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University of California at San Francisco (I.D.G., B.A.M. G.M.G.), San Francisco, California 94143; and Medical Research Institute (J.L.E.), San Bruno, California 94066
Correspondence: Address all correspondence and requests for reprints to: Joseph L. Evans, Ph.D., Medical Research Institute, 1001 Bayhill Drive, Suite 208, San Bruno, California 94066. E-mail: jevansphd{at}earthlink.net
In both type 1 and type 2 diabetes, the late diabetic complications in nerve, vascular endothelium, and kidney arise from chronic elevations of glucose and possibly other metabolites including free fatty acids (FFA). Recent evidence suggests that common stress-activated signaling pathways such as nuclear factor-
B, p38 MAPK, and NH2-terminal Jun kinases/stress-activated protein kinases underlie the development of these late diabetic complications. In addition, in type 2 diabetes, there is evidence that the activation of these same stress pathways by glucose and possibly FFA leads to both insulin resistance and impaired insulin secretion. Thus, we propose a unifying hypothesis whereby hyperglycemia and FFA-induced activation of the nuclear factor-B, p38 MAPK, and NH2-terminal Jun kinases/stress-activated protein kinases stress pathways, along with the activation of the advanced glycosylation end-products/receptor for advanced glycosylation end-products, protein kinase C, and sorbitol stress pathways, plays a key role in causing late complications in type 1 and type 2 diabetes, along with insulin resistance and impaired insulin secretion in type 2 diabetes. Studies with antioxidants such as vitamin E, 
-lipoic acid, and N-acetylcysteine suggest that new strategies may become available to treat these conditions.
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 A. S. Dias, M. Porawski, M. Alonso, N. Marroni, P. S. Collado, and J. Gonzalez-Gallego Quercetin Decreases Oxidative Stress, NF-{kappa}B Activation, and iNOS Overexpression in Liver of Streptozotocin-Induced Diabetic Rats J. Nutr., October 1, 2005; 135(10): 2299 - 2304. [Abstract] [Full Text] [PDF]
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 M. Suematsu, A. Katsuki, Y. Sumida, E. C Gabazza, S. Murashima, K. Matsumoto, N. Kitagawa, H. Akatsuka, Y. Hori, K. Nakatani, et al. Decreased circulating levels of active ghrelin are associated with increased oxidative stress in obese subjects Eur. J. Endocrinol., September 1, 2005; 153(3): 403 - 407. [Abstract] [Full Text] [PDF]
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F. Gonzalez, J. Minium, N. S. Rote, and J. P. Kirwan Hyperglycemia Alters Tumor Necrosis Factor-{alpha} Release from Mononuclear Cells in Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., September 1, 2005; 90(9): 5336 - 5342. [Abstract] [Full Text] [PDF]
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P. W. Franks, J. Luan, I. Barroso, S. Brage, J. L. G. Sanchez, U. Ekelund, M. S. Rios, A. J. Schafer, S. O'Rahilly, and N. J. Wareham Variation in the eNOS Gene Modifies the Association Between Total Energy Expenditure and Glucose Intolerance Diabetes, September 1, 2005; 54(9): 2795 - 2801. [Abstract] [Full Text] [PDF]
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D. K. Jagadeesha, T. E. Lindley, J. DeLeon, R. V. Sharma, F. Miller, and R. C. Bhalla Tempol therapy attenuates medial smooth muscle cell apoptosis and neointima formation after balloon catheter injury in carotid artery of diabetic rats Am J Physiol Heart Circ Physiol, September 1, 2005; 289(3): H1047 - H1053. [Abstract] [Full Text] [PDF]
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E. Sobngwi, J.-F. Gautier, J.-P. Kevorkian, J.-M. Villette, J.-P. Riveline, S. Zhang, P. Vexiau, S. M. Leal, C. Vaisse, and F. Mauvais-Jarvis High Prevalence of Glucose-6-Phosphate Dehydrogenase Deficiency without Gene Mutation Suggests a Novel Genetic Mechanism Predisposing to Ketosis-Prone Diabetes J. Clin. Endocrinol. Metab., August 1, 2005; 90(8): 4446 - 4451. [Abstract] [Full Text] [PDF]
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A. A. Banday, A. Marwaha, L. S. Tallam, and M. F. Lokhandwala Tempol Reduces Oxidative Stress, Improves Insulin Sensitivity, Decreases Renal Dopamine D1 Receptor Hyperphosphorylation, and Restores D1 Receptor-G-Protein Coupling and Function in Obese Zucker Rats Diabetes, July 1, 2005; 54(7): 2219 - 2226. [Abstract] [Full Text] [PDF]
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G. Wolf, S. Chen, and F. N. Ziyadeh From the Periphery of the Glomerular Capillary Wall Toward the Center of Disease: Podocyte Injury Comes of Age in Diabetic Nephropathy Diabetes, June 1, 2005; 54(6): 1626 - 1634. [Abstract] [Full Text] [PDF]
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G. A. Martens, Y. Cai, S. Hinke, G. Stange, M. Van de Casteele, and D. Pipeleers Glucose Suppresses Superoxide Generation in Metabolically Responsive Pancreatic {beta} Cells J. Biol. Chem., May 27, 2005; 280(21): 20389 - 20396. [Abstract] [Full Text] [PDF]
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 Y. H. Suh, Y. Kim, J. H. Bang, K. S. Choi, J. W. Lee, W.-H. Kim, T. J. Oh, S. An, and M. H. Jung Analysis of gene expression profiles in insulin-sensitive tissues from pre-diabetic and diabetic Zucker diabetic fatty rats J. Mol. Endocrinol., April 1, 2005; 34(2): 299 - 315. [Abstract] [Full Text] [PDF]
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J. M. Schattenberg, Y. Wang, R. Singh, R. M. Rigoli, and M. J. Czaja Hepatocyte CYP2E1 Overexpression and Steatohepatitis Lead to Impaired Hepatic Insulin Signaling J. Biol. Chem., March 18, 2005; 280(11): 9887 - 9894. [Abstract] [Full Text] [PDF]
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 D. Veneri, M. Franchini, and E. Bonora Imatinib and Regression of Type 2 Diabetes N. Engl. J. Med., March 10, 2005; 352(10): 1049 - 1050. [Full Text] [PDF]
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B. J. Goldstein, K. Mahadev, and X. Wu Redox Paradox: Insulin Action Is Facilitated by Insulin-Stimulated Reactive Oxygen Species With Multiple Potential Signaling Targets Diabetes, February 1, 2005; 54(2): 311 - 321. [Abstract] [Full Text] [PDF]
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M. C. Blendea, D. Jacobs, C. S. Stump, S. I. McFarlane, C. Ogrin, G. Bahtyiar, S. Stas, P. Kumar, Q. Sha, C. M. Ferrario, et al. Abrogation of oxidative stress improves insulin sensitivity in the Ren-2 rat model of tissue angiotensin II overexpression Am J Physiol Endocrinol Metab, February 1, 2005; 288(2): E353 - E359. [Abstract] [Full Text] [PDF]
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I. Talior, T. Tennenbaum, T. Kuroki, and H. Eldar-Finkelman PKC-{delta}-dependent activation of oxidative stress in adipocytes of obese and insulin-resistant mice: role for NADPH oxidase Am J Physiol Endocrinol Metab, February 1, 2005; 288(2): E405 - E411. [Abstract] [Full Text] [PDF]
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J. Asbun, A. M. Manso, and F. J. Villarreal Profibrotic influence of high glucose concentration on cardiac fibroblast functions: effects of losartan and vitamin E Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H227 - H234. [Abstract] [Full Text] [PDF]
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Y. Nakatani, H. Kaneto, D. Kawamori, M. Hatazaki, T. Miyatsuka, T.-a. Matsuoka, Y. Kajimoto, M. Matsuhisa, Y. Yamasaki, and M. Hori Modulation of the JNK Pathway in Liver Affects Insulin Resistance Status J. Biol. Chem., October 29, 2004; 279(44): 45803 - 45809. [Abstract] [Full Text] [PDF]
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J.-D. Luo, Y.-Y. Wang, W.-L. Fu, J. Wu, and A. F. Chen Gene Therapy of Endothelial Nitric Oxide Synthase and Manganese Superoxide Dismutase Restores Delayed Wound Healing in Type 1 Diabetic Mice Circulation, October 19, 2004; 110(16): 2484 - 2493. [Abstract] [Full Text] [PDF]
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 T. P. Fleming, W. Y. Kwong, R. Porter, E. Ursell, I. Fesenko, A. Wilkins, D. J. Miller, A. J. Watkins, and J. J. Eckert The Embryo and Its Future Biol Reprod, October 1, 2004; 71(4): 1046 - 1054. [Abstract] [Full Text] [PDF]
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 L. De Young, D. Yu, R. M. Bateman, and G. B. Brock Oxidative Stress and Antioxidant Therapy: Their Impact in Diabetes-Associated Erectile Dysfunction J Androl, September 1, 2004; 25(5): 830 - 836. [Abstract] [Full Text] [PDF]
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 J. Kaput, K. G. Klein, E. J. Reyes, W. A. Kibbe, C. A. Cooney, B. Jovanovic, W. J. Visek, and G. L. Wolff Identification of genes contributing to the obese yellow Avy phenotype: caloric restriction, genotype, diet x genotype interactions Physiol Genomics, August 11, 2004; 18(3): 316 - 324. [Abstract] [Full Text] [PDF]
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 M. A. Abdelmegeed, S. K. Kim, K. J. Woodcroft, and R. F. Novak Acetoacetate Activation of Extracellular Signal-Regulated Kinase 1/2 and p38 Mitogen-Activated Protein Kinase in Primary Cultured Rat Hepatocytes: Role of Oxidative Stress J. Pharmacol. Exp. Ther., August 1, 2004; 310(2): 728 - 736. [Abstract] [Full Text] [PDF]
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L. E. Fridlyand and L. H. Philipson Does the Glucose-Dependent Insulin Secretion Mechanism Itself Cause Oxidative Stress in Pancreatic {beta}-Cells? Diabetes, August 1, 2004; 53(8): 1942 - 1948. [Abstract] [Full Text] [PDF]
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S. Srinivasan, D. T. Bolick, M. E. Hatley, R. Natarajan, K. B. Reilly, M. Yeh, C. Chrestensen, T. W. Sturgill, and C. C. Hedrick Glucose Regulates Interleukin-8 Production in Aortic Endothelial Cells through Activation of the p38 Mitogen-activated Protein Kinase Pathway in Diabetes J. Biol. Chem., July 23, 2004; 279(30): 31930 - 31936. [Abstract] [Full Text] [PDF]
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M. G. Hartman, D. Lu, M.-L. Kim, G. J. Kociba, T. Shukri, J. Buteau, X. Wang, W. L. Frankel, D. Guttridge, M. Prentki, et al. Role for Activating Transcription Factor 3 in Stress-Induced {beta}-Cell Apoptosis Mol. Cell. Biol., July 1, 2004; 24(13): 5721 - 5732. [Abstract] [Full Text] [PDF]
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J. P. McClung, C. A. Roneker, W. Mu, D. J. Lisk, P. Langlais, F. Liu, and X. G. Lei Development of insulin resistance and obesity in mice overexpressing cellular glutathione peroxidase PNAS, June 15, 2004; 101(24): 8852 - 8857. [Abstract] [Full Text] [PDF]
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M.-T. Lin, C.-C. Chang, S.-T. Chen, H.-L. Chang, J.-L. Su, Y.-P. Chau, and M.-L. Kuo Cyr61 Expression Confers Resistance to Apoptosis in Breast Cancer MCF-7 Cells by a Mechanism of NF-{kappa}B-dependent XIAP Up-Regulation J. Biol. Chem., June 4, 2004; 279(23): 24015 - 24023. [Abstract] [Full Text] [PDF]
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 B. Liu, M. Bhat, A. K. Padival, D. G. Smith, and R. H. Nagaraj Effect of Dicarbonyl Modification of Fibronectin on Retinal Capillary Pericytes Invest. Ophthalmol. Vis. Sci., June 1, 2004; 45(6): 1983 - 1995. [Abstract] [Full Text] [PDF]
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D. Weihrauch, N. L. Lohr, B. Mraovic, L. M. Ludwig, W. M. Chilian, P. S. Pagel, D. C. Warltier, and J. R. Kersten Chronic Hyperglycemia Attenuates Coronary Collateral Development and Impairs Proliferative Properties of Myocardial Interstitial Fluid by Production of Angiostatin Circulation, May 18, 2004; 109(19): 2343 - 2348. [Abstract] [Full Text] [PDF]
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