Antioxidants: Do they have a role in the treatment of insulin resistance?

Indian Journal of Medical Research

Volumn 125, Issue 3, 2007, Pages 355-372

  Evans, Joseph L ^a  

^a Medical Research Institute   (United States)

Author keywords

Antioxidants; Diabetes; Insulin resistance; Lipoic acid

Indexed keywords

2,4 THIAZOLIDINEDIONE DERIVATIVE; ACETYLCYSTEINE; ALPHA TOCOPHEROL; ANTIOXIDANT; ASCORBIC ACID; FLAVANOID; FLAVANOL DERIVATIVE; GLUTATHIONE; INSULIN; METFORMIN; PLACEBO; POLYPHENOL; RAPAMYCIN; THIOCTIC ACID;

ACQUIRED IMMUNE DEFICIENCY SYNDROME; BREAST CANCER; CARDIOVASCULAR DISEASE; CHRONIC INFLAMMATION; CLINICAL TRIAL; DIABETIC NEUROPATHY; DISEASE ASSOCIATION; DISEASE EXACERBATION; DRUG COST; DRUG HALF LIFE; DRUG MEGADOSE; ESSENTIAL HYPERTENSION; FINANCIAL MANAGEMENT; HUMAN; INSULIN RESISTANCE; LIPOGENESIS; NON INSULIN DEPENDENT DIABETES MELLITUS; NONALCOHOLIC FATTY LIVER; NONHUMAN; OBESITY; OVARY POLYCYSTIC DISEASE; OXIDATIVE STRESS; REVIEW; VITAMIN BLOOD LEVEL;

ANTIOXIDANTS; HUMANS; INSULIN RESISTANCE; MODELS, BIOLOGICAL; OXIDATIVE STRESS;

EID: 34249290760     PISSN: 09715916     EISSN: 09715916     Source Type: Journal    
DOI: None     Document Type: Review

References (136)

1. Reaven GM. All obese individuals are not created equal: insulin resistance is the major determinant of cardiovascular disease in overweight/obese individuals. Diab Vasc Dis Res 2005; 2: 105-12.
2. Reaven GM. Insulin resistance and its consequences: Type 2 diabetes and the insulin resistance syndrome. In: LeRoith D, Taylor SI, Olefsky JM, editors. Diabetes Mellitus. 3rd ed. Philadelphia: Lippincott-Raven; 2004 p. 899-915.
3. Shikuma CM, Day LJ, Gerschenson M. Insulin resistance in the HIV-infected population: the potential role of mitochondrial dysfunction. Curr Drug Targets Infect Disord 2005; 5: 255-62.
4. Kim SH, Reaven GM. The metabolic syndrome: one step forward, two steps back. Diab Vasc Dis Res 2004; 1: 68-75.
5. Reaven GM. Why Syndrome X? From Harold Himsworth to the insulin resistance syndrome. Cell Metab 2005; 1: 9-14.
6. Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Nature 2001; 414: 782-7.
7. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. J Am Med Assoc 2002; 287: 356-9.
8. Meigs JB, Wilson PW, Nathan DM, D'Agostino RB Sr, Williams K, Haffner SM. Prevalence and characteristics of the metabolic syndrome in the San Antonio Heart and Framingham Offspring Studies. Diabetes 2003; 52: 2160-7.
9. Hill JO, Wyatt HR, Reed GW, Peters JC. Obesity and the environment: where do we go from here? Science 2003; 299: 853-5.
10. Kimm SY, Obarzanek E. Childhood obesity: a new pandemic of the new millennium. Pediatrics 2002; 110: 1003-7.
11. Hedley AA, Ogden CL, Johnson CL, Carroll MD, Curtin LR, Flegal KM. Prevalence of overweight and obesity among US children, adolescents, and adults, 1999-2002. J Am Med Assoc 2004; 291: 2847-50.
12. Speiser PW, Rudolf MC, Anhalt H, Camacho-Hubner C, Chiarelli F, Eliakim A, et al. Childhood obesity. J Clin Endocrinol Metab 2005; 90: 1871-87.
13. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med 1999; 131: 281-303.
14. Evans JL, Youngren JF, Goldfine ID. Effective treatments for insulin resistance: trim the fat and douse the fire. Trends Endocrinol Metab 2004; 15: 425-31.
15. Fuhr JP, He H, Goldfarb N, Nash DB. Use of chromium picolinate and biotin in the management of type 2 diabetes: an economic analysis. Dis Manag 2005; 8: 265-75.
16. Altman SH, Parks-Thomas C. Controlling spending for prescription drugs. N Engl J Med 2002; 346: 855-6.
17. Laakso M. Gene variants, insulin resistance, and dyslipidaemia. Curr Opin Lipidol 2004; 15: 115-20.
18. DeFronzo RA. Pathogenesis of type 2 diabetes: metabolic and molecular implications for identifying diabetes genes. Diabet Rev 1997; 5: 177-269.
19. Evans JL, Goldfine ID, Maddux BA, Grodsky GM. Are oxidative stress-activated signaling pathways mediators of insulin resistance and β-cell dysfunction? Diabetes 2003; 52: 1-8.
20. Bonora E, Kiechl S, Willeit J, Oberhollenzer F, Egger G, Targher G, et al. Prevalence of insulin resistance in metabolic disorders: The Bruneck Study. Diabetes 1998; 47: 1643-9.
21. Reaven GM. Role of insulin resistance in human disease. Diabetes 1988; 37: 1595-607.
22. Facchini FS, Hua N, Abbasi F, Reaven GM. Insulin resistance as a predictor of age-related diseases. J Clin Endocrinol Metab 2001; 86: 3574-8.
23. Giannarelli R, Aragona M, Coppelli A, Del Prato S. Reducing insulin resistance with metformin: the evidence today. Diabetes Metab 2003; 29: 6S28-35.
24. Diamant M, Heine RJ. Thiazolidinediones in type 2 diabetes mellitus: current clinical evidence. Drugs 2003; 63: 1373-405.
25. Henry RR. Insulin resistance: from predisposing factor to therapeutic target in type 2 diabetes. Clin Ther 2003; 25 (Suppl B): B47-63.
26. Evans JL, Maddux BA, Goldfine ID. Antioxidants in diabetic complications and insulin resistance. In: Raz I, Skyler JS, Shafrir E, editors. Diabetes: From research to diagnosis and treatment. 1st ed. London: Martin Dunitz; 2003 p. 479-96.
27. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 2003; 112: 1821-30.
28. Rosen P, Nawroth PP, King G, Moller W, Tritschler HJ, Packer L. The role of oxidative stress in the onset and progression of diabetes and its complications: A summary of a Congress Series sponsored by UNESCO-MCBN, the American Diabetes Association, and the German Diabetes Society. Diabetes Metab Res Rev 2001; 17: 189-212.
29. West IC. Radicals and oxidative stress in diabetes. Diabet Med 2000; 17: 171-80.
30. Nishikawa T, Edelstein D, Brownlee M. The missing link: A single unifying mechanism for diabetic complications. Kidney Int 2000; 58: 26-30.
31. Rahimi R, Nikfar S, Larijani B, Abdollahi M. A review on the role of antioxidants in the management of diabetes and its complications. Biomed Pharmacother 2005; 59: 365-73.
32. Evans JL, Goldfine ID, Maddux BA, Grodsky GM. Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes. Endocr Rev 2002; 23: 599-622.
33. Evans JL, Maddux BA, Goldfine ID. The molecular basis for oxidative stress-induced insulin resistance. Antioxid Redox Signal 2005; 7: 1040-52.
34. Maddux BA, See W, Lawrence JC Jr., Goldfine AL, Goldfine ID, Evans JL. Protection against oxidative stress-induced insulin resistance in rat L6 muscle cells by micromolar concentrations of a-lipoic acid. Diabetes 2001; 50: 404-10.
35. Paolisso G, D'Amore A, Volpe C, Balbi V, Saccomanno F, Galzerano D, et al. Evidence for a relationship between oxidative stress and insulin action in non-insulin-dependent (type II) diabetic patients. Metabolism 1994; 43: 1426-9.
36. Paolisso G, Giugliano D. Oxidative stress and insulin action: is there a relationship? Diabetologia 1996; 39: 357-63.
37. Ceriello A. Oxidative stress and glycemic regulation. Metabolism 2000; 49: 27-9.
38. Reaven GM. Insulin resistance and its consequences: type 2 diabetes mellitus and coronary heart disease. In: LeRoith D, Taylor SI, Olefsky JM, editors. Diabetes mellitus: A fundamental and clinical text. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2000 p. 604-15.
39. Froguel P, Velho G. Genetic determinants of type 2 diabetes. Recent Prog Horm Res 2001; 56: 91-105.
40. Kahn CR, Vicent D, Doria A. Genetics of non-insulin-dependent (type-II) diabetes mellitus. Annu Rev Med 1996; 47: 509-31.
41. Reaven GM. The insulin resistance syndrome: definition and dietary approaches to treatment. Annu Rev Nutr 2005; 25: 391-406.
42. Reaven GM. Compensatory hyperinsulinemia and the development of an atherogenic lipoprotein profile: the price paid to maintain glucose homeostasis in insulin-resistant individuals. Endocrinol Metab Clin North Am 2005; 34: 49-62.
43. Cohen P. Dissection of protein kinase cascades that mediate cellular response to cytokines and cellular stress. Adv Pharmacol 1996; 36: 15-27.
44. Kyriakis JM, Avruch J. Sounding the alarm: protein kinase cascades activated by stress and inflammation. J Biol Chem 1996; 271: 24313-6.
45. Adler V, Yin Z, Tew KD, Ronai Z. Role of redox potential and reactive oxygen species in stress signaling. Oncogene 1999; 18: 6104-11.
46. Mahadev K, Zilbering A, Zhu L, Goldstein BJ. Insulin-stimulated hydrogen peroxide reversibly inhibits protein-tyrosine phosphatase 1b in vivo and enhances the early insulin action cascade. J Biol Chem 2001; 276: 21938-42.
47. van Montfort RL, Congreve M, Tisi D, Carr R, Jhoti H. Oxidation state of the active-site cysteine in protein tyrosine phosphatase 1B. Nature 2003; 423: 773-7.
48. Salmeen A, Andersen JN, Myers MP, Meng TC, Hinks JA, Tonk NK, et al. Redox regulation of protein tyrosine phosphatase 1B involves a sulphenyl-amide intermediate. Nature 2003; 423: 769-73.
49. Dröge W. Free radicals in the physiological control of cell function. Physiol Rev 2002; 82: 47-95.
50. Arrigo AP. Gene expression and the thiol redox state. Free Radic Biol Med 1999; 27: 936-44.
51. Bloch-Damti A, Bashan N. Proposed mechanisms for the induction of insulin resistance by oxidative stress. Antioxid Redox Signal 2005; 7: 1553-67.
52. Paz K, Hemi R, LeRoith D, Karasik A, Elhanany E, Kanety H, et al. A molecular basis for insulin resistance. Elevated serine/threonine phosphorylation of IRS-1 and IRS-2 inhibits their binding to the juxtamembrane region of the insulin receptor and impairs their ability to undergo insulin-induced tyrosine phosphorylation. J Biol Chem 1997; 272: 29911-8.
53. Kellerer M, Mushack J, Seffer E, Mischak H, Ullrich A, Haring HU. Protein kinase C isoforms alpha, delta and theta require insulin receptor substrate-1 to inhibit the tyrosine kinase activity of the insulin receptor in human kidney embryonic cells (HEK 293 cells). Diabetologia 1998; 41: 833-8.
54. Li J, DeFea K, Roth RA. Modulation of insulin receptor substrate-1 tyrosine phosphorylation by an Akt/phosphatidylinositol 3-kinase pathway. J Biol Chem 1999; 274: 9351-6.
55. Qiao LY, Goldberg JL, Russell JC, Sun XJ. Identification of enhanced serine kinase activity in insulin resistance. J Biol Chem 1999; 274: 10625-32.
56. Griffin ME, Marcucci MJ, Cline GW, Bell K, Barucci N, Lee D, et al. Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade. Diabetes 1999; 48: 1270-4.
57. Aguirre V, Uchida T, Yenush L, Davis R, White MF. The c-jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307). J Biol Chem 2000; 275: 9047-54.
58. Hemi R, Paz K, Wertheim N, Karasik A, Zick Y, Kanety H. Transactivation of ErbB2 and ErbB3 by tumor necrosis factor-alpha and anisomycin leads to impaired insulin signaling through serine/threonine phosphorylation of IRS proteins. J Biol Chem 2002; 277: 8961-9.
59. Zick Y. Insulin resistance: a phosphorylation-based uncoupling of insulin signaling. Trends Cell Biol 2001; 11: 437-41.
60. White MF. IRS proteins and the common path to diabetes. Am J Physiol Endocrinol Metab 2002; 283: E413-22.
61. Paz K, Voliovitch H, Hadari YR, Roberts CT, LeRoith D, Zick Y. Interaction between the insulin receptor and its downstream effectors - Use of individually expressed receptor domains for structure function analysis. J Biol Chem 1996; 271: 6998-7003.
62. Birnbaum MJ. Turning down insulin signaling. J Clin Invest 2001; 108: 655-9.
63. Sykiotis GP, Papavassiliou AG. Serine phosphorylation of insulin receptor substrate-1: a novel target for the reversal of insulin resistance. Mol Endocrinol 2001; 15: 1864-9.
64. Haruta T, Uno T, Kawahara J, Takano A, Egawa K, Sharma PM, et al. A rapamycin-sensitive pathway down-regulates insulin signaling via phosphorylation and proteasomal degradation of insulin receptor substrate-1. Mol Endocrinol 2000; 14: 783-94.
65. Zhande R, Mitchell JJ, Wu J, Sun XJ. Molecular mechanism of insulin-induced degradation of insulin receptor substrate 1. Mol Cell Biol 2002; 22: 1016-26.
66. Pederson TM, Kramer DL, Rondinone CM. Serine/threonine phosphorylation of IRS-1 triggers its degradation: possible regulation by tyrosine phosphorylation. Diabetes 2001; 50: 24-31.
67. Greene MW, Sakaue H, Wang L, Alessi DR, Roth RA. Modulation of insulin- stimulated degradation of human insulin receptor substrate-1 by Serine 312 phosphorylation. J Biol Chem 2003; 278: 8199-211.
68. Aguirre V, Werner ED, Giraud J, Lee YH, Shoelson SE, White MF. Phosphorylation of ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action. J Biol Chem 2002; 277: 1531-7.
69. Lee YH, Giraud J, Davis RJ, White MF. c-Jun N-terminal kinase (JNK) mediates feedback inhibition of the insulin signaling cascade. J Biol Chem 2003; 278: 2896-902.
70. Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT, Moeda K, et al. A central role for JNK in obesity and insulin resistance. Nature 2002; 420: 333-6.
71. Yuan M, Lee J, Konstantopoulos N, Hansen L, Shoelson SE. Salicylate inhibition of Ikkβ (IkB kinase) reverses insulin resistance in Zucker (fa/fa) rats. Diabetes 2000; 49 (Suppl 1): A292.
72. Gao Z, Hwang D, Bataille F, Lefevre M, York D, Quon MJ, et al. Serine phosphorylation of insulin receptor substrate 1 by inhibitor kappa β kinase complex. J Biol Chem 2002; 277: 48115-21.
73. Rossi A, Kapahi P, Natoli G, Takahashi T, Chen Y, Karin M, et al. Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of Ikappa β kinase. Nature 2000; 403: 103-8.
74. 2 inhibits multiple steps in the NF-kappa β signaling pathway. Proc Natl Acad Sci USA 2000; 97: 4844-9.
75. Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, Karin M, et al. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of IKKβ. Science 2001; 293: 1673-7.
76. Kim JK, Kim YJ, Fillmore JJ, Chen Y, Moore I, Lee J, et al. Prevention of fat-induced insulin resistance by salicylate. J Clin Invest 2001; 108: 437-46.
77. Jiang G, Dallas-Yang Q, Liu F, Moller DE, Zhang BB. Salicylic acid reverses phorbol 12-myristate- 13 -acetate (PMA)- and tumor necrosis factor alpha (TNFalpha)-induced insulin receptor substrate 1 (IRS1) serine 307 phosphorylation and insulin resistance in human embryonic kidney 293 (HEK293) cells. J Biol Chem 2003; 278: 180-6.
78. Gao Z, Zuberi A, Quon MJ, Dong Z, Ye J. Aspirin inhibits serine phosphorylation of insulin receptor substrate 1 in tumor necrosis factor-treated cells through targeting multiple serine kinases. J Biol Chem 2003; 278: 24944-50.
79. Hundal RS, Mayerson AB, Petersen KF, Rife FS, Randhawa PS, Inzuchhi SE, et al. Potential for a novel class of insulin Sensitizing agents by inhibition of IKKβ activity. Diabetes 2001; 50 (Suppl 2): A117.
80. Blair AS, Hajduch E, Litherland GJ, Hundal HS. Regulation of glucose transport and glycogen synthesis in L6 muscle cells during oxidative stress. Evidence for cross-talk between the insulin and SAPK2/p38 mitogen-activated protein kinase signaling pathways. J Biol Chem 1999; 274: 36293-9.
81. Sweeney G, Somwar R, Ramlal T, Volchuk A, Ueyama A, Klip A. An inhibitor of p38 mitogen-activated protein kinase prevents insulin-stimulated glucose transport but not glucose transporter translocation in 3T3-L1 adipocytes and L6 myotubes. J Biol Chem 1999; 274: 10071-8.
82. Konrad D, Somwar R, Sweeney G, Yaworsky K, Hayashi M, Ramlal T, et al. The antihyperglycemic drug alpha-lipoic acid stimulates glucose uptake via both GLUT4 translocation and GLUT4 activation: potential role of p38 mitogen-activated protein kinase in GLUT4 activation. Diabetes 2001; 50: 1464-71.
83. Obata T, Brown GE, Yaffe MB. MAP kinase pathways activated by stress: the p38 MAPK pathway. Crit Care Med 2000; 28: N67-77.
84. Tibbles LA, Woodgett JR. The stres s-activated protein kinase pathways. Cell Mol Life Sci 1999; 55: 1230-54.
85. Gual P, Gonzalez T, Gremeaux T, Barres R, Marchand-Brustel Y, Tanti JF. Hyperosmotic stress inhibits insulin receptor substrate-1 function by distinct mechanisms in 3T3-L1 adipocytes. J Biol Chem 2003; 278: 26550-7.
86. Greene MW, Morrice N, Garofalo RS, Roth RA. Modulation of human insulin receptor substrate-1 tyrosine phosphorylation by protein kinase Cδ. Biochem J 2003; 378: 105-16.
87. Horike N, Takemori H, Katoh Y, Doi J, Min L, Asano T, et al. Adipose-specific expression, phosphorylation of Ser794 in insulin receptor substrate-1, and activation in diabetic animals of salt-inducible kinase-2. J Biol Chem 2003; 278: 18440-7.
88. Qiao LY, Zhande R, Jetton TL, Zhou G, Sun XJ. In vivo phosphorylation of insulin receptor substrate 1 at serine 789 by a novel serine kinase in insulin-resistant rodents. J Biol Chem 2002; 277: 26530-9.
89. Potashnik R, Bloch-Damti A, Bashan N, Rudich A. IRS1 degradation and increased serine phosphorylation cannot predict the degree of metabolic insulin resistance induced by oxidative stress. Diabetologia 2003; 46: 639-48.
90. Henriksen EJ. Oxidative stress and antioxidant treatment: effects on muscle glucose transport in animal models of type 1 and type 2 diabetes. In: Packer L, Rösen P, Tritschler HJ, King GL, editors. Antioxidants in diabetes management. 1st ed. New York: Marcel Dekker; 2000 p. 303-17.
91. Jacob S, Henriksen EJ, Schiemann AL, Simon I, Clancy DE, Tritschler HJ, et al. Enhancement of glucose disposal in patients with type 2 diabetes by alpha-lipoic acid. Arzneimittel-Forschung 1995; 45: 872-4.
92. Jacob S, Henriksen EJ, Tritschler HJ, Augustin HJ, Dietze GJ. Improvement of insulin-stimulated glucose-disposal in type 2 diabetes after repeated parenteral administration of thioctic acid. Exp Clin Endocrinol Diabetes 1996; 104: 284-8.
93. Jacob S, Runs P, Hermann R, Tritschler HJ, Maerker E, Renn W, et al. Oral administration of RAC-alpha-lipoic acid modulates insulin sensitivity in patients with type 2 diabetes mellitus: a placebo-controlled pilot trial. Free Radic Biol Med 1999; 27: 309-14.
94. Konrad T, Vicini P, Kusterer K, Haflich A, Assaolkhani A, Bohles HJ, et al. Alpha-lipoic acid treatment decreases serum lactate and pyruvate concentrations and improves glucose effectiveness in lean and obese patients with type 2 diabetes. Diabetes Care 1999; 22: 280-7.
95. Evans JL, Goldfine ID. α-Lipoic acid: a multi-functional antioxidant that improves insulin sensitivity in patients with type 2 diabetes. Diabetes Technol Therap 2000; 2: 401-13.
96. Ferrannini E, Mari A. How to measure insulin sensitivity. J Hypertension 1998; 6: 895-906.
97. Evans JL, Heymann CJ, Goldfine ID, Gavin LA. Pharmacokinetics, tolerability, and fructosamine-lowering effect of a novel, controlled release formulation of a-lipoic acid. Endocr Pract 2002; 8: 29-35.
98. Ziegler D, Nowak H, Kempler P, Vargha P, Low PA. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a meta-analysis. Diabet Med 2004; 21: 114-21.
99. Rudich A, Tirosh A, Potashnik R, Khamaisi M, Bashan N. Lipoic acid protects against oxidative stress induced impairment in insulin stimulation of protein kinase B and glucose transport in 3T3-L1 adipocytes. Diabetologia 1999; 42: 949-57.
100. Zhang WJ, Frei β. Alpha-lipoic acid inhibits TNF-alpha-induced NF-kappaβ activation and adhesion molecule expression in human aortic endothelial cells. FASEB J 2001; 15: 2423-32.
101. Ruderman N, Prentki M. AMP kinase and malonyl-CoA: targets for therapy of the metabolic syndrome. Nat Rev Drug Discov 2004; 3: 340-51.
102. Kim MS, Park JY, Namkoong C, Jang PG, Ryu JW, Song HS, et al. Anti-obesity effects of alpha-lipoic acid mediated by suppression of hypothalamic AMP-activated protein kinase. Nat Med 2004; 10: 727-33.
103. Lee WJ, Song KH, Koh EH, Won JC, Kim HS, Park HS, et al. Alpha-lipoic acid increases insulin sensitivity by activating AMPK in skeletal muscle. Biochem Biophys Res Commun 2005; 332: 885-91.
104. Slatter DA, Bolton CH, Bailey AJ. The importance of lipid-derived malondialdehyde in diabetes mellitus. Diabetologia 2000; 43: 550-7.
105. Bouloumie A, Marumo T, Lafontan M, Busse R. Leptin induces oxidative stress in human endothelial cells. FASEB J 1999; 1: 1231-8.
106. Sen CK. Redox signaling and the emerging therapeutic potential of thiol antioxidants. Biochem Pharmacol 1998; 55: 1747-58.
107. Marchetti G, Lodola E, Licciardello L, Colombo A. Use of N-acetylcysteine in the management of coronary artery diseases. Cardiologia 1999; 44: 633-7.
108. Biasco G, Paganelli GM. European trials on dietary supplementation for cancer prevention. Ann NY Acad Sci 1999; 889: 152-6.
109. Droge W, Breitkreutz R. N-acetyl-cysteine in the therapy of HIV-positive patients. Curr Opin Clin Nutr Metab Care 1999; 2: 493-8.
110. Lakhani K, Prelevic GM, Seifalian AM, Atiomo WU, Hardiman P. Polycystic ovary syndrome, diabetes and cardiovascular disease: risks and risk factors. J Obstet Gynaecol 2004; 24: 613-21.
111. Dunaif A, Thomas A. Current concepts in the polycystic ovary syndrome. Annu Rev Med 2001; 52: 401-19.
112. Fenkci V, Fenkci S, Yilmazer M, Serteser M. Decreased total antioxidant status and increased oxidative stress in women with polycystic ovary syndrome may contribute to the risk of cardiovascular disease. Fertil Steril 2003; 80: 123-7.
113. Polak G, Koziol-Montewka M, Gogacz M, Blaszkowska I, Kotarski J. Total antioxidant status of peritoneal fluid in infertile women. Eur J Obstet Gynecol Reprod Biol 2001; 94: 261-3.
114. Sabuncu T, Vural H, Harma M, Harma M. Oxidative stress in polycystic ovary syndrome and its contribution to the risk of cardiovascular disease. Clin Biochem 2001; 34: 407-13.
115. Yilmaz M, Bukan N, Ayvaz G, Karakoc A, Toruner F, Cakir N, et al. The effects of rosiglitazone and metformin on oxidative stress and homocysteine levels in lean patients with polycystic ovary syndrome. Hum Reprod 2005; 20: 3333-40.
116. Teede HJ, Meyer C, Norman RJ. Insulin-sensitisers in the treatment of polycystic ovary syndrome. Expert Opin Pharmacother 2005; 6: 2419-27.
117. Fulghesu AM, Ciampelli M, Muzj G, Belosi C, Selvaggi L, Ayala GF, et al. N-acetyl-cysteine treatment improves insulin sensitivity in women with polycystic ovary syndrome. Fertil Steril 2002; 77: 1128-35.
118. Baron AD, Quon MJ. Insulin action and endothelial function. In: Reaven GM, Laws A, editors. Insulin resistance: The metabolic syndrome X. Totowa: Humana Press; 1999 p. 247-63.
119. Hirai N, Kawano H, Hirashima O, Motoyama T, Moriyama Y, Sakamoto T, et al. Insulin resistance and endothelial dysfunction in smokers: effects of vitamin C. Am J Physiol 2000; 279: H1172-8.
120. Hirashima O, Kawano H, Motoyama T, Hirai N, Ohgushi M, Kugiyama K, et al. Improvement of endothelial function and insulin sensitivity with vitamin C in patients with coronary spastic angina: possible role of reactive oxygen species. J Am Coll Cardiol 2000; 35: 1860-6.
121. Chen H, Karne RJ, Hall G, Campia V, Panza JA, Cannon RO 3rd, et al. High-dose oral vitamin C partially replenishes vitamin C levels in patients with Type 2 diabetes and low vitamin C levels but does not improve endothelial dysfunction or insulin resistance. Am J Physiol Heart Circ Physiol 2006; 290: H137-45.
122. Caballero B. Vitamin E improves the action of insulin. Nutr Rev 1993; 51: 339-40.
123. Paolisso G, D'Amore A, Galzerano D, Balbi V, Gingliano D, Varricchio M, et al. Daily vitamin E supplements improve metabolic control but not insulin secretion in elderly type II diabetic patients. Diabetes Care 1993; 16: 1433-7.
124. Paolisso G, D'Amore A, Giugliano D, Ceriello A, Varricchio M, D'Onofrio F. Pharmacological doses of vitamin E improve insulin action in healthy subjects and non-insulin-dependent diabetic patients. Am J Clin Nutr 1993; 57: 650-6.
125. Paolisso G, Di Maro G, Galzerano D, Cacciapuoti F, Varricchio G, Varricchio M, et al. Pharmacological doses of vitamin E and insulin action in elderly subjects. Am J Clin Nutr 1994; 59: 1291-6.
126. Barbagallo M, Dominguez LJ, Tagliamonte MR, Resnick LM, Paolisso G. Effects of vitamin E and glutathione on glucose metabolism: role of magnesium. Hypertension 1999; 34: 1002-6.
127. Manzella D, Barbieri M, Ragno E, Paolisso G. Chronic administration of pharmacologic doses of vitamin E improves the cardiac autonomic nervous system in patients with type 2 diabetes. Am J Clin Nutr 2001; 73: 1052-7.
128. McSorley PT, Bell PM, Young IS, Atkinson AB, Sheridan B, Fee JP, et al. Endothelial function, insulin action and cardiovascular risk factors in young healthy adult offspring of parents with Type 2 diabetes: effect of vitamin E in a randomized double-blind, controlled clinical trial. Diabet Med 2005; 22: 703-10.
129. Hung HC, Joshipura KJ, Jiang R, Hu FB, Hunter D, Smith-Warner SA, et al. Fruit and vegetable intake and risk of major chronic disease. J Natl Cancer Inst 2004; 96: 1577-84.
130. Fraga CG. Cocoa, diabetes, and hypertension: should we eat more chocolate? Am J Clin Nutr 2005; 81: 541-2.
131. Fisher ND, Hughes M, Gerhard-Herman M, Hollenberg NK. Flavanol-rich cocoa induces nitric-oxide-dependent vasodilation in healthy humans. J Hypertens 2003; 21: 2281-6.
132. Fisher ND, Hollenberg NK. Flavanols for cardiovascular health: the science behind the sweetness. J Hypertens 2005; 23: 1453-9.
133. Rein D, Lotito S, Holt RR, Keen CL, Schmitz HH, Fraga CG. Epicatechin in human plasma: in vivo determination and effect of chocolate consumption on plasma oxidation status. J Nutr 2000; 130: 2109S-14.
134. Vlachopoulos C, Aznaouridis K, Alexopoulos N, Economou E, Andreadou I, Stefanadis C. Effect of dark chocolate on arterial function in healthy individuals. Am J Hypertens 2005; 18: 785-91.
135. Grassi D, Lippi C, Necozione S, Desideri G, Ferri C. Short-term administration of dark chocolate is followed by a significant increase in insulin sensitivity and a decrease in blood pressure in healthy persons. Am J Clin Nutr 2005; 81: 611-4.
136. Grassi D, Necozione S, Lippi C, Croce G, Valeri L, Pasqualetti P, et al. Cocoa reduces blood pressure and insulin resistance and improves endothelium-dependent vasodilation in hypertensives. Hypertension 2005; 46: 398-405.