Biochemistry and molecular cell biology of diabetic complications

Abstract

Diabetes-specific microvascular disease is a leading cause of blindness, renal failure and nerve damage, and diabetes-accelerated atherosclerosis leads to increased risk of myocardial infarction, stroke and limb amputation. Four main molecular mechanisms have been implicated in glucose-mediated vascular damage. All seem to reflect a single hyperglycaemia-induced process of overproduction of superoxide by the mitochondrial electron-transport chain. This integrating paradigm provides a new conceptual framework for future research and drug discovery.

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Figure 1: Aldose reductase and the polyol pathway.
Figure 2: Mechanisms by which intracellular production of advanced glycation end-product (AGE) precursors damages vascular cells.
Figure 3: Consequences of hyperglycaemia-induced activation of protein kinase C (PKC).
Figure 4: The hexosamine pathway.
Figure 5: Production of superoxide by the mitochondrial electron-transport chain.
Figure 6: Potential mechanism by which hyperglycaemia-induced mitochondrial superoxide overproduction activates four pathways of hyperglycaemic damage.

References

  1. 1

    The Diabetes Control and Complications Trial Research 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. 329, 977–986 (1993).

  2. 2

    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 352, 837–853 (1998).

  3. 3

    Wei, M., Gaskill, S. P., Haffner, S. M. & Stern, M. P. Effects of diabetes and level of glycemia on all-cause and cardiovascular mortality. The San Antonio Heart Study. Diabetes Care 7, 1167–1172 (1998).

    Google Scholar 

  4. 4

    Ebara, T. et al. Delayed catabolism of apoB-48 lipoproteins due to decreased heparan sulfate proteoglycan production in diabetic mice. J. Clin. Invest. 105, 1807–1818 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Ginsberg, H. N. Insulin resistance and cardiovascular disease. J. Clin. Invest. 106, 453–458 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Lusis, A. J. Atherosclerosis. Nature 407, 233–241 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Hsueh, W. A. & Law, R. E. Cardiovascular risk continuum: implications of insulin resistance and diabetes. Am. J. Med. 105, 4S–14S (1998).

    CAS  PubMed  Google Scholar 

  8. 8

    Jiang, Z. Y. et al. Characterization of selective resistance to insulin signaling in the vasculature of obese Zucker (fa/fa) rats. J. Clin. Invest. 104, 447–457 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Williams, S. B. et al. Acute hyperglycemia attenuates endothelium-dependent vasodilation in humans in vivo. Circulation 97, 1695–1701 (1998).

    CAS  PubMed  Google Scholar 

  10. 10

    Du, X. L. et al. Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation. Proc. Natl Acad. Sci. USA 97, 12222–12226 (2000).

    ADS  CAS  PubMed  Google Scholar 

  11. 11

    Temelkova-Kurktschiev, T. S. et al. Postchallenge plasma glucose and glycemic spikes are more strongly associated with atherosclerosis than fasting glucose or HbA1c levels. Diabetes Care 12, 1830–1834 (2000).

    Google Scholar 

  12. 12

    Wilson, D. K., Bohren, K. M., Gabbay, K. H. & Quiocho, F. A. An unlikely sugar substrate site in the 1.65 A structure of the human aldose reductase holoenzyme implicated in diabetic complications. Science 257, 81–84 (1992).

    ADS  CAS  PubMed  Google Scholar 

  13. 13

    Xia, P., Kramer, R. M. & King, G. L. Identification of the mechanism for the inhibition of Na,K-adenosine triphosphatase bv hyperglycemia involving activation of protein kinase C and cytosolic phospholipase A2. J. Clin. Invest. 96, 733–740 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Williamson, J. R. et al. Hyperglycemic pseudohypoxia and diabetic complications. Diabetes 42, 801–813 (1993).

    CAS  PubMed  Google Scholar 

  15. 15

    Garcia Soriano, F. et al. Diabetic endothelial dysfunction: the role of poly(ADP-ribose) polymerase activation. Nature Med. 7, 108–113 (2001).

    CAS  PubMed  Google Scholar 

  16. 16

    Lee, A. Y. & Chung, S. S. Contributions of polyol pathway to oxidative stress in diabetic cataract. FASEB J. 13, 23–30 (1999).

    CAS  PubMed  Google Scholar 

  17. 17

    Engerman, R. L., Kern, T. S. & Larson, M. E. Nerve conduction and aldose reductase inhibition during 5 years of diabetes or galactosaemia in dogs. Diabetologia 37, 141–144 (1994).

    CAS  PubMed  Google Scholar 

  18. 18

    Sorbinil Retinopathy Trial Research Group. A randomized trial of sorbinil, an aldose reductase inhibitor, in diabetic retinopathy. Arch. Ophthalmol. 108, 1234–1244 (1990).

  19. 19

    Greene, D. A., Arezzo, J. C. & Brown, M. B. Effect of aldose reductase inhibition on nerve conduction and morphometry in diabetic neuropathy. Zenarestat Study Group. Neurology 53, 580–591 (1999).

    CAS  PubMed  Google Scholar 

  20. 20

    Stitt, A. W. et al. Advanced glycation end products (AGEs) co-localize with AGE receptors in the retinal vasculature of diabetic and of AGE-infused rats. Am. J. Pathol. 150, 523–528 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Horie, K. et al. Immunohistochemical colocalization of glycoxidation products and lipid peroxidation products in diabetic renal glomerular lesions. Implication for glycoxidative stress in the pathogenesis of diabetic nephropathy. J. Clin. Invest. 100, 2995–2999 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Degenhardt, T. P., Thorpe, S. R. & Baynes, J. W. Chemical modification of proteins by methylglyoxal. Cell Mol. Biol. 44, 1139–1145 (1998).

    CAS  PubMed  Google Scholar 

  23. 23

    Wells-Knecht, K. J. et al. Mechanism of autoxidative glycosylation: identification of glyoxal and arabinose as intermediates in the autoxidative modification of proteins by glucose. Biochemistry 34, 3702–3709 (1995).

    CAS  PubMed  Google Scholar 

  24. 24

    Thornalley, P. J. The glyoxalase system: new developments towards functional characterization of a metabolic pathway fundamental to biological life. Biochem J. 269, 1–11 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Suzuki, K. et al. Overexpression of aldehyde reductase protects PC12 cells from the cytotoxicity of methylglyoxal or 3-deoxyglucosone. J. Biochem. 123, 353–357 (1998).

    CAS  PubMed  Google Scholar 

  26. 26

    Soulis-Liparota T., Cooper, M., Papazoglou, D., Clarke, B. & Jerums, G. Retardation by aminoguanidine of development of albuminuria, mesangial expansion, and tissue fluorescence in streptozocin-induced diabetic rat. Diabetes 40, 1328–1334 (1991).

    CAS  PubMed  Google Scholar 

  27. 27

    Nakamura, S. et al. Progression of nephropathy in spontaneous diabetic rats is prevented by OPB-9195, a novel inhibitor of advanced glycation. Diabetes 46, 895–899 (1997).

    CAS  PubMed  Google Scholar 

  28. 28

    Hammes, H-P. et al. Aminoguanidine treatment inhibits the development of experimental diabetic retinopathy. Proc. Natl Acad. Sci. USA 88, 11555–11559 (1991).

    ADS  CAS  PubMed  Google Scholar 

  29. 29

    Giardino, I., Edelstein, D. & Brownlee, M. Nonenzymatic glycosylation in vitro and in bovine endothelial cells alters basic fibroblast growth factor activity. A model for intracellular glycosylation in diabetes. J. Clin. Invest. 94, 110–117 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Shinohara, M. et al. Overexpression of glyoxalase-I in bovine endothelial cells inhibits intracellular advanced glycation endproduct formation and prevents hyperglycemia-induced increases in macromolecular endocytosis. J. Clin. Invest. 101, 1142–1147 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Maisonpierre, P. C. et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277, 55–60 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Tanaka, S., Avigad, G., Brodsky, B. & Eikenberry, E. F. Glycation induces expansion of the molecular packing of collagen. J. Mol. Biol. 203, 495–505 (1988).

    CAS  PubMed  Google Scholar 

  33. 33

    Huijberts, M. S. P. et al. Aminoguanidine treatment increases elasticity and decreases fluid filtration of large arteries from diabetic rats. J. Clin. Invest. 92, 1407–1411 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Tsilbary, E. C. et al. The effect of nonenzymatic glucosylation the binding of the main noncollagenous NC1 domain to type IV collagen. J. Biol. Chem. 263, 4302–4308 (1990).

    Google Scholar 

  35. 35

    Charonis, A. S. et al. Laminin alterations after in vitro nonenzymatic glucosylation. Diabetes 39, 807–814 (1988).

    Google Scholar 

  36. 36

    Haitoglou, C. S., Tsilibary, E. C., Brownlee, M. & Charonis, A. S. Altered cellular interactions between endothelial cells and nonenzymatically glucosylated laminin/type IV collagen. J. Biol. Chem. 267, 12404–12407 (1992).

    CAS  PubMed  Google Scholar 

  37. 37

    Federoff, H. J., Lawrence, D. & Brownlee, M. Nonenzymatic glycosylation of laminin and the laminin peptide CIKVAVS inhibits neurite outgrowth. Diabetes 42, 509–513 (1993).

    CAS  PubMed  Google Scholar 

  38. 38

    Li, Y. M. et al. Molecular identity and cellular distribution of advanced glycation endproduct receptors: relationship of p60 to OST-48 and p90 to 80K-H membrane proteins. Proc. Natl Acad. Sci. USA 93, 11047–11052 (1996).

    ADS  CAS  PubMed  Google Scholar 

  39. 39

    Smedsrod, B. et al. Advanced glycation end products are eliminated by scavenger-receptor-mediated endocytosis in hepatic sinusoidal kupffer and endothelial cells. Biochem J. 322, 567–573 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Vlassara, H. et al. Identification of galectin-3 as a high-affinity binding protein for advanced glycation end products (AGE): a new member of the AGE-receptor complex. Mol. Med. 1, 634–646 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Neeper, M. et al. Cloning and expression of RAGE: a cell surface receptor for advanced glycosylation end products of proteins. J. Biol. Chem. 267, 14998–15004 (1992).

    CAS  PubMed  Google Scholar 

  42. 42

    Vlassara, H. et al. Cachectin/TNF and IL-1 induced by glucose-modified proteins: role in normal tissue remodeling. Science 240, 1546–1548 (1988).

    ADS  CAS  PubMed  Google Scholar 

  43. 43

    Kirstein, M., Aston, C., Hintz, R. & Vlassara, H. Receptor-specific induction of insulin-like growth factor I in human monocytes by advanced glycosylation end product-modified proteins. J. Clin. Invest. 90, 439–446 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Abordo, E. A., Westwood, M. E. & Thornalley, P. J. Synthesis and secretion of macrophage colony stimulating factor by mature human monocytes and human monocytic THP-1 cells induced by human serum albumin derivatives modified with methylglyoxal and glucose-derived advanced glycation endproducts. Immunol. Lett. 53, 7–13 (1996).

    CAS  PubMed  Google Scholar 

  45. 45

    Skolnik, E. Y. et al. Human and rat mesangial cell receptors for glucose-modified proteins: potential role in kidney tissue remodelling and diabetic nephropathy. J. Exp. Med. 174, 931–939 (1991).

    CAS  PubMed  Google Scholar 

  46. 46

    Doi, T. et al. Receptor specific increase in extracellular matrix productions in mouse mesangial cells by advanced glycosylation end products is mediated via platelet derived growth factor. Proc. Natl Acad. Sci. USA 89, 2873–2877 (1992).

    ADS  CAS  PubMed  Google Scholar 

  47. 47

    Schmidt, A. M. et al. Advanced glycation endproducts interacting with their endothelial receptor induce expression of vascular cell adhesion molecule-1 (VCAM-1) in cultured human endothelial cells and in mice: a potential mechanism for the accelerated vasculopathy of diabetes. J. Clin. Invest. 96, 1395–1403 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Lu, M. et al. Advanced glycation end products increase retinal vascular endothelial growth factor expression. J. Clin. Invest. 101, 1219–1224 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Park, L. et al. Suppression of accelerated diabetic atherosclerosis by the soluble receptor for advanced glycation endproducts. Nature Med. 4, 1025–1031 (1998).

    CAS  PubMed  Google Scholar 

  50. 50

    Yan, S. D. et al. Enhanced cellular oxidant stress by the interaction of advanced glycation end products with their receptors/binding proteins. J. Biol. Chem. 269, 9889–9897 (1994).

    CAS  PubMed  Google Scholar 

  51. 51

    Lander, H. M. 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. 272, 17810–17814 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Yamagishi, S. et al. Advanced glycation endproducts inhibit prostacyclin production and induce plasminogen activator inhibitor-1 in human microvascular endothelial cells. Diabetologia 41, 1435–1441 (1998).

    CAS  PubMed  Google Scholar 

  53. 53

    Tsuji, H. et al. Ribozyme targeting of receptor for advanced glycation end products in mouse mesangial cells. Biochem. Biophys. Res. Commun. 245, 583–588 (1998).

    CAS  PubMed  Google Scholar 

  54. 54

    Koya, D. & King, G. L. Protein kinase C activation and the development of diabetic complications. Diabetes 47, 859–866 (1998).

    CAS  PubMed  Google Scholar 

  55. 55

    Xia, P. et al. Characterization of the mechanism for the chronic activation of diacylglycerol-protein kinase C pathway in diabetes and hypergalactosemia. Diabetes 43, 1122–1129 (1994).

    CAS  PubMed  Google Scholar 

  56. 56

    Koya, D. et al. Characterization of protein kinase C beta isoform activation on the gene expression of transforming growth factor-beta, extracellular matrix components, and prostanoids in the glomeruli of diabetic rats. J. Clin. Invest. 100, 115–126 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Portilla, D. et al. Etomoxir -induced PPARalpha-modulated enzymes protect during acute renal failure. Am. J. Physiol. Renal Physiol. 278, F667–F675 (2000).

    CAS  PubMed  Google Scholar 

  58. 58

    Keogh, R. J., Dunlop, M. E. & Larkins R. G. . Effect of inhibition of aldose reductase on glucose flux, diacylglycerol formation, protein kinase C, and phospholipase A2 activation. Metabolism 46, 41–47 (1997).

    CAS  PubMed  Google Scholar 

  59. 59

    Ishii, H. et al. Amelioration of vascular dysfunctions in diabetic rats by an oral PKC beta inhibitor. Science 272, 728–731 (1996).

    ADS  CAS  Google Scholar 

  60. 60

    Craven, P. A., Studer, R. K. & DeRubertis, F. R. Impaired nitric oxide-dependent cyclic guanosine monophosphate generation in glomeruli from diabetic rats. Evidence for protein kinase C-mediated suppression of the cholinergic response. J. Clin. Invest. 93, 311–320 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Ganz, M. B. & Seftel, A. Glucose-induced changes in protein kinase C and nitric oxide are prevented by vitamin E. Am. J. Physiol. 278, E146–E152 (2000).

    CAS  Google Scholar 

  62. 62

    Kuboki, K. et al. Regulation of endothelial constitutive nitric oxide synthase gene expression in endothelial cells and in vivo a specific vascular action of insulin. Circulation 101, 676–681 (2000).

    CAS  PubMed  Google Scholar 

  63. 63

    Glogowski, E. A., Tsiani, E., Zhou, X., Fantus, I. G. & Whiteside, C. High glucose alters the response of mesangial cell protein kinase C isoforms to endothelin-1. Kidney Int. 55, 486–499 (1999).

    CAS  PubMed  Google Scholar 

  64. 64

    Hempel, A. et al. High glucose concentrations increase endothelial cell permeability via activation of protein kinase C alpha. Circ. Res. 81, 363–371 (1997).

    CAS  PubMed  Google Scholar 

  65. 65

    Williams, B., Gallacher, B., Patel, H. & Orme, C. Glucose-induced protein kinase C activation regulates vascular permeability factor mRNA expression and peptide production by human vascular smooth muscle cells in vitro. Diabetes 46, 1497–1503 (1997).

    CAS  PubMed  Google Scholar 

  66. 66

    Studer, R. K., Craven, P. A. & DeRubertis, F. R. Role for protein kinase C in the mediation of increased fibronectin accumulation by mesangial cells grown in high-glucose medium. Diabetes 42, 118–126 (1993).

    CAS  PubMed  Google Scholar 

  67. 67

    Koya, D. et al. Characterization of protein kinase C beta isoform activation on the gene expression of transforming growth factor-beta, extracellular matrix components, and prostanoids in the glomeruli of diabetic rats. J. Clin. Invest. 100, 115–126 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Craven, P. A., Studer, R. K., Felder, J., Phillips, S. & DeRubertis, F. R. Nitric oxide inhibition of transforming growth factor-beta and collagen synthesis in mesangial cells. Diabetes 46, 671–681 (1997).

    CAS  PubMed  Google Scholar 

  69. 69

    Phillips, S. L., DeRubertis, F. R. & Craven, P. A. Regulation of the laminin C1 promoter in cultured mesangial cells. Diabetes 48, 2083–2089 (1999).

    CAS  PubMed  Google Scholar 

  70. 70

    Feener, E. P. et al. Role of protein kinase C in glucose- and angiotensin II-induced plasminogen activator inhibitor expression. Contrib. Nephrol. 118, 180–187 (1996).

    CAS  PubMed  Google Scholar 

  71. 71

    Pieper, G. M. & Riaz-ul-Haq, J. Activation of nuclear factor-kappaB in cultured endothelial cells by increased glucose concentration: prevention by calphostin C. Cardiovasc. Pharmacol. 30, 528–532 (1997).

    CAS  Google Scholar 

  72. 72

    Yerneni, K. K., Bai, W., Khan, B. V., Medford, R. M. & Natarajan, R. Hyperglycemia-induced activation of nuclear transcription factor kappaB in vascular smooth muscle cells. Diabetes 48, 855–864 (1999).

    CAS  PubMed  Google Scholar 

  73. 73

    Koya, D. et al. Amelioration of accelerated diabetic mesangial expansion by treatment with a PKC beta inhibitor in diabetic db/db mice, a rodent model for type 2 diabetes. FASEB J. 14, 439–447 (2000).

    CAS  PubMed  Google Scholar 

  74. 74

    Kolm-Litty, V., Sauer, U., Nerlich, A., Lehmann, R. & Schleicher, E. D. High glucose-induced transforming growth factor beta1 production is mediated by the hexosamine pathway in porcine glomerular mesangial cells. J. Clin. Invest. 101, 160–169 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Marshall, S., Bacote, V. & Traxinger, R. R. Discovery of a metabolic pathway mediating glucose-induced desensitization of the glucose transport system. Role of hexosamine biosynthesis in the induction of insulin resistance. J. Biol. Chem. 266, 4706–4712 (1991).

    CAS  PubMed  Google Scholar 

  76. 76

    Hawkins, M. et al. Role of the glucosamine pathway in fat-induced insulin resistance. J. Clin. Invest. 99, 2173–2182 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Chen, Y. Q. et al. Sp1 sites mediate activation of the plasminogen activator inhibitor-1 promoter by glucose in vascular smooth muscle cells. J. Biol. Chem. 273, 8225–8231 (1998).

    CAS  PubMed  Google Scholar 

  78. 78

    Goldberg, H. J., Scholey, J. & Fantus, I. G. Glucosamine activates the plasminogen activator inhibitor 1 gene promoter through Sp1 DNA binding sites in glomerular mesangial cells. Diabetes 49, 863–871 (2000).

    CAS  PubMed  Google Scholar 

  79. 79

    Kadonaga, J. T., Courey, A. J., Ladika, J. & Tjian, R. Distinct regions of Sp1 modulate DNA binding and transcriptional activation. Science 242, 1566–1570 (1988).

    ADS  CAS  PubMed  Google Scholar 

  80. 80

    Haltiwanger, R. S., Grove, K. & Philipsberg, G. A. Modulation of O-linked N-acetylglucosamine levels on nuclear and cytoplasmic proteins in vivo using the peptide O-GlcNAc-beta-N-acetylglucosaminidase inhibitor O-(2-acetamido-2-deoxy-D-glucopyranosylidene)amino-N-phenylcarbamate. J. Biol. Chem. 273, 3611–3617 (1998).

    CAS  PubMed  Google Scholar 

  81. 81

    Hart, G. W. Dynamic O-linked glycosylation of nuclear and cytoskeletal proteins Annu. Rev. Biochem. 66, 315–335 (1997).

    CAS  PubMed  Google Scholar 

  82. 82

    Du, X. D. et al. Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the AKT site. J. Clin. Invest. (in the press).

  83. 83

    Lee, A. Y., Chung, S. K. & Chung, S. S. Demonstration that polyol accumulation is responsible for diabetic cataract by the use of transgenic mice expressing the aldose reductase gene in the lens. Proc. Natl Acad. Sci. USA 92, 2780–2784 (1995).

    ADS  CAS  PubMed  Google Scholar 

  84. 84

    Nishikawa, T. et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 404, 787–790 (2000).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Giugliano, D., Ceriello, A. & Paolisso, G. Oxidative stress and diabetic vascular complications. Diabetes Care 19, 257–267 (1996).

    CAS  PubMed  Google Scholar 

  86. 86

    Giardino, I., Edelstein, D. & Brownlee, M. BCL-2 expression or antioxidants prevent hyperglycemia-induced formation of intracellular advanced glycation endproducts in bovine endothelial cells. J. Clin. Invest. 97, 1422–1428 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Korshunov, S. S., Skulachev, V. P. & Starkov, A. A. High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria. FEBS Lett. 416, 15–18 (1997).

    CAS  PubMed  Google Scholar 

  88. 88

    Craven, R. P., Phillip, S. L., Melhem, M. F., Liachenko, J. & De Rubertis, F. R. Overexpression of Mn2+ superoxide dismutase suppresses increases in collagen accumulation induced by culture in measangial cells in high media glucose. Metabolism (in the press).

  89. 89

    Yamagishi, S. I., Edelstein, D., Du, X. L. & Brownlee, M. Hyperglycemia potentiates collagen-induced platelet activation through mitochondrial superoxide overproduction. Diabetes 50, 1491–1494 (2001).

    CAS  PubMed  Google Scholar 

  90. 90

    Craven, P. A., Melham, M. F., Phillip, S. L. & DeRubertis, F. R. Overexpression of Cu2+/Zn2+ superoxide dismutase protects against early diabetic glomerular injury in transgenic mice. Diabetes 50, 2114–2125 (2001).

    CAS  PubMed  Google Scholar 

  91. 91

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

    CAS  PubMed  Google Scholar 

  92. 92

    The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N. Engl. J. Med. 342, 381–389 (2000).

  93. 93

    Quinn, M., Angelico, M. C., Warram, J. H. & Krolewski, A. S. Familial factors determine the development of diabetic nephropathy in patients with IDDM. Diabetologia 39, 940–945 (1996).

    CAS  PubMed  Google Scholar 

  94. 94

    The Diabetes Control and Complications Trial Research Group. Clustering of long-term complications in families with diabetes in the diabetes control and complications trial. Diabetes 46, 1829–1839 (1997).

  95. 95

    Wagenknecht, L. E. et al. Familial aggregation of coronary artery calcium in families with type 2 diabetes. Diabetes 50, 861–866 (2001).

    CAS  PubMed  Google Scholar 

  96. 96

    Kowluru, R. A., Tang, J. & Kern, T. S. Abnormalities of retinal metabolism in diabetes and experimental galactosemia. VII. Effect of long-term administration of antioxidants on the development of retinopathy. Diabetes 50, 1938–1942 (2001).

    CAS  PubMed  Google Scholar 

  97. 97

    Ting, H. H. et al. Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin-dependent diabetes mellitus. J. Clin. Invest. 97, 22–28 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98

    Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 355, 253–259 (2000).

  99. 99

    Salvemini, D. et al. A nonpeptidyl mimic of superoxide dismutase with therapeutic activity in rats. Science 286, 304–306 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    Coppey, L. J. et al. Brit. J. Pharmacol. 134, 21–29 (2001).

    CAS  Google Scholar 

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Acknowledgements

This work was supported by grants from NIH, Juvenile Diabetes Research Foundation and American Diabetes Association. Owing to space limitations, a comprehensive list of reference citations could not be included. I apologize to those colleagues whose work is not specifically referenced, and gratefully acknowledge their contributions to the field.

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Correspondence to Michael Brownlee.

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Brownlee, M. Biochemistry and molecular cell biology of diabetic complications. Nature 414, 813–820 (2001). https://doi.org/10.1038/414813a

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