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Metabolic memory and diabetic nephropathy: potential role for epigenetic mechanisms

Abstract

Many clinical studies have shown that intensive glycemic control in patients with diabetes can reduce the incidence and progression of diabetic nephropathy and can also reduce the incidence of other complications. These beneficial effects persist after patients return to usual (often worse) glycemic control. The Diabetes Control and Complications Trial was the first to refer to this phenomenon as 'metabolic memory'. Many patients with diabetes, however, still develop diabetic nephropathy despite receiving intensified glycemic control. Preliminary work in endothelial cells has shown that transient episodes of hyperglycemia can induce changes in gene expression that are dependent on modifications to histone tails (for example, methylation), and that these changes persist after return to normoglycemia. The persistence of such modifications cannot yet be fully explained, but certain epigenetic changes, as well as biochemical mechanisms such as advanced glycation, may provide new and interesting clues towards explaining the pathogenesis of this phenomenon. Further elucidation of the molecular events that enable prior glycemic control to result in end-organ protection in diabetes may lead to the development of new approaches for reducing the burden of diabetic nephropathy.

Key Points

  • The seminal study confirming the importance of optimizing glycemic control in type 1 diabetes was the Diabetes Control and Complications Trial (DCCT) and its follow-up observational study, the Epidemiology of Diabetes Intervention and Complications (EDIC) study

  • Intensive glycemic control can reduce the incidence and progression of diabetic complications, including diabetic nephropathy; these benefits often persist despite a return to more usual, often worse, glycemic control

  • 'Metabolic memory' is a term that has been used to describe the fact that prior glucose control has sustained effects that persist even after return to more usual glycemic control

  • Even with intensive glycemic control, some patients will still develop diabetic nephropathy and other diabetic vascular complications

  • Preliminary studies in vascular endothelial cells have suggested that transient hyperglycemia can influence gene expression by epigenetic mechanisms, including the methylation of particular histone tails, and that these changes persist after a return to normoglycemia

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Figure 1: Hazard ratios for the prespecified aggregate clinical outcome of microvascular disease in the UKPDS.
Figure 2: Organizational network of chromatin in the cell.
Figure 3: Transient hyperglycemia causes a sustained increase in p65 gene expression caused by Set7/9-mediated histone methylation.

References

  1. Santesson, C. G. (ed.) Les Prix Nobel en 1902 (The Nobel Foundation, Stockholm, 1905).

    Google Scholar 

  2. Alberts, B. et al. (eds) Molecular Biology of the Cell, 4th edn (Garland Science, New York, 2002).

    Google Scholar 

  3. American Diabetes Association. Standards of medical care in diabetes—2008. Diabetes Care 31 (Suppl. 1), S12–S54 (2008).

  4. Holcomb, S. S. Update: standards of medical care in diabetes. Nurse Pract. 33, 12–15 (2008).

    Article  PubMed  Google Scholar 

  5. Chase, H. P. et al. Glucose control and the renal and retinal complications of insulin-dependent diabetes. JAMA 261, 1155–1160 (1989).

    Article  CAS  PubMed  Google Scholar 

  6. Gabbay, K. H. The sorbitol pathway and the complications of diabetes. N. Engl. J. Med. 288, 831–836 (1973).

    Article  CAS  PubMed  Google Scholar 

  7. Calcutt, N. A., Cooper, M. E., Kern, T. S. & Schmidt, A. M. Therapies for hyperglycaemia-induced diabetic complications: from animal models to clinical trials. Nat. Rev. Drug Discov. 8, 417–429 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Gu, K., Cowie, C. C. & Harris, M. I. Diabetes and decline in heart disease mortality in US adults. JAMA 281, 1291–1297 (1999).

    Article  CAS  PubMed  Google Scholar 

  9. Dale, A. C., Vatten, L. J., Nilsen, T. I., Midthjell, K. & Wiseth, R. Secular decline in mortality from coronary heart disease in adults with diabetes mellitus: cohort study. BMJ 337, a236 (2008).

    Article  PubMed  Google Scholar 

  10. Bartels, C. C. & Rullo, F. R. Unsuspected diabetes mellitus in peripheral vascular disease. N. Engl. J. Med. 259, 633–635 (1958).

    Article  CAS  PubMed  Google Scholar 

  11. Partamian, J. O. & Bradley, R. F. Acute myocardial infarction in 258 cases of diabetes. Immediate mortality and five-year survival. N. Engl. J. Med. 273, 455–461 (1965).

    Article  CAS  PubMed  Google Scholar 

  12. [No authors listed] Diabetes mellitus and atherosclerosis. N. Engl. J. Med. 273, 505–506 (1965).

  13. Erlander, S. R. Common enzyme deficiencies may cause atherosclerosis and diabetes mellitus. Enzymologia 28, 139–151 (1965).

    CAS  PubMed  Google Scholar 

  14. Hoar, C. S. Jr & Torres, J. Evaluation of below-the-knee amputation in the treatment of diabetic gangrene. N. Engl. J. Med. 266, 440–443 (1962).

    Article  PubMed  Google Scholar 

  15. Root, H. F. Factors favoring successful transmetatarsal amputation in diabetes. N. Engl. J. Med. 239, 453–458 (1948).

    Article  CAS  PubMed  Google Scholar 

  16. Wheelock, F. C. Jr. Transmetatarsal amputations and arterial surgery in diabetic patients. N. Engl. J. Med. 264, 316–320 (1961).

    Article  PubMed  Google Scholar 

  17. Amico, J. A. & Klein, I. Diabetic management in patients with renal failure. Diabetes Care 4, 430–434 (1981).

    Article  CAS  PubMed  Google Scholar 

  18. Mogensen, C. E., Christensen, C. K. & Vittinghus, E. The stages in diabetic renal disease. With emphasis on the stage of incipient diabetic nephropathy. Diabetes 32 (Suppl. 2), 64–78 (1983).

    Article  PubMed  Google Scholar 

  19. United Kingdom Prospective Diabetes Study (UKPDS). Urinary albumin excretion over 3 years in diet-treated type 2, (non-insulin-dependent) diabetic patients, and association with hypertension, hyperglycaemia and hypertriglyceridaemia. Diabetologia 36, 1021–1029 (1993).

  20. Cooper, M. E. Pathogenesis, prevention, and treatment of diabetic nephropathy. Lancet 352, 213–219 (1998).

    Article  CAS  PubMed  Google Scholar 

  21. Shore, T. H. Diabetic neuropathy. Lancet 2, 738 (1947).

    Article  CAS  PubMed  Google Scholar 

  22. Howard, F. M. Jr. Peripheral neuropathy as a sign of systemic disease. Postgrad. Med. 50, 107–113 (1971).

    Article  PubMed  Google Scholar 

  23. Thomas, P. K. Metabolic neuropathy. J. R. Coll. Physicians Lond. 7, 154–160 (1973).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Chimenes, H. & Planchon, C. A. Focal neurological symptoms associated with uncontrolled diabetes. Lancet 1, 883 (1978).

    Article  CAS  PubMed  Google Scholar 

  25. Bresnick, G. H., Engerman, R., Davis, M. D., de Venecia, G. & Myers, F. L. Patterns of ischemia in diabetic retinopathy. Trans. Sect. Ophthalmol. Am. Acad. Ophthalmol. Otolaryngol. 81, OP694–OP709 (1976).

    CAS  PubMed  Google Scholar 

  26. Frank, R. N. Diabetic retinopathy. N. Engl. J. Med. 350, 48–58 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Kempen, J. H. et al. The prevalence of diabetic retinopathy among adults in the United States. Arch. Ophthalmol. 122, 552–563 (2004).

    Article  PubMed  Google Scholar 

  28. Roy, M. S. et al. The prevalence of diabetic retinopathy among adult type 1 diabetic persons in the United States. Arch. Ophthalmol. 122, 546–551 (2004).

    Article  PubMed  Google Scholar 

  29. Gilbertson, D. T. et al. Projecting the number of patients with end-stage renal disease in the United States to the year 2015. J. Am. Soc. Nephrol. 16, 3736–3741 (2005).

    Article  PubMed  Google Scholar 

  30. Cooper, M. E. Interaction of metabolic and haemodynamic factors in mediating experimental diabetic nephropathy. Diabetologia 44, 1957–1972 (2001).

    Article  CAS  PubMed  Google Scholar 

  31. Pirart, J. Diabetes mellitus and its degenerative complications: a prospective study of 4,400 patients observed between 1947 and 1973 [2nd part] [author's transl]. Diabetes Metab. 3, 173–182 (1977).

    CAS  Google Scholar 

  32. [No authors listed] Blood glucose control and the evolution of diabetic retinopathy and albuminuria. A preliminary multicenter trial. The Kroc Collaborative Study Group. N. Engl. J. Med. 311, 365–372 (1984).

  33. Dahl-Jorgensen, K. et al. Effect of near normoglycaemia for two years on progression of early diabetic retinopathy, nephropathy, and neuropathy: the Oslo study. Br. Med. J. (Clin. Res. Ed.) 293, 1195–1199 (1986).

    Article  CAS  Google Scholar 

  34. [No authors listed] Effect of 6 months of strict metabolic control on eye and kidney function in insulin-dependent diabetics with background retinopathy. Steno study group. Lancet 1, 121–124 (1982).

  35. Feldt-Rasmussen, B., Mathiesen, E. R. & Deckert, T. Effect of two years of strict metabolic control on progression of incipient nephropathy in insulin-dependent diabetes. Lancet 2, 1300–1304 (1986).

    Article  CAS  PubMed  Google Scholar 

  36. Reichard, P., Nilsson, B. Y. & Rosenqvist, U. The effect of long-term intensified insulin treatment on the development of microvascular complications of diabetes mellitus. N. Engl. J. Med. 329, 304–309 (1993).

    Article  CAS  PubMed  Google Scholar 

  37. [No authors listed] The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Group. N. Engl. J. Med. 329, 977–986 (1993).

  38. [No authors listed] Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. N. Engl. J. Med. 342, 381–389 (2000).

  39. Writing team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. 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. JAMA 290, 2159–2167 (2003).

  40. Wang, P. H., Lau, J. & Chalmers, T. C. Meta-analysis of effects of intensive blood-glucose control on late complications of type I diabetes. Lancet 341, 1306–1309 (1993).

    Article  CAS  PubMed  Google Scholar 

  41. Gaede, P., Vedel, P., Parving, H. H. & Pedersen, O. Intensified multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: the Steno type 2 randomised study. Lancet 353, 617–622 (1999).

    Article  CAS  PubMed  Google Scholar 

  42. Gaede, P. et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N. Engl. J. Med. 348, 383–393 (2003).

    Article  PubMed  Google Scholar 

  43. Pedersen, O. & Gaede, P. Intensified multifactorial intervention and cardiovascular outcome in type 2 diabetes: the Steno-2 study. Metabolism 52, 19–23 (2003).

    Article  CAS  PubMed  Google Scholar 

  44. Gaede, P., Tarnow, L., Vedel, P., Parving, H. H. & Pedersen, O. Remission to normoalbuminuria during multifactorial treatment preserves kidney function in patients with type 2 diabetes and microalbuminuria. Nephrol. Dial. Transplant. 19, 2784–2788 (2004).

    Article  PubMed  Google Scholar 

  45. Gaede, P., Lund-Andersen, H., Parving, H. H. & Pedersen, O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N. Engl. J. Med. 358, 580–591 (2008).

    Article  CAS  PubMed  Google Scholar 

  46. [No authors listed] Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). United Kingdom Prospective Diabetes Study (UKPDS) Group. Lancet 352, 837–853 (1998).

  47. Holman, R. R., Paul, S. K., Bethel, M. A., Matthews, D. R. & Neil, H. A. 10-year follow-up of intensive glucose control in type 2 diabetes. N. Engl. J. Med. 359, 1577–1589 (2008).

    Article  CAS  PubMed  Google Scholar 

  48. Patel, A. et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 370, 829–840 (2007).

    Article  CAS  PubMed  Google Scholar 

  49. Patel, A. et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N. Engl. J. Med. 358, 2560–2572 (2008).

    Article  CAS  PubMed  Google Scholar 

  50. de Galan, B. E. et al. Lowering blood pressure reduces renal events in type 2 diabetes. J. Am. Soc. Nephrol. 20, 883–892 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Ninomiya, T. et al. Albuminuria and kidney function independently predict cardiovascular and renal outcomes in diabetes. J. Am. Soc. Nephrol. 20, 1813–1821 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Brugts, J. J. et al. The consistency of the treatment effect of an ACE-inhibitor based treatment regimen in patients with vascular disease or high risk of vascular disease: a combined analysis of individual data of ADVANCE, EUROPA, and PROGRESS trials. Eur. Heart J. 30, 1385–1394 (2009).

    Article  CAS  PubMed  Google Scholar 

  53. Du, X. et al. Risks of cardiovascular events and effects of routine blood pressure lowering among patients with type 2 diabetes and atrial fibrillation: results of the ADVANCE study. Eur. Heart J. 30, 1128–1135 (2009).

    Article  PubMed  Google Scholar 

  54. Duckworth, W. et al. Glucose control and vascular complications in veterans with type 2 diabetes. N. Engl. J. Med. 360, 129–139 (2009).

    Article  CAS  PubMed  Google Scholar 

  55. Gerstein, H. C. et al. Effects of intensive glucose lowering in type 2 diabetes. N. Engl. J. Med. 358, 2545–2559 (2008).

    Article  CAS  PubMed  Google Scholar 

  56. Holman, R. R., Paul, S. K., Bethel, M. A., Neil, H. A. & Matthews, D. R. Long-term follow-up after tight control of blood pressure in type 2 diabetes. N. Engl. J. Med. 359, 1565–1576 (2008).

    Article  CAS  PubMed  Google Scholar 

  57. Zoungas, S. et al. Combined effects of routine blood pressure lowering and intensive glucose control on macrovascular and microvascular outcomes in patients with type 2 diabetes: new results from the ADVANCE trial. Diabetes Care 32, 2068–2074 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Nathan, D. M. et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N. Engl. J. Med. 353, 2643–2653 (2005).

    Article  PubMed  Google Scholar 

  59. Monnier, V. M., Kohn, R. R. & Cerami, A. Accelerated age-related browning of human collagen in diabetes mellitus. Proc. Natl Acad. Sci. USA 81, 583–587 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Monnier, V. M. Nonenzymatic glycosylation, the Maillard reaction and the aging process. J. Gerontol. 45, B105–B111 (1990).

    Article  CAS  PubMed  Google Scholar 

  61. Sell, D. R. & Monnier, V. M. End-stage renal disease and diabetes catalyze the formation of a pentose-derived crosslink from aging human collagen. J. Clin. Invest. 85, 380–384 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Forbes, J. M. et al. The breakdown of preexisting advanced glycation end products is associated with reduced renal fibrosis in experimental diabetes. FASEB J. 17, 1762–1764 (2003).

    Article  CAS  PubMed  Google Scholar 

  63. Wendt, T. et al. Glucose, glycation, and RAGE: implications for amplification of cellular dysfunction in diabetic nephropathy. J. Am. Soc. Nephrol. 14, 1383–1395 (2003).

    Article  CAS  PubMed  Google Scholar 

  64. Monnier, V. M. 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 48, 870–880 (1999).

    Article  CAS  PubMed  Google Scholar 

  65. Genuth, S. 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 54, 3103–3111 (2005).

    Article  CAS  PubMed  Google Scholar 

  66. Engerman, R. L. & Kern, T. S. Progression of incipient diabetic retinopathy during good glycemic control. Diabetes 36, 808–812 (1987).

    Article  CAS  PubMed  Google Scholar 

  67. 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. USA 87, 404–408 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. DCCT/EDIC 20th Anniversary Symposium. Metabolic Imprinting and the Long-Term Complications of Diabetes Mellitus: Bench to Bedside and Back. National Institute of Diabetes and Digestive and Kidney Diseases [online], (2003).

  69. Suzuki, M. M. & Bird, A. DNA methylation landscapes: provocative insights from epigenomics. Nat. Rev. Genet. 9, 465–476 (2008).

    Article  CAS  PubMed  Google Scholar 

  70. El-Osta, A. et al. Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia. J. Exp. Med. 205, 2409–2417 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Brasacchio, D. et al. Hyperglycemia induces a dynamic cooperativity of histone methylase and demethylase enzymes associated with gene-activating epigenetic marks that coexist on the lysine tail. Diabetes 58, 1229–1236 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Miao, F. et al. Lymphocytes from patients with type 1 diabetes display a distinct profile of chromatin histone H3 lysine 9 dimethylation: an epigenetic study in diabetes. Diabetes 57, 3189–3198 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Li, Y. et al. Role of the histone H3 lysine 4 methyltransferase, SET7/9, in the regulation of NF-kappaB-dependent inflammatory genes. Relevance to diabetes and inflammation. J. Biol. Chem. 283, 26771–26781 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Villeneuve, L. M. et al. Epigenetic histone H3 lysine 9 methylation in metabolic memory and inflammatory phenotype of vascular smooth muscle cells in diabetes. Proc. Natl Acad. Sci. USA 105, 9047–9052 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Marumo, T., Schini-Kerth, V. B. & Busse, R. Vascular endothelial growth factor activates nuclear factor-κB and induces monocyte chemoattractant protein-1 in bovine retinal endothelial cells. Diabetes 48, 1131–1137 (1999).

    Article  CAS  PubMed  Google Scholar 

  76. Golovchenko, I., Goalstone, M. L., Watson, P., Brownlee, M. & Draznin, B. Hyperinsulinemia enhances transcriptional activity of nuclear factor-κB induced by angiotensin II, hyperglycemia, and advanced glycosylation end products in vascular smooth muscle cells. Circ. Res. 87, 746–752 (2000).

    Article  CAS  PubMed  Google Scholar 

  77. Harada, C. et al. Diverse NF-κB expression in epiretinal membranes after human diabetic retinopathy and proliferative vitreoretinopathy. Mol. Vis. 10, 31–36 (2004).

    CAS  PubMed  Google Scholar 

  78. Henke, N. et al. Vascular endothelial cell-specific NF-κB suppression attenuates hypertension-induced renal damage. Circ. Res. 101, 268–276 (2007).

    Article  CAS  PubMed  Google Scholar 

  79. Mauer, S. M., Steffes, M. W., Michael, A. F. & Brown, D. M. Studies of diabetic nephropathy in animals and man. Diabetes 25, 850–857 (1976).

    Article  CAS  PubMed  Google Scholar 

  80. Sorger, K. et al. Renal biopsies performed on diabetics. Exp. Pathol. (Jena) 13, 106–117 (1977).

    CAS  Google Scholar 

  81. Pozzi, A. et al. Modification of collagen IV by glucose or methylglyoxal alters distinct mesangial cell functions. J. Am. Soc. Nephrol. 20, 2119–2125 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Pagtalunan, M. E. et al. Podocyte loss and progressive glomerular injury in type II diabetes. J. Clin. Invest. 99, 342–348 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Gilbert, R. E. & Cooper, M. E. The tubulointerstitium in progressive diabetic kidney disease: more than an aftermath of glomerular injury? Kidney Int. 56, 1627–1637 (1999).

    Article  CAS  PubMed  Google Scholar 

  84. Kiritoshi, S. et al. Reactive oxygen species from mitochondria induce cyclooxygenase-2 gene expression in human mesangial cells: potential role in diabetic nephropathy. Diabetes 52, 2570–2577 (2003).

    Article  CAS  PubMed  Google Scholar 

  85. D'Apolito, M. et al. Urea-induced ROS generation causes insulin resistance in mice with chronic renal failure. J. Clin. Invest. 120, 203–213 (2010).

    Article  PubMed  Google Scholar 

  86. Ihnat, M. A. et al. Reactive oxygen species mediate a cellular 'memory' of high glucose stress signalling. Diabetologia 50, 1523–1531 (2007).

    Article  CAS  PubMed  Google Scholar 

  87. Seaquist, E. R., Goetz, F. C., Rich, S. & Barbosa, J. Familial clustering of diabetic kidney disease. Evidence for genetic susceptibility to diabetic nephropathy. N. Engl. J. Med. 320, 1161–1165 (1989).

    Article  CAS  PubMed  Google Scholar 

  88. Borch-Johnsen, K. et al. Is diabetic nephropathy an inherited complication? Kidney Int. 41, 719–722 (1992).

    Article  CAS  PubMed  Google Scholar 

  89. Moczulski, D. K., Rogus, J. J., Antonellis, A., Warram, J. H. & Krolewski, A. S. Major susceptibility locus for nephropathy in type 1 diabetes on chromosome 3q: results of novel discordant sib-pair analysis. Diabetes 47, 1164–1169 (1998).

    Article  CAS  PubMed  Google Scholar 

  90. Chistiakov, D. A. et al. Confirmation of a susceptibility locus for diabetic nephropathy on chromosome 3q23-q24 by association study in Russian type 1 diabetic patients. Diabetes Res. Clin. Pract. 66, 79–86 (2004).

    Article  CAS  PubMed  Google Scholar 

  91. Iyengar, S. K. et al. Genome-wide scans for diabetic nephropathy and albuminuria in multiethnic populations: the family investigation of nephropathy and diabetes (FIND). Diabetes 56, 1577–1585 (2007).

    Article  CAS  PubMed  Google Scholar 

  92. Imperatore, G., Knowler, W. C., Nelson, R. G. & Hanson, R. L. Genetics of diabetic nephropathy in the Pima Indians. Curr. Diab. Rep. 1, 275–281 (2001).

    Article  CAS  PubMed  Google Scholar 

  93. Kankova, K. et al. Genetic risk factors for diabetic nephropathy on chromosomes 6p and 7q identified by the set-association approach. Diabetologia 50, 990–999 (2007).

    Article  CAS  PubMed  Google Scholar 

  94. Tong, Z. et al. Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications. Proc. Natl Acad. Sci. USA 105, 6998–7003 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Boright, A. P. et al. Genetic variation at the ACE gene is associated with persistent microalbuminuria and severe nephropathy in type 1 diabetes: the DCCT/EDIC Genetics Study. Diabetes 54, 1238–1244 (2005).

    Article  CAS  PubMed  Google Scholar 

  96. Al-Kateb, H. et al. Multiple superoxide dismutase 1/splicing factor serine alanine 15 variants are associated with the development and progression of diabetic nephropathy: the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Genetics study. Diabetes 57, 218–228 (2008).

    Article  CAS  PubMed  Google Scholar 

  97. Pezzolesi, M. G. et al. Genome-wide association scan for diabetic nephropathy susceptibility genes in type 1 diabetes. Diabetes 58, 1403–1410 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Lindner, T. H., Monks, D., Wanner, C. & Berger, M. Genetic aspects of diabetic nephropathy. Kidney Int. Suppl. S186–S191 (2003).

  99. Paterson, A. D. et al. A genome-wide association study identifies a novel major locus for glycemic control in type 1 diabetes, as measured by both HbA1c and glucose. Diabetes 59, 539–549 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. He, B. et al. Association of genetic variants at 3q22 with nephropathy in patients with type 1 diabetes mellitus. Am. J. Hum. Genet. 84, 5–13 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The work of the authors is funded by grants from the Juvenile Diabetes Research Foundation (JDRF), National Health and Medical Research Council (NHMRC) and National Heart Foundation (NHF) of Australia.

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Tonna, S., El-Osta, A., Cooper, M. et al. Metabolic memory and diabetic nephropathy: potential role for epigenetic mechanisms. Nat Rev Nephrol 6, 332–341 (2010). https://doi.org/10.1038/nrneph.2010.55

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