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Hyperglycemia and Vascular Metabolic Memory: Truth or Fiction?

  • Macrovascular Complications in Diabetes (PD Reaven, Section Editor)
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Abstract

Prevention of long-term complications remains the main challenge in the treatment of diabetes. A strong relationship between glucose control and development of complications is apparent in all epidemiologic studies. Yet, intervention trials have yielded questionable results, particularly when intensive treatment was introduced in patients with long-standing diabetes. It has been postulated that in these subjects, prior exposure to chronic hyperglycemia may have generated a negative “metabolic memory,” preventing full exertion of the beneficial effects of any subsequent improvement of glucose control. This phenomenon has been replicated in animal models and it recognizes a molecular basis in the role of oxidative stress, advanced glycation processes, and epigenetic mechanisms accounting for self-perpetuating modifications of gene expression. Conversely, early intervention in both type 1 and type 2 diabetes has proven that good glycemic control reduces the risk of development and progression of complications with a beneficial effect that extends well beyond the duration of near-normoglycemia. This has brought up the concept of “metabolic legacy,” an advantage handed down by early and effective implementation of treatments designed to reduce blood glucose levels as safely as possible along with multifactorial intervention of all cardiovascular risk factors. The evidence, nature, and clinical implication of these concepts are reviewed.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Hossain P, Kawar B, El Nahas M. Obesity and diabetes in the developing world: a growing challenge. N Engl J Med. 2007;356:213–5.

    Article  PubMed  CAS  Google Scholar 

  2. Danaei G, Finucane MM, Lu Y, Singh GM, Cowan MJ, Paciorek CJ, et al. Global burden of metabolic risk factors of chronic diseases collaborating Group (Blood Glucose). National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2·7 million participants. Lancet. 2011;378:31–40.

    Article  PubMed  CAS  Google Scholar 

  3. Deshpande AD, Harris-Hayes M, Schootman M. Epidemiology of diabetes and diabetes-related complications. Phys Ther. 2008;88:1254–64.

    Article  PubMed  Google Scholar 

  4. Raman R, Gupta A, Krishna S, Kulothungan V, Sharma T. Prevalence and risk factors for diabetic microvascular complications in newly diagnosed type II diabetes mellitus. Sankara Nethralaya Diabetic Retinopathy Epidemiology and Molecular Genetic Study (SN-DREAMS, report 27). J Diabetes Complicat. 2012;26:123–8.

    Article  PubMed  Google Scholar 

  5. Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham Study. JAMA. 1979;241:2035–8.

    Article  PubMed  CAS  Google Scholar 

  6. Pan WH, Cedres LB, Liu K, Dyer A, Schoenberger JA, Shekelle RB, et al. Relationship of clinical diabetes and asymptomatic hyperglycemia to risk of coronary heart disease mortality in men and women. Am J Epidemiol. 1986;123:504–16.

    PubMed  CAS  Google Scholar 

  7. Seshasai SR, Kaptoge S, Thompson A, Di Angelantonio E, Gao P, The Emerging Risk Factors Collaboration, et al. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med. 2011;364:829–41.

    Article  PubMed  CAS  Google Scholar 

  8. Gerstein HC, Miller ME, Byington RP, Goff Jr DC, Bigger JT, Buse JB, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545–59.

    Article  PubMed  CAS  Google Scholar 

  9. Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560–72.

    Article  PubMed  CAS  Google Scholar 

  10. Duckworth W, Abraira C, Moritz T, et al. Intensive glucose control and complications in American veterans with type 2 diabetes. N Engl J Med. 2009;360:129–39.

    Article  PubMed  CAS  Google Scholar 

  11. Turnbull F, Zoungas S. Intensive glucose-lowering therapy in people with type 2 diabetes: what do we learn from a new meta-analysis of randomized controlled trials? Evid Based Med. 2012;17:98–9.

    Article  PubMed  Google Scholar 

  12. Del Prato S. Mega-trials in type 2 diabetes. From excitement to frustration? Diabetologia. 2009;52:1219–26.

    Article  PubMed  CAS  Google Scholar 

  13. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837–53.

    Article  Google Scholar 

  14. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577–89.

    Article  PubMed  CAS  Google Scholar 

  15. DCCT Study Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977–86.

    Article  Google Scholar 

  16. Diabetes control and complications trial/epidemiology of diabetes interventions and complications research group prolonged effect of intensive therapy on the risk of retinopathy complications in patients with type 1 diabetes mellitus. Ten years after the diabetes control and complications trial. Arch Ophthalmol. 2008; 126:1707–15.

    Google Scholar 

  17. Martin CL, Waberski BH, Pop-Busui R, Cleary PA, Catton S, Albers JW, et al. Vibration perception threshold as a measure of distal symmetrical peripheral neuropathy in type 1 diabetes: results from the DCCT/EDIC study. Diabetes Care. 2010;33:2635–41.

    Article  PubMed  Google Scholar 

  18. Pop-Busui R, Cleary PA, Braffett BH, Martin CL, Herman WH, Low PA, et al. Association between cardiovascular autonomic neuropathy and left ventricular dysfunction in the diabetes control and complications trial/epidemiology of diabetes interventions and complications (DCCT/EDIC) study. J Am Coll Cardiol. 2013;61:447–54.

    Google Scholar 

  19. • de Boer IH, Sun W, Cleary PA, Lachin JM, Molitch ME, Steffes MW, et al. Intensive diabetes therapy and glomerular filtration rate in type 1 diabetes. N Engl J Med. 2011;365:2366–76. This is the most recent paper from the DCCT/EDIC investigators confirming persistent beneficial effects in type 1 diabetic patients with initial intensive vs conventional treatment.

    Article  PubMed  Google Scholar 

  20. Nathan DM, Cleary PA, Backlund JY, Genuth SM, Lachin JM, Orchard TJ, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353:2643–53.

    Article  PubMed  Google Scholar 

  21. Lind M, Odén A, Fahlén M, Eliasson B. The shape of the metabolic memory of HbA1c: re-analyzing the DCCT with respect to time-dependent effects. Diabetologia. 2010;53:1093–8.

    Article  PubMed  CAS  Google Scholar 

  22. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348:383–93.

    Article  PubMed  Google Scholar 

  23. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358:580–91.

    Article  PubMed  CAS  Google Scholar 

  24. Gerstein HC, Miller ME, Genuth S, Ismail-Beigi F, Buse JB, Goff Jr DC, et al. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med. 2011;364:818–28.

    Article  PubMed  CAS  Google Scholar 

  25. Reaven PD, Moritz TE, Schwenke DC, Anderson RJ, Criqui M, Detrano R, et al. Intensive glucose-lowering therapy reduces cardiovascular disease events in Veterans Affairs Diabetes Trial participants with lower calcified coronary atherosclerosis. Diabetes. 2009;58:2642–8.

    Article  PubMed  CAS  Google Scholar 

  26. Griffin SJ, Borch-Johnsen K, Davies MJ, Khunti K, Rutten GE, Sandbæk A, et al. Effect of early intensive multifactorial therapy on 5-year cardiovascular outcomes in individuals with type 2 diabetes detected by screening (ADDITION Europe): a cluster-randomized trial. Lancet. 2011;378:156–67.

    Article  PubMed  Google Scholar 

  27. • Yang Y, Yao JJ, Du JL, Bai R, Sun LP, Sun GH, et al. Primary prevention of macroangiopathy in patients with short-duration type 2 diabetes by intensified multifactorial intervention: seven-year follow-up of diabetes complications in Chinese. Diabetes Care. 2012. doi:10.2337/dc12-0227. An initial proof of concept of feasibility of primary CV prevention in Type 2 diabetes.

  28. Gerstein HC, Bosch J, Dagenais GR, Díaz R, Jung H, Maggioni AP, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012;367:319–28.

    Article  PubMed  CAS  Google Scholar 

  29. The ORIGINALE Study. http://origintrial.org/Assets/PDF/ORIGINALE%20Protocol.pdf. Accessed on January 3, 2013.

  30. Engerman RL, Kern TS. Progression of incipient diabetic retinopathy during good glycemic control. Diabetes. 1987;36:808–12.

    Article  PubMed  CAS  Google Scholar 

  31. Hammes HP, Klinzing I, Wiegand S, Bretzel RG, Cohen AM, Federlin K. Islet transplantation inhibits diabetic retinopathy in the sucrose-fed diabetic Cohen rat. Invest Ophthalmol Vis Sci. 1993;34:2092–6.

    PubMed  CAS  Google Scholar 

  32. Kowluru RA. Effect of reinstitution of good glycemic control on retinal oxidative stress and nitrative stress in diabetic rats. Diabetes. 2003;52:818–23.

    Article  PubMed  CAS  Google Scholar 

  33. Kowluru RA, Chakrabarti S, Chen S. Re-institution of good metabolic control in diabetic rats and activation of caspase-3 and nuclear transcriptional factor (NF-kappaB) in the retina. Acta Diabetol. 2004;41:194–9.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  Google Scholar 

  35. Kowluru RA, Chan PS. Metabolic memory in diabetes - from in vitro oddity to in vivo problem: role of apoptosis. Brain Res Bull. 2010;81:297–302.

    Article  PubMed  CAS  Google Scholar 

  36. Kowluru RA, Abbas SN, Odenbach S. Reversal of hyperglycemia and diabetic nephropathy: effect of reinstitution of good metabolic control on oxidative stress in the kidney of diabetic rats. J Diabetes Complicat. 2004;18:282–8.

    Article  PubMed  Google Scholar 

  37. Roy S, Sala R, Cagliero E, Lorenzi M. Overexpression of fibronectin induced by diabetes or high glucose: phenomenon with a memory. Proc Natl Acad Sci U S A. 1990;87:404–8.

    Article  PubMed  CAS  Google Scholar 

  38. Brownlee M. The pathobiology of diabetes complications: a unifying mechanism. Diabetes. 2005;54:1615–25.

    Article  PubMed  CAS  Google Scholar 

  39. Stitt AW. The role of advanced glycation in the pathogenesis of diabetic retinopathy. Exp Mol Pathol. 2003;1:95–108.

    Article  Google Scholar 

  40. Siebel AL, Fernandez AZ, El-Osta A. Glycemic memory associated epigenetic changes. Biochem Pharmacol. 2010;80:1853–9.

    Article  PubMed  CAS  Google Scholar 

  41. •• Cooper ME, El-Osta A. Epigenetics: mechanisms and implications for diabetic complications. Circ Res. 2010;107:1403–13. This study provides a thorough description of the current understanding the molecular changes to chromatin structure and the functional relationship with altered signaling pathways that represents the basis of metabolic memory.

    Article  PubMed  CAS  Google Scholar 

  42. El-Osta A, Brasacchio D, Yao D, Pocai A, Jones PL, Roeder RG, et al. Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia. J Exp Med. 2008;205:2409–17.

    Article  PubMed  CAS  Google Scholar 

  43. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414:813–20.

    Article  PubMed  CAS  Google Scholar 

  44. Ihnat MA, Thorpe JE, Kamat CD, Szabó C, Green DE, Warnke LA, et al. Reactive oxygen species mediate a cellular ‘memory’ of high glucose stress signaling. Diabetologia. 2007;50:1523–31.

    Article  PubMed  CAS  Google Scholar 

  45. Monnier VM, Bautista O, Kenny D, Sell DR, Fogarty J, Dahms W, et al. Skin collagen glycation, glycoxidation, and crosslinking are lower in subjects with long-term intensive vs conventional therapy of type 1 diabetes: relevance of glycated collagen products vs HbA1c as markers of diabetic complications. Diabetes. 1999;48:870–80.

    Article  PubMed  CAS  Google Scholar 

  46. Genuth S, Sun W, Cleary P, Sell DR, Dahms W, Malone J, et al. Glycation and carboxymethyllysine levels in skin collagen predict the risk of future 10-year progression of diabetic retinopathy and nephropathy in the Diabetes Control and Complications Trial and Epidemiology of Diabetes Interventions and Complications participants with type 1 diabetes. Diabetes. 2005;54:3103–11.

    Article  PubMed  CAS  Google Scholar 

  47. White NH, Sun W, Cleary PA, Tamborlane WV, Danis RP, Hainsworth DP, et al. Effect of prior intensive therapy in type 1 diabetes on 10-year progression of retinopathy in the DCCT/EDIC: comparison of adults and adolescents. Diabetes. 2010;59:1244–53.

    Article  PubMed  CAS  Google Scholar 

  48. Albers JW, Herman WH, Pop-Busui R, Feldman EL, Martin CL, Cleary PA, et al. Effect of prior intensive insulin treatment during the Diabetes Control and Complications Trial (DCCT) on peripheral neuropathy in type 1 diabetes during the Epidemiology of Diabetes Interventions and Complications (EDIC) study. Diabetes Care. 2010;33:1090–6.

    Article  PubMed  CAS  Google Scholar 

  49. Polak JF, Backlund JY, Cleary PA, Harrington AP, O'Leary DH, Lachin JM, et al. Progression of carotid artery intima-media thickness during 12 years in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. Diabetes. 2011;60:607–13.

    Article  PubMed  CAS  Google Scholar 

  50. Helgadottir A, Thorleifsson G, Manolescu A, et al. A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science. 2007;316:1491–3.

    Article  PubMed  CAS  Google Scholar 

  51. Doria A, Wojcik J, Xu R, Gervino EV, Hauser TH, Johnstone MT, et al. Interaction between poor glycemic control and 9p21 locus on risk of coronary artery disease in type 2 diabetes. JAMA. 2008;300:2389–97.

    Article  PubMed  CAS  Google Scholar 

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Conflict of Interest

Cristina Bianchi declares that she has no conflict of interest.

Roberto Miccoli declares that he has no conflict of interest.

Stefano Del Prato has board membership with Sanofi, Novo Nordisk, Eli Lily and Co., Novartis Pharmaceuticals, Roche Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, AstraZeneca, GlaxoSmithKline, Takeda Pharmaceuticals, Janssen Pharmaceuticals, and Intarcia. He has also received grant support from Sanofi, Novo Nordisk, Takeda Pharmaceuticals, Bristol-Myers Squibb, and Novartis Pharmaceuticals. He has also received payment for development of educational presentations including service on speakers’ bureaus from Bristol-Myers Squibb, Novartis Pharmaceuticals, and Janssen.

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  1. Department of Clinical and Experimental Medicine, Section of Diabetes and Metabolic Diseases, Nuovo Ospedale Santa Chiara, Via Paradisa, 2, 56124, Pisa, Italy

    Cristina Bianchi, Roberto Miccoli & Stefano Del Prato

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  1. Cristina Bianchi
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  2. Roberto Miccoli
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Correspondence to Stefano Del Prato.

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Bianchi, C., Miccoli, R. & Del Prato, S. Hyperglycemia and Vascular Metabolic Memory: Truth or Fiction?. Curr Diab Rep 13, 403–410 (2013). https://doi.org/10.1007/s11892-013-0371-2

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  • DOI: https://doi.org/10.1007/s11892-013-0371-2

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