Immune Disorders - Drug Targets, 19 (6), 744-753. doi: 10.2174/1871530319666190305131813.
20) Kato, M. and Natarajan, M. (2019). “Epigenetics and Epigenomics in Diabetic Kidney Disease and Metabolic Memory”. Nature Reviews Nephrology, 15 (6), 327-345. doi: 10.1038/s41581-019-0135-6.
21) Chen, Z, Miao, F, Paterson, A.D, Lachin, J.M, Zhang, L, Schones D.E, Wu, X, Wang, J, Tompkins, J.D, Genuth, S, Braffett, B.H, Riggs, A.D. and DCCT/EDIC Research Group; Rama Natarajan. (2016). “Epigenomic Profiling Reveals an Association Between Persistence of DNA Methylation and Metabolic Memory in The DCCT/EDIC Type 1 Diabetes Cohort”. Proceedings of the National Academy of Sciences of the United States of America, 113 (21), E3002-11. doi: 10.1073/pnas.1603712113.
22) Ceriello, A, Ihnat, M.A. and Thorpe, J.E. (2009). “Clinical Review 2: The "Metabolic Memory": Is More Than Just Tight Glucose Control Necessary to Prevent Diabetic Complications?” The Journal of Clinical Endocrinology & Metabolism, 94 (2), 410-415. doi: 10.1210/jc.2008-1824.
23) Eser, B.E, Yazgan, Ü.C, Gürses, S.A. ve Aydın, M. (2016). “Diabetes Mellitus ve Epigenetik Mekanizmalar”. Dicle Tıp Dergisi, 43 (2), 375-382. doi: 10.5798/diclemedj.0921. 2016.02.0700
24) Janssen, H.L.A, Reesink, H.W, Lawitz, E.J, Zeuzem, S, Rodriguez-Torres, M, Patel K, van der Meer, A.J, Patick, A.K, Chen, A, Zhou, Y, Persson, R, King, B.D, Kauppinen, S, Levin, A.A. and Hodges, M.R. (2013). “Treatment of HCV Infection by Targeting MicroRNA”. The New England Journal of Medicine, 368 (18), 1685-1694. doi: 10.1056/NEJ Moa1209026.
25) Davalos, A. and Chroni, A. (2015). “Antisense Oligonucleotides, MicroRNAs, and Antibodies”. Handbook of Experimental Pharmacology, 224, 649-689. DOI 10.1007/978-3-319-09665-0