The role of «metabolic memory» mechanisms in the development and progression of vascular complications of diabetes mellitus

The study of diabetes mellitus (DM), its complications and related pathologies has been continuously performed for many years; however, despite the substantial work and outstanding achievements in studying the mechanisms of DM development and the success of new medicinal products for controlling glycaemia, the problems associated with the late complications of DM continue to increase. The importance of glycaemic control in the early stages of DM for the development of complications is seen only after a sufficiently long period of observation. Such a delayed effect of primary good or unsatisfactory metabolic control, which shapes the patient’s clinical fate to a greater extent, is termed ‘metabolic memory’. The disorders developed under the influence of hyperglycaemia persist for long periods after the normalisation of carbohydrate metabolism; moreover, the effect of previous hyperglycaemia extends over the next 20 and even 30 years. Current research is focused on the possible mechanisms of metabolic memory development, including oxidative stress, advanced glycation end products and epigenetic mechanisms. This research will provide insight into potential markers for the early development and progression of vascular complications and new therapeutic possibilities for the future. However, determining the probable ‘point of no return’ is more important, which implies that a point exists; after this point is crossed, the progression of vascular complications associated with DM cannot be prevented or reversed. The results of numerous experimental studies demonstrate that the prerequisite components of metabolic memory can be used as potential markers of the progression of DM complications, and may be potential therapeutic targets.

1. International Diabetes Federation. IDF Diabetes Atlas. 7th Edition [Internet]. Brussels, Belgium: IDF; 2015. Available from http://www.diabetesatlas.org/ Accessed 20 February 2016

2. Rivellese AA, Riccardi G, Vaccaro O. Cardiovascular risk in women with diabetes. Nutr Metab Cardiovasc Dis. 2010;20(6):474-480. doi: 10.1016/j.numecd.2010.01.008.

3. Nathan DM, DCCT EDIC Research Group. The diabetes control and complications trial/epidemiology of diabetes interventions and complications study at 30 years: overview. Diabetes Care. 2014;37(1):9-16. doi: 10.2337/dc13-2112.

4. Дедов И.И., Шестакова М.В. Феномен «метаболической памяти» в прогнозировании риска развития сосудистых осложнений при сахарном диабете // Терапевтический архив. — 2015. — Т. 87. — №10. — С. 4-10. [Dedov II, Shestakova MV. The metabolic memory phenomenon in predicting a risk for vascular complications in diabetes mellitus. Ter Arkh. 2015;87(10):4-10. (in Russ.)] doi: 10.17116/terarkh201587104-10.

5. Wong MG, Perkovic V, Chalmers J, et al. Long-term Benefits of Intensive Glucose Control for Preventing End-Stage Kidney Disease: ADVANCE-ON. Diabetes Care. 2016;39(5):694-700. doi: 10.2337/dc15-2322.

6. ACCORD Study Group. Nine-Year Effects of 3.7 Years of Intensive Glycemic Control on Cardiovascular Outcomes. Diabetes Care. 2016;39(5):701-708. doi: 10.2337/dc15-2283.

7. Abdul-Ghani M, Del Prato S, Chilton R, DeFronzo RA. SGLT2 Inhibitors and Cardiovascular Risk: Lessons Learned From the EMPA-REG OUTCOME Study. Diabetes Care. 2016;39(5):717-725. doi: 10.2337/dc16-0041.

8. 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(2):410-415. doi: 10.1210/jc.2008-1824.

9. Ihnat MA, Thorpe JE, Kamat CD, et al. Reactive oxygen species mediate a cellular 'memory' of high glucose stress signalling. Diabetologia. 2007;50(7):1523-1531. doi: 10.1007/s00125-007-0684-2.

10. Foury F, Hu J, Vanderstraeten S. Mitochondrial DNA mutators. Cell Mol Life Sci. 2004;61(22):2799-2811. doi: 10.1007/s00018-004-4220-y.

11. Beckman JS, Koppenol WH. Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am J Physiol. 1996;271(5 Pt 1):C1424-1437.

12. Zheng Z, Chen H, Li J, et al. Sirtuin 1-mediated cellular metabolic memory of high glucose via the LKB1/AMPK/ROS pathway and therapeutic effects of metformin. Diabetes. 2012;61(1):217-228. doi: 10.2337/db11-0416.

13. Kowluru RA, Mishra M. Oxidative stress, mitochondrial damage and diabetic retinopathy. Biochim Biophys Acta. 2015;1852(11):2474-2483. doi: 10.1016/j.bbadis.2015.08.001.

14. Cai L, Kang YJ. Cell death and diabetic cardiomyopathy. Cardiovasc Toxicol. 2003;3(3):219-228.

15. Kowluru RA, Kanwar M, Kennedy A. Metabolic memory phenomenon and accumulation of peroxynitrite in retinal capillaries. Exp Diabetes Res. 2007;2007:21976. doi: 10.1155/2007/21976.

16. Schisano B, Tripathi G, McGee K, et al. Glucose oscillations, more than constant high glucose, induce p53 activation and a metabolic memory in human endothelial cells. Diabetologia. 2011;54(5):1219-1226. doi: 10.1007/s00125-011-2049-0.

17. Yamagishi S, Nakamura N, Suematsu M, et al. Advanced Glycation End Products: A Molecular Target for Vascular Complications in Diabetes. Mol Med. 2015;21 Suppl 1:S32-40. doi: 10.2119/molmed.2015.00067.

18. Rosca MG, Mustata TG, Kinter MT, et al. Glycation of mitochondrial proteins from diabetic rat kidney is associated with excess superoxide formation. Am J Physiol Renal Physiol. 2005;289(2):F420-430. doi: 10.1152/ajprenal.00415.2004.

19. Lander HM, Tauras JM, Ogiste JS, et al. Activation of the receptor for advanced glycation end products triggers a p21(ras)-dependent mitogen-activated protein kinase pathway regulated by oxidant stress. J Biol Chem. 1997;272(28):17810-17814.

20. Koyama H, Nishizawa Y. AGEs/RAGE in CKD: irreversible metabolic memory road toward CVD? Eur J Clin Invest. 2010;40(7):623-635. doi: 10.1111/j.1365-2362.2010.02298.x.

21. Bucciarelli LG, Wendt T, Qu W, et al. RAGE blockade stabilizes established atherosclerosis in diabetic apolipoprotein E-null mice. Circulation. 2002;106(22):2827-2835.

22. Daffu G, del Pozo CH, O'Shea KM, et al. Radical roles for RAGE in the pathogenesis of oxidative stress in cardiovascular diseases and beyond. Int J Mol Sci. 2013;14(10):19891-19910. doi: 10.3390/ijms141019891.

23. Fukami K, Yamagishi S, Okuda S. Role of AGEs-RAGE system in cardiovascular disease. Curr Pharm Des. 2014;20(14):2395-2402.

24. Bucala R, Makita Z, Vega G, et al. Modification of low density lipoprotein by advanced glycation end products contributes to the dyslipidemia of diabetes and renal insufficiency. Proc Natl Acad Sci U S A. 1994;91(20):9441-9445. PMC44828.

25. Ishibashi Y, Matsui T, Takeuchi M, Yamagishi S. Rosuvastatin blocks advanced glycation end products-elicited reduction of macrophage cholesterol efflux by suppressing NADPH oxidase activity via inhibition of geranylgeranylation of Rac-1. Horm Metab Res. 2011;43(9):619-624. doi: 10.1055/s-0031-1283148.

26. Chen Q, Dong L, Wang L, et al. Advanced glycation end products impair function of late endothelial progenitor cells through effects on protein kinase Akt and cyclooxygenase-2. Biochem Biophys Res Commun. 2009;381(2):192-197. doi: 10.1016/j.bbrc.2009.02.040.

27. Bhatwadekar AD, Glenn JV, Li G, et al. Advanced glycation of fibronectin impairs vascular repair by endothelial progenitor cells: implications for vasodegeneration in diabetic retinopathy. Invest Ophthalmol Vis Sci. 2008;49(3):1232-1241. doi: 10.1167/iovs.07-1015.

28. Monnier VM, Bautista O, Kenny D, et al. Skin collagen glycation, glycoxidation, and crosslinking are lower in subjects with long-term intensive versus conventional therapy of type 1 diabetes: relevance of glycated collagen products versus HbA1c as markers of diabetic complications. DCCT Skin Collagen Ancillary Study Group. Diabetes Control and Complications Trial. Diabetes. 1999;48(4):870-880. PMC2862597.

29. Reddy MA, Natarajan R. Epigenetic mechanisms in diabetic vascular complications. Cardiovasc Res. 2011;90(3):421-429. doi: 10.1093/cvr/cvr024.

30. Zhong Q, Kowluru RA. Epigenetic changes in mitochondrial superoxide dismutase in the retina and the development of diabetic retinopathy. Diabetes. 2011;60(4):1304-1313. doi: 10.2337/db10-0133.

31. Yu J, Auwerx J. Protein deacetylation by SIRT1: an emerging key post-translational modification in metabolic regulation. Pharmacol Res. 2010;62(1):35-41. doi: 10.1016/j.phrs.2009.12.006.

32. Kadiyala CSR, Zheng L, Du Y, et al. Acetylation of retinal histones in diabetes increases inflammatory proteins: effects of minocycline and manipulation of histone acetyltransferase (HAT) and histone deacetylase (HDAC). J Biol Chem. 2012;287(31):25869–25880. doi: 10.1074/jbc.M112.375204.

33. Vahtola E, Louhelainen M, Forsten H, et al. Sirtuin1-p53, forkhead box O3a, p38 and post-infarct cardiac remodeling in the spontaneously diabetic Goto-Kakizaki rat. Cardiovasc Diabetol. 2010;9:5. doi: 10.1186/1475-2840-9-5.

34. Advani A, Wiggins KJ, Cox AJ, et al. Inhibition of the epidermal growth factor receptor preserves podocytes and attenuates albuminuria in experimental diabetic nephropathy. Nephrology (Carlton). 2011;16(6):573-581. doi: 10.1111/j.1440-1797.2011.01451.x.

35. Gilbert RE, Huang Q, Thai K, et al. Histone deacetylase inhibition attenuates diabetes-associated kidney growth: potential role for epigenetic modification of the epidermal growth factor receptor. Kidney Int. 2011;79(12):1312-1321. doi: 10.1038/ki.2011.39.

36. Zhou Q, Shaw PG, Davidson NE. Inhibition of histone deacetylase suppresses EGF signaling pathways by destabilizing EGFR mRNA in ER-negative human breast cancer cells. Breast Cancer Res Treat. 2009;117(2):443-451. doi: 10.1007/s10549-008-0148-5.

37. Gilbert RE, Huang Q, Thai K, et al. Histone deacetylase inhibition attenuates diabetes-associated kidney growth: potential role for epigenetic modification of the epidermal growth factor receptor. Kidney Int. 2011;79(12):1312-1321. doi: 10.1038/ki.2011.39.

38. Shantikumar S, Caporali A, Emanueli C. Role of microRNAs in diabetes and its cardiovascular complications. Cardiovasc Res. 2012;93(4):583-593. doi: 10.1093/cvr/cvr300.

39. Liang R, Bates DJ, Wang E. Epigenetic Control of MicroRNA Expression and Aging. Curr Genomics. 2009;10(3):184-193. doi: 10.2174/138920209788185225.

40. Long J, Wang Y, Wang W, et al. MicroRNA-29c is a signature microRNA under high glucose conditions that targets Sprouty homolog 1, and its in vivo knockdown prevents progression of diabetic nephropathy. J Biol Chem. 2011;286(13):11837-11848. doi: 10.1074/jbc.M110.194969.

41. Dey N, Das F, Mariappan MM, et al. MicroRNA-21 orchestrates high glucose-induced signals to TOR complex 1, resulting in renal cell pathology in diabetes. J Biol Chem. 2011;286(29):25586-25603. doi: 10.1074/jbc.M110.208066.

42. Wang B, Koh P, Winbanks C, et al. miR-200a Prevents renal fibrogenesis through repression of TGF-beta2 expression. Diabetes. 2011;60(1):280-287. doi: 10.2337/db10-0892.

43. Putta S, Lanting L, Sun G, et al. Inhibiting microRNA-192 ameliorates renal fibrosis in diabetic nephropathy. J Am Soc Nephrol. 2012;23(3):458-469. doi: 10.1681/ASN.2011050485.

44. Kato M, Zhang J, Wang M, et al. MicroRNA-192 in diabetic kidney glomeruli and its function in TGF-beta-induced collagen expression via inhibition of E-box repressors. Proc Natl Acad Sci U S A. 2007;104(9):3432-3437. doi: 10.1073/pnas.0611192104.

45. Feng B, Chen S, McArthur K, et al. miR-146a-Mediated extracellular matrix protein production in chronic diabetes complications. Diabetes. 2011;60(11):2975-2984. doi: 10.2337/db11-0478.

46. Maunakea AK, Chepelev I, Zhao K. Epigenome mapping in normal and disease States. Circ Res. 2010;107(3):327-339. doi: 10.1161/CIRCRESAHA.110.222463.

47. Lister R, Pelizzola M, Dowen RH, et al. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature. 2009;462(7271):315-322. doi: 10.1038/nature08514.

48. Ball MP, Li JB, Gao Y, et al. Targeted and genome-scale strategies reveal gene-body methylation signatures in human cells. Nat Biotechnol. 2009;27(4):361-368. doi: 10.1038/nbt.1533.

49. Laurent L, Wong E, Li G, et al. Dynamic changes in the human methylome during differentiation. Genome Res. 2010;20(3):320-331. doi: 10.1101/gr.101907.109.

50. Caramori ML, Kim Y, Moore JH, et al. Gene expression differences in skin fibroblasts in identical twins discordant for type 1 diabetes. Diabetes. 2012;61(3):739-744. doi: 10.2337/db11-0617.

51. Park JH, Stoffers DA, Nicholls RD, Simmons RA. Development of type 2 diabetes following intrauterine growth retardation in rats is associated with progressive epigenetic silencing of Pdx1. J Clin Invest. 2008;118(6):2316-2324. doi: 10.1172/JCI33655.

52. Zhao J, Goldberg J, Bremner JD, Vaccarino V. Global DNA methylation is associated with insulin resistance: a monozygotic twin study. Diabetes. 2012;61(2):542-546. doi: 10.2337/db11-1048.

53. Sapienza C, Lee J, Powell J, et al. DNA methylation profiling identifies epigenetic differences between diabetes patients with ESRD and diabetes patients without nephropathy. Epigenetics. 2014;6(1):20-28. doi: 10.4161/epi.6.1.13362.

54. Akirav EM, Lebastchi J, Galvan EM, et al. Detection of beta cell death in diabetes using differentially methylated circulating DNA. Proc Natl Acad Sci U S A. 2011;108(47):19018-19023. doi: 10.1073/pnas.1111008108.

55. 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(6):1405-1426. doi: 10.1038/emboj.2011.503.

56. Williams KT, Garrow TA, Schalinske KL. Type I diabetes leads to tissue-specific DNA hypomethylation in male rats. J Nutr. 2008;138(11):2064-2069. doi: 10.3945/jn.108.094144.

57. Williams KT, Schalinske KL. Tissue-specific alterations of methyl group metabolism with DNA hypermethylation in the Zucker (type 2) diabetic fatty rat. Diabetes Metab Res Rev. 2012;28(2):123-131. doi: 10.1002/dmrr.1281.

58. Pirola L, Balcerczyk A, Tothill RW, et al. Genome-wide analysis distinguishes hyperglycemia regulated epigenetic signatures of primary vascular cells. Genome Res. 2011;21(10):1601-1615. doi: 10.1101/gr.116095.110.

59. 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(2):485-491. doi: 10.2337/db11-0588.

60. Alhosin M, Sharif T, Mousli M, et al. Down-regulation of UHRF1, associated with re-expression of tumor suppressor genes, is a common feature of natural compounds exhibiting anti-cancer properties. J Exp Clin Cancer Res. 2011;30:41. doi: 10.1186/1756-9966-30-41.