Please wait a minute...
 Home  About the Journal Editorial Board Aims & Scope Peer Review Policy Subscription Contact us
Early Edition  //  Current Issue  //  Open Special Issues  //  Archives  //  Most Read  //  Most Downloaded  //  Most Cited
Aging and disease    2016, Vol. 7 Issue (1) : 90-110     DOI: 10.14336/AD.2015.0702
Review Article |
Hyperglycemic Stress and Carbon Stress in Diabetic Glucotoxicity
Luo Xiaoting1,2, Wu Jinzi1, Jing Siqun1,3, Yan Liang-Jun1,*
1 Department of Pharmaceutical Sciences, UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
2 Department of Biochemistry and Molecular Biology, Gannan Medical University, Ganzhou, Jiangxi province, China, 341000
3 College of Life Sciences and Technology, Xinjiang University, Urumqi, Xinjiang, China, 830046
Download: PDF(1213 KB)   HTML
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks    

Diabetes and its complications are caused by chronic glucotoxicity driven by persistent hyperglycemia. In this article, we review the mechanisms of diabetic glucotoxicity by focusing mainly on hyperglycemic stress and carbon stress. Mechanisms of hyperglycemic stress include reductive stress or pseudohypoxic stress caused by redox imbalance between NADH and NAD+ driven by activation of both the polyol pathway and poly ADP ribose polymerase; the hexosamine pathway; the advanced glycation end products pathway; the protein kinase C activation pathway; and the enediol formation pathway. Mechanisms of carbon stress include excess production of acetyl-CoA that can over-acetylate a proteome and excess production of fumarate that can over-succinate a proteome; both of which can increase glucotoxicity in diabetes. For hyperglycemia stress, we also discuss the possible role of mitochondrial complex I in diabetes as this complex, in charge of NAD+ regeneration, can make more reactive oxygen species (ROS) in the presence of excess NADH. For carbon stress, we also discuss the role of sirtuins in diabetes as they are deacetylases that can reverse protein acetylation thereby attenuating diabetic glucotoxicity and improving glucose metabolism. It is our belief that targeting some of the stress pathways discussed in this article may provide new therapeutic strategies for treatment of diabetes and its complications.

Keywords glucotoxicity      carbon stress      diabetes      hyperglycemic stress      reactive oxygen species      redox imbalance      pseudohypoxia     
Corresponding Authors: Yan Liang-Jun   
About author:

These authors equally contribute this work

Issue Date: 01 February 2016
E-mail this article
E-mail Alert
Articles by authors
Luo Xiaoting
Wu Jinzi
Jing Siqun
Yan Liang-Jun
Cite this article:   
Luo Xiaoting,Wu Jinzi,Jing Siqun, et al. Hyperglycemic Stress and Carbon Stress in Diabetic Glucotoxicity[J]. Aging and disease, 2016, 7(1): 90-110.
URL:     OR
Figure 1.  Major pathways upregulated by chronic hyperglycemia. These pathways include the polyol pathway, the hexosamine pathway, PKC activation, formation of advanced glycation end products (AGEs), and the enediol formation pathway. These pathways usually remain dormant under euglycemia conditions whereby majority of the body's glucose is combusted through glycolysis and TCA cycle.
Figure 2.  Regulation of glucose homeostasis and pathophysiology of hyperglycemia. Glucose is extracted from food stuff in the gastrointestinal tract and is then released to the blood stream. High level of blood glucose stimulates insulin secretion from islet β cell in the pancreas, leading to uptake of glucose by muscle and adipose tissues. Insulin also suppresses the gluconeogenesis in the liver. Excess glucose is stored in the liver and the muscle as glycogen, and in the adipose tissue as fat. This glucose uptake and storage process and the overall control of glucose homeostasis are impaired in diabetes.
Figure 3.  Summary of insulin-stimulated biological processes. Hyperglycemia-induced secretion of insulin can mediate numerous biological processes such as glucose uptake, activation of Na+/K+ pumps, synthesis of fatty acid from acetyl-CoA and glycogen from glucose, amino acid uptake, gene expression, and protein synthesis. Figure adapted from reference [58].
Figure 4.  Glucose disposal via the polyol pathway under chronic hyperglycemic conditions in diabetes. This pathway includes two-step reactions. The first one is glucose reduction by aldose reductase to form sorbitol; while the second reaction is sorbitol oxidation by sorbitol dehydrogenase to form fructose. Reducing equivalent is transferred from NADPH to NADH, leading to elevated level of NADH and reductive stress. The glycolytic pathway is also shown.
Figure 5.  Glucose disposal via the hexosamine pathway. This pathway involves activation of glutamine fructose-6-P amidotransferase that converts fructose 6-P to glucosamine 6-P. This is followed by the formation of UDP-GlcNAc that is the substrate for protein translational modifications. This pathway is known to be involved in insulin resistance and diabetes. The glycolytic pathway is also shown.
Figure 6.  Summary of events leading to redox imbalance between NADH and NAD+ in diabetes. On one hand, the polyol pathway produces excess NADH; on the other hand, the activation of poly ADP ribose polymerase could potentially deplete NAD+, leading to great pressure on mitochondrial complex I that is in charge of NADH oxidation and NAD+ production. NADH overload on complex I can lead to more ROS production. Therefore, complex I could be a pathogenic factor in diabetes and could also be a target for diabetic therapies.
Figure 7.  Sources and fates of acetyl-CoA. Acetyl-CoA is mainly generated by combustion of glucose, fatty acid, and proteins. When in excess, acetyl-CoA can be used to make sterols and fatty acids, and can also conjugate to proteins, forming acetylated protein products. In long term fasting or starvation, acetyl-CoA can be used to form ketone bodies that are needed for brain function [288, 289]. Under normal conditions, acetyl-CoA is metabolized to provide energy via TCA cycle and oxidative phosphorylation inside mitochondria.
Figure 8.  Excess acetyl-CoA produced by hyperglycemia and hyperlipidemia in diabetes can increase nonenzymatic acetylation of proteins via lysine residues. This modification can regulate protein function under stress conditions via sirtuins actions that remove the acetyl groups from the target proteins.
[1] Bensellam M, Laybutt DR, Jonas JC (2012). The molecular mechanisms of pancreatic beta-cell glucotoxicity: recent findings and future research directions. Molecular and cellular endocrinology, 364: 1-27
[2] Del Prato S (2009). Role of glucotoxicity and lipotoxicity in the pathophysiology of Type 2 diabetes mellitus and emerging treatment strategies. Diabet Med, 26: 1185-1192
[3] Dedoussis GV, Kaliora AC, Panagiotakos DB (2007). Genes, diet and type 2 diabetes mellitus: a review. The review of diabetic studies : RDS, 4: 13-24
[4] Somesh BP, Verma MK, Sadasivuni MK, Mammen-Oommen A, Biswas S, Shilpa PC,et al. (2013). Chronic glucolipotoxic conditions in pancreatic islets impair insulin secretion due to dysregulated calcium dynamics, glucose responsiveness and mitochondrial activity. BMC Cell Biol, 14: 31
[5] Leibowitz G, Kaiser N, Cerasi E (2011). beta-Cell failure in type 2 diabetes. Journal of diabetes investigation, 2: 82-91
[6] Leibowitz G, Bachar E, Shaked M, Sinai A, Ketzinel-Gilad M, Cerasi E,et al. (2010). Glucose regulation of beta-cell stress in type 2 diabetes. Diabetes, obesity & metabolism, 12 Suppl 2: 66-75
[7] Barnett AH (2012) Type 2 diabetes, Oxford University Press
[8] Ruderman NB, Carling D, Prentki M, Cacicedo JM (2013). AMPK, insulin resistance, and the metabolic syndrome. J Clin Invest, 123: 2764-2772
[9] Bacha F, Gungor N, Lee S, Arslanian SA (2013). Progressive deterioration of beta-cell function in obese youth with type 2 diabetes. Pediatr Diabetes, 14: 106-111
[10] Gallwitz B, Kazda C, Kraus P, Nicolay C, Schernthaner G (2013). Contribution of insulin deficiency and insulin resistance to the development of type 2 diabetes: nature of early stage diabetes. Acta Diabetol, 50: 39-45
[11] DeFronzo RA (1997). Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidaemia and atherosclerosis. The Netherlands journal of medicine, 50: 191-197
[12] Abdul-Ghani MA, DeFronzo RA (2010). Pathogenesis of insulin resistance in skeletal muscle. Journal of biomedicine & biotechnology, 2010: 476279
[13] Gungor N, Arslanian S (2004). Progressive beta cell failure in type 2 diabetes mellitus of youth. J Pediatr, 144: 656-659
[14] Funk SD, Yurdagul A, Jr., Orr AW (2012). Hyperglycemia and endothelial dysfunction in atherosclerosis: lessons from type 1 diabetes. International journal of vascular medicine, 2012: 569654
[15] Eiselein L, Schwartz HJ, Rutledge JC (2004). The challenge of type 1 diabetes mellitus. ILAR journal / National Research Council, Institute of Laboratory Animal Resources, 45: 231-236
[16] Tuch B, Dunlop M, Proietto J (2000) Diabetes Research: A guide for postgraduates, Harwood Academic Publishers
[17] Larsen MO (2009). Beta-cell function and mass in type 2 diabetes. Danish medical bulletin, 56: 153-164
[18] Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC (2003). Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes, 52: 102-110
[19] Abdul-Ghani MA, DeFronzo RA (2008) Oxidative stress in type 2 diabetes. In Oxidative stress in aging (Miwa, S., Beckman, K. B., Muller, F. L., eds) pp. 191-212, Humana Press
[20] Kaiser N, Leibowitz G, Nesher R (2003). Glucotoxicity and beta-cell failure in type 2 diabetes mellitus. J Pediatr Endocrinol Metab, 16: 5-22
[21] Szendroedi J, Phielix E, Roden M (2012). The role of mitochondria in insulin resistance and type 2 diabetes mellitus. Nature reviews. Endocrinology, 8: 92-103
[22] Maedler K, Donath MY (2004). Beta-cells in type 2 diabetes: a loss of function and mass. Horm Res, 62 Suppl 3: 67-73
[23] Chang-Chen KJ, Mullur R, Bernal-Mizrachi E (2008). Beta-cell failure as a complication of diabetes. Rev Endocr Metab Disord, 9: 329-343
[24] Muoio DM, Newgard CB (2008). Mechanisms of disease: molecular and metabolic mechanisms of insulin resistance and beta-cell failure in type 2 diabetes. Nature reviews. Molecular cell biology, 9: 193-205
[25] Lee SA, Lee WJ, Kim EH, Yu JH, Jung CH, Koh EH,et al. (2011). Progression to insulin deficiency in Korean patients with Type 2 diabetes mellitus positive for anti-GAD antibody. Diabet Med, 28: 319-324
[26] Cnop M, Welsh N, Jonas JC, Jorns A, Lenzen S, Eizirik DL (2005). Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities. Diabetes, 54 Suppl 2: S97-107
[27] Gholap NN, Davies MJ, Mostafa SA, Khunti K (2013). Diagnosing type 2 diabetes and identifying high-risk individuals using the new glycated haemoglobin (HbA1c) criteria. The British journal of general practice : the journal of the Royal College of General Practitioners, 63: e165-167
[28] Wu J, Luo X, Yan LJ (2015). Two dimensional blue native/SDS-PAGE to identify mitochondrial complex I subunits modified by 4-hydroxynonenal (HNE). Frontiers in Physiology, 6
[29] Korsgren O, Jansson L, Sandler S, Andersson A (1990). Hyperglycemia-induced B cell toxicity. The fate of pancreatic islets transplanted into diabetic mice is dependent on their genetic background. J Clin Invest, 86: 2161-2168
[30] Poitout V, Robertson RP (2002). Minireview: Secondary beta-cell failure in type 2 diabetes--a convergence of glucotoxicity and lipotoxicity. Endocrinology, 143: 339-342
[31] Roseman HM (2005). Progression from obesity to type 2 diabetes: lipotoxicity, glucotoxicity, and implications for management. Journal of managed care pharmacy : JMCP, 11: S3-S11
[32] Weir GC, Marselli L, Marchetti P, Katsuta H, Jung MH, Bonner-Weir S (2009). Towards better understanding of the contributions of overwork and glucotoxicity to the beta-cell inadequacy of type 2 diabetes. Diabetes, obesity & metabolism, 11 Suppl 4: 82-90
[33] Poitout V, Robertson RP (2008). Glucolipotoxicity: fuel excess and beta-cell dysfunction. Endocrine reviews, 29: 351-366
[34] Kawahito S, Kitahata H, Oshita S (2009). Problems associated with glucose toxicity: role of hyperglycemia-induced oxidative stress. World J Gastroenterol, 15: 4137-4142
[35] Giaccari A, Sorice G, Muscogiuri G (2009). Glucose toxicity: the leading actor in the pathogenesis and clinical history of type 2 diabetes - mechanisms and potentials for treatment. Nutr Metab Cardiovasc Dis, 19: 365-377
[36] Yan LJ (2014). Pathogenesis of Chronic Hyperglycemia: From Reductive Stress to Oxidative Stress. Journal of diabetes research, 2014: 137919
[37] Robertson RP (2004). Chronic oxidative stress as a central mechanism for glucose toxicity in pancreatic islet beta cells in diabetes. J Biol Chem, 279: 42351-42354
[38] Iyer A, Fairlie DP, Brown L (2012). Lysine acetylation in obesity, diabetes and metabolic disease. Immunol Cell Biol, 90: 39-46
[39] Frizzell N, Lima M, Baynes JW (2011). Succination of proteins in diabetes. Free Radic Res, 45: 101-109
[40] Wagner GR, Hirschey MD (2014). Nonenzymatic protein acylation as a carbon stress regulated by sirtuin deacylases. Mol Cell, 54: 5-16
[41] Abel ED (2010). Free fatty acid oxidation in insulin resistance and obesity. Heart Metab, 48: 5-10
[42] Poretsky L (2010) Principles of diabetes mellitus, Springer, New York
[43] de Koning L, Amlik VS, Hu FB (2014)Dietary carbohydrates and type 2 diabetes. In Nutrition and type 2 diabetes etiology and prevention(Pereira, M. A., ed) pp. 11-64, CRC Press, New York
[44] Seely L, Olefsky JM (1993) Potential cellular and genetic mechanisms for insulin resistance in the common disorders of diabetes and obesity. In Insulin resistance (Moller, D. E., ed) pp. 187-252, Wiley, New York
[45] Cook JR, Langlet F, Kido Y, Accili D (2015). On the Pathogenesis of Selective Insulin Resistance in Isolated Hepatocytes. J Biol Chem
[46] Sajan MP, Jurzak MJ, Samuels VT, Shulman GI, Braun U, Leitges M,et al. (2014). Impairment of insulin-stimulated glucose transport and ERK activation by adipocyte-specific knockout of PKC-lambda produces a phenotype characterized by diminished adiposity and enhanced insulin suppression of hepatic gluconeogenesis. Adipocyte, 3: 19-29
[47] Turner N, Cooney GJ, Kraegen EW, Bruce CR (2014). Fatty acid metabolism, energy expenditure and insulin resistance in muscle. J Endocrinol, 220: T61-79
[48] Yang J (2014). Enhanced skeletal muscle for effective glucose homeostasis. Prog Mol Biol Transl Sci, 121: 133-163
[49] Gustafson B, Hedjazifar S, Gogg S, Hammarstedt A, Smith U (2015). Insulin resistance and impaired adipogenesis. Trends Endocrinol Metab, 26: 193-200
[50] Yki-Jarvinen H (2002). Insulin resistance in patients with IDDM. In: Insulin resistance in patients with IDDM. In: Hormone resistance and hypersensitivity states. Lippincott William & Wilkins, Baltimore, 175-185
[51] Groop L, Orho M (1998). Metabolic aspects of glycogen synthase activation. In: Metabolic aspects of glycogen synthase activation. In: Molecular and cell biology of type 2 diabetes and its complications. Karger, Basel,47-55
[52] Stolar M (2010). Glycemic control and complications in type 2 diabetes mellitus. The American journal of medicine, 123: S3-11
[53] Brownlee M (2001). Biochemistry and molecular cell biology of diabetic complications. Nature, 414: 813-820
[54] Brownlee M (2005). The pathobiology of diabetic complications: a unifying mechanism. Diabetes, 54: 1615-1625
[55] Finocchietto P, Barreyro F, Holod S, Peralta J, Franco MC, Mendez C,et al. (2008). Control of muscle mitochondria by insulin entails activation of Akt2-mtNOS pathway: implications for the metabolic syndrome. PLoS ONE, 3: e1749
[56] Cheng Z, Tseng Y, White MF (2010). Insulin signaling meets mitochondria in metabolism. Trends Endocrinol Metab, 21: 589-598
[57] Cline GW (2011). Fuel-Stimulated Insulin Secretion Depends upon Mitochondria Activation and the Integration of Mitochondrial and Cytosolic Substrate Cycles. Diabetes Metab J, 35: 458-465
[58] White MF, Khan CR (1993) Mechanisms of insulin action. In Insulin resistance (Moller, D. E., ed) pp. 9-47, Wiley, New York
[59] Brunner Y, Schvartz D, Priego-Capote F, Coute Y, Sanchez JC (2009). Glucotoxicity and pancreatic proteomics. J Proteomics, 71: 576-591
[60] Seltzer HS, Harris VL (1964). Exhaustion of Insulogenic Reserve in Maturity-Onset Diabetic Patients during Prolonged and Continuous Hyperglycemic Stress. Diabetes, 13: 6-13
[61] Lipinski B (2002). Evidence in support of a concept of reductive stress. The British journal of nutrition, 87: 93-94; discussion 94
[62] Teodoro JS, Rolo AP, Palmeira CM (2013). The NAD ratio redox paradox: why does too much reductive power cause oxidative stress? Toxicology Mechanisms and Methods, 23: 297-302
[63] Pung YF, Chilian WM (2010). Corruption of coronary collateral growth in metabolic syndrome: Role of oxidative stress. World journal of cardiology, 2: 421-427
[64] Tilton RG (2002). Diabetic vascular dysfunction: links to glucose-induced reductive stress and VEGF. Microscopy research and technique, 57: 390-407
[65] Valadi H, Valadi A, Ansell R, Gustafsson L, Adler L, Norbeck J,et al. (2004). NADH-reductive stress in Saccharomyces cerevisiae induces the expression of the minor isoform of glyceraldehyde-3-phosphate dehydrogenase (TDH1). Current genetics, 45: 90-95
[66] Chung SS, Chung SK (2005). Aldose reductase in diabetic microvascular complications. Curr Drug Targets, 6: 475-486
[67] Dunlop M (2000). Aldose reductase and the role of the polyol pathway in diabetic nephropathy. Kidney Int Suppl, 77: S3-12
[68] Hodgkinson AD, Sondergaard KL, Yang B, Cross DF, Millward BA, Demaine AG (2001). Aldose reductase expression is induced by hyperglycemia in diabetic nephropathy. Kidney Int, 60: 211-218
[69] Iwata K, Nishinaka T, Matsuno K, Kakehi T, Katsuyama M, Ibi M,et al. (2007). The activity of aldose reductase is elevated in diabetic mouse heart. J Pharmacol Sci, 103: 408-416
[70] Yabe-Nishimura C (1998). Aldose reductase in glucose toxicity: a potential target for the prevention of diabetic complications. Pharmacol Rev, 50: 21-33
[71] Tang WH, Martin KA, Hwa J (2012). Aldose reductase, oxidative stress, and diabetic mellitus. Frontiers in pharmacology, 3: 87
[72] Fantus IG (2002). The pathogenesis of the chronic complications of the diabetes mellitus. Endocrinology Rounds, 2: 1-8
[73] Gomes AP, Price NL, Ling AJ, Moslehi JJ, Montgomery MK, Rajman L,et al. (2013). Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell, 155: 1624-1638
[74] Ido Y, Williamson JR (1997). Hyperglycemic cytosolic reductive stress 'pseudohypoxia': implications for diabetic retinopathy. Invest Ophthalmol Vis Sci, 38: 1467-1470
[75] Williamson JR, Chang K, Frangos M, Hasan KS, Ido Y, Kawamura T,et al. (1993). Hyperglycemic pseudohypoxia and diabetic complications. Diabetes, 42: 801-813
[76] Hotta N (1997). New concepts and insights on pathogenesis and treatment of diabetic complications: polyol pathway and its inhibition. Nagoya J Med Sci, 60: 89-100
[77] Yasunari K, Kohno M, Kano H, Minami M, Yoshikawa J (2000). Aldose reductase inhibitor improves insulin-mediated glucose uptake and prevents migration of human coronary artery smooth muscle cells induced by high glucose. Hypertension, 35: 1092-1098
[78] Chavez JC, Agani F, Pichiule P, LaManna JC (2000). Expression of hypoxia-inducible factor-1alpha in the brain of rats during chronic hypoxia. J Appl Physiol (1985), 89: 1937-1942
[79] Benderro GF, LaManna JC (2013). Kidney EPO expression during chronic hypoxia in aged mice. Adv Exp Med Biol, 765: 9-14
[80] Li R, Luo X, Wu J, Thangthaeng N, Jung ME, Jing S,et al. (2015). Mitochondrial dihydrolipoamide dehydrogenase is upregulated in response to intermittent hypoxic preconditioning. Int. J. Med. Sci., 12: 432-440
[81] Houtkooper RH, Canto C, Wanders RJ, Auwerx J (2010). The secret life of NAD+: an old metabolite controlling new metabolic signaling pathways. Endocrine reviews, 31: 194-223
[82] Braidy N, Guillemin GJ, Mansour H, Chan-Ling T, Poljak A, Grant R (2011). Age related changes in NAD+ metabolism oxidative stress and Sirt1 activity in wistar rats. PLoS One, 6: e19194
[83] Chiarugi A, Dolle C, Felici R, Ziegler M (2012). The NAD metabolome--a key determinant of cancer cell biology. Nat Rev Cancer, 12: 741-752
[84] Houtkooper RH, Auwerx J (2012). Exploring the therapeutic space around NAD+. J Cell Biol, 199: 205-209
[85] Chandra D, Jackson EB, Ramana KV, Kelley R, Srivastava SK, Bhatnagar A (2002). Nitric oxide prevents aldose reductase activation and sorbitol accumulation during diabetes. Diabetes, 51: 3095-3101
[86] Lee AY, Chung SS (1999). Contributions of polyol pathway to oxidative stress in diabetic cataract. FASEB J, 13: 23-30
[87] Obrosova IG (2005). Increased sorbitol pathway activity generates oxidative stress in tissue sites for diabetic complications. Antioxid Redox Signal, 7: 1543-1552
[88] Harding JJ, Blakytny R, Ganea E (1996). Glutathione in disease. Biochem Soc Trans, 24: 881-884
[89] Yan LJ, Christians ES, Liu L, Xiao X, Sohal RS, Benjamin IJ (2002). Mouse heat shock transcription factor 1 deficiency alters cardiac redox homeostasis and increases mitochondrial oxidative damage. EMBO J, 21: 5164-5172
[90] Lou MF, Dickerson JE, Jr., Garadi R, York BM, Jr. (1988). Glutathione depletion in the lens of galactosemic and diabetic rats. Experimental eye research, 46: 517-530
[91] Sato T, Sasaki H, Watanabe R, Yoshinaga K (1988). Enhancement of pentose phosphate pathway in vascular intima from diabetic rabbit. Tohoku J Exp Med, 155: 97-100
[92] Rosa AP, Jacques CE, de Souza LO, Bitencourt F, Mazzola PN, Coelho JG,et al. (2015). Neonatal hyperglycemia induces oxidative stress in the rat brain: the role of pentose phosphate pathway enzymes and NADPH oxidase. Mol Cell Biochem, 403: 159-167
[93] Bast A, Haenen GR (2002) Lipoic acid: a multifunctional antioxidant. In Thiol metabolism and redox regulation of cellular function (Pompella, A., Banhegyi G., Wellman-Rousseau M., eds) pp. 230-237, IOS Press, Amsterdam, Netherlands
[94] Winkler BS, DeSantis N, Solomon F (1986). Multiple NADPH-producing pathways control glutathione (GSH) content in retina. Experimental eye research, 43: 829-847
[95] Tang WH, Wu S, Wong TM, Chung SK, Chung SS (2008). Polyol pathway mediates iron-induced oxidative injury in ischemic-reperfused rat heart. Free Radic Biol Med, 45: 602-610
[96] Yang Y, Hayden MR, Sowers S, Bagree SV, Sowers JR (2010). Retinal redox stress and remodeling in cardiometabolic syndrome and diabetes. Oxid Med Cell Longev, 3: 392-403
[97] Ussher JR, Jaswal JS, Lopaschuk GD (2012). Pyridine nucleotide regulation of cardiac intermediary metabolism. Circ Res, 111: 628-641
[98] Suzen S, Buyukbingol E (2003). Recent studies of aldose reductase enzyme inhibition for diabetic complications. Curr Med Chem, 10: 1329-1352
[99] Reddy AB, Ramana KV (2010). Aldose reductase inhibition: emerging drug target for the treatment of cardiovascular complications. Recent Pat Cardiovasc Drug Discov, 5: 25-32
[100] Tang J, Du Y, Petrash JM, Sheibani N, Kern TS (2013). Deletion of aldose reductase from mice inhibits diabetes-induced retinal capillary degeneration and superoxide generation. PLoS One, 8: e62081
[101] Alzaid A, Rizza RA (1993). Insulin resistance and its role in the pathogenesis of impaired glucose tolerance and non-insulin-dependent diabetes mellitus: perspectives gained from in vivo studies. In: Insulin resistance. John Wiley & Sons Ltd, New York, 143-186
[102] Bevilacqua S, Buzzigoli G, Bonadonna R, Brandi LS, Oleggini M, Boni C,et al. (1990). Operation of Randle's cycle in patients with NIDDM. Diabetes, 39: 383-389
[103] Nuutila P, Koivisto VA, Knuuti J, Ruotsalainen U, Teras M, Haaparanta M,et al. (1992). Glucose-free fatty acid cycle operates in human heart and skeletal muscle in vivo. J Clin Invest, 89: 1767-1774
[104] Ferrannini E, Barrett EJ, Bevilacqua S, DeFronzo RA (1983). Effect of fatty acids on glucose production and utilization in man. J Clin Invest, 72: 1737-1747
[105] Dolle C, Rack JG, Ziegler M (2013). NAD and ADP-ribose metabolism in mitochondria. FEBS J, 280: 3530-3541
[106] Ying W (2008). NAD+/NADH and NADP+/NADPH in cellular functions and cell death: regulation and biological consequences. Antioxid Redox Signal, 10: 179-206
[107] Szabados E, Fischer GM, Gallyas F, Jr., Kispal G, Sumegi B (1999). Enhanced ADP-ribosylation and its diminution by lipoamide after ischemia-reperfusion in perfused rat heart. Free Radic Biol Med, 27: 1103-1113
[108] Szabo C (2005). Roles of poly(ADP-ribose) polymerase activation in the pathogenesis of diabetes mellitus and its complications. Pharmacol Res, 52: 60-71
[109] Pittelli M, Felici R, Pitozzi V, Giovannelli L, Bigagli E, Cialdai F,et al. (2011). Pharmacological effects of exogenous NAD on mitochondrial bioenergetics, DNA repair, and apoptosis. Mol Pharmacol, 80: 1136-1146
[110] Szabo C, Zanchi A, Komjati K, Pacher P, Krolewski AS, Quist WC,et al. (2002). Poly(ADP-Ribose) polymerase is activated in subjects at risk of developing type 2 diabetes and is associated with impaired vascular reactivity. Circulation, 106: 2680-2686
[111] Pacher P, Liaudet L, Soriano FG, Mabley JG, Szabo E, Szabo C (2002). The role of poly(ADP-ribose) polymerase activation in the development of myocardial and endothelial dysfunction in diabetes. Diabetes, 51: 514-521
[112] Horvath EM, Magenheim R, Kugler E, Vacz G, Szigethy A, Levardi F,et al. (2009). Nitrative stress and poly(ADP-ribose) polymerase activation in healthy and gestational diabetic pregnancies. Diabetologia, 52: 1935-1943
[113] Du X, Matsumura T, Edelstein D, Rossetti L, Zsengeller Z, Szabo C,et al. (2003). Inhibition of GAPDH activity by poly(ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells. J Clin Invest, 112: 1049-1057
[114] Pacher P, Szabo C (2005). Role of poly(ADP-ribose) polymerase-1 activation in the pathogenesis of diabetic complications: endothelial dysfunction, as a common underlying theme. Antioxid Redox Signal, 7: 1568-1580
[115] Obrosova IG, Drel VR, Pacher P, Ilnytska O, Wang ZQ, Stevens MJ,et al. (2005). Oxidative-nitrosative stress and poly(ADP-ribose) polymerase (PARP) activation in experimental diabetic neuropathy: the relation is revisited. Diabetes, 54: 3435-3441
[116] Chiu J, Xu BY, Chen S, Feng B, Chakrabarti S (2008). Oxidative stress-induced, poly(ADP-ribose) polymerase-dependent upregulation of ET-1 expression in chronic diabetic complications. Can J Physiol Pharmacol, 86: 365-372
[117] Puthanveetil P, Zhang D, Wang Y, Wang F, Wan A, Abrahani A,et al. (2012). Diabetes triggers a PARP1 mediated death pathway in the heart through participation of FoxO1. J Mol Cell Cardiol, 53: 677-686
[118] Masutani M, Suzuki H, Kamada N, Watanabe M, Ueda O, Nozaki T,et al. (1999). Poly(ADP-ribose) polymerase gene disruption conferred mice resistant to streptozotocin-induced diabetes. Proc Natl Acad Sci U S A, 96: 2301-2304
[119] Pieper AA, Brat DJ, Krug DK, Watkins CC, Gupta A, Blackshaw S,et al. (1999). Poly(ADP-ribose) polymerase-deficient mice are protected from streptozotocin-induced diabetes. Proc Natl Acad Sci U S A, 96: 3059-3064
[120] Virag L, Szabo C (2002). The therapeutic potential of poly(ADP-ribose) polymerase inhibitors. Pharmacol Rev, 54: 375-429
[121] Long CA, Boulom V, Albadawi H, Tsai S, Yoo HJ, Oklu R,et al. (2013). Poly-ADP-ribose-polymerase inhibition ameliorates hind limb ischemia reperfusion injury in a murine model of type 2 diabetes. Ann Surg, 258: 1087-1095
[122] Sarras MP, Jr., Mason S, McAllister G, Intine RV (2014). Inhibition of poly-ADP ribose polymerase enzyme activity prevents hyperglycemia-induced impairment of angiogenesis during wound healing. Wound Repair Regen, 22: 666-670
[123] Szkudelski T (2012). Streptozotocin-nicotinamide-induced diabetes in the rat. Characteristics of the experimental model. Exp Biol Med (Maywood), 237: 481-490
[124] Fukaya M, Tamura Y, Chiba Y, Tanioka T, Mao J, Inoue Y,et al. (2013). Protective effects of a nicotinamide derivative, isonicotinamide, against streptozotocin-induced beta-cell damage and diabetes in mice. Biochem Biophys Res Commun, 442: 92-98
[125] Obrosova IG, Minchenko AG, Frank RN, Seigel GM, Zsengeller Z, Pacher P,et al. (2004). Poly(ADP-ribose) polymerase inhibitors counteract diabetes- and hypoxia-induced retinal vascular endothelial growth factor overexpression. Int J Mol Med, 14: 55-64
[126] Beyer AM, Weihrauch D (2012). Hexosamine pathway activation and O-linked-N-acetylglucosamine: novel mediators of endothelial dysfunction in hyperglycemia and diabetes. Vascul Pharmacol, 56: 113-114
[127] Schleicher ED, Weigert C (2000). Role of the hexosamine biosynthetic pathway in diabetic nephropathy. Kidney Int Suppl, 77: S13-18
[128] Yki-Jarvinen H, Daniels MC, Virkamaki A, Makimattila S, DeFronzo RA, McClain D (1996). Increased glutamine:fructose-6-phosphate amidotransferase activity in skeletal muscle of patients with NIDDM. Diabetes, 45: 302-307
[129] Yki-Jarvinen H, Vogt C, Iozzo P, Pipek R, Daniels MC, Virkamaki A,et al. (1997). UDP-N-acetylglucosamine transferase and glutamine: fructose 6-phosphate amidotransferase activities in insulin-sensitive tissues. Diabetologia, 40: 76-81
[130] Ma J, Hart GW (2013). Protein O-GlcNAcylation in diabetes and diabetic complications. Expert review of proteomics, 10: 365-380
[131] Issad T, Kuo M (2008). O-GlcNAc modification of transcription factors, glucose sensing and glucotoxicity. Trends Endocrinol Metab, 19: 380-389
[132] Kuo M, Zilberfarb V, Gangneux N, Christeff N, Issad T (2008). O-GlcNAc modification of FoxO1 increases its transcriptional activity: a role in the glucotoxicity phenomenon? Biochimie, 90: 679-685
[133] Hardiville S, Hart GW (2014). Nutrient regulation of signaling, transcription, and cell physiology by O-GlcNAcylation. Cell Metab, 20: 208-213
[134] Semba RD, Huang H, Lutty GA, Van Eyk JE, Hart GW (2014). The role of O-GlcNAc signaling in the pathogenesis of diabetic retinopathy. Proteomics. Clinical applications, 8: 218-231
[135] Lima VV, Spitler K, Choi H, Webb RC, Tostes RC (2012). O-GlcNAcylation and oxidation of proteins: is signalling in the cardiovascular system becoming sweeter? Clin Sci (Lond), 123: 473-486
[136] Issad T, Masson E, Pagesy P (2010). O-GlcNAc modification, insulin signaling and diabetic complications. Diabetes & metabolism, 36: 423-435
[137] Xia L, Wang H, Munk S, Frecker H, Goldberg HJ, Fantus IG,et al. (2007). Reactive oxygen species, PKC-beta1, and PKC-zeta mediate high-glucose-induced vascular endothelial growth factor expression in mesangial cells. American journal of physiology. Endocrinology and metabolism, 293: E1280-1288
[138] Xia L, Wang H, Munk S, Kwan J, Goldberg HJ, Fantus IG,et al. (2008). High glucose activates PKC-zeta and NADPH oxidase through autocrine TGF-beta1 signaling in mesangial cells. American journal of physiology. Renal physiology, 295: F1705-1714
[139] Bey EA, Xu B, Bhattacharjee A, Oldfield CM, Zhao X, Li Q,et al. (2004). Protein kinase C delta is required for p47phox phosphorylation and translocation in activated human monocytes. J Immunol, 173: 5730-5738
[140] Fontayne A, Dang PM, Gougerot-Pocidalo MA, El-Benna J (2002). Phosphorylation of p47phox sites by PKC alpha, beta II, delta, and zeta: effect on binding to p22phox and on NADPH oxidase activation. Biochemistry, 41: 7743-7750
[141] Thornalley PJ, Langborg A, Minhas HS (1999). Formation of glyoxal, methylglyoxal and 3-deoxyglucosone in the glycation of proteins by glucose. Biochem J, 344 Pt 1: 109-116
[142] Dmitriev LF, Dugin SF (2007). Aldehydes and disturbance of carbohydrate metabolism: some consequences and possible approaches to its normalization. Arch Physiol Biochem, 113: 87-95
[143] Allaman I, Belanger M, Magistretti PJ (2015). Methylglyoxal, the dark side of glycolysis. Front Neurosci, 9: 23
[144] Maessen DE, Stehouwer CD, Schalkwijk CG (2015). The role of methylglyoxal and the glyoxalase system in diabetes and other age-related diseases. Clin Sci (Lond), 128: 839-861
[145] Queisser MA, Yao D, Geisler S, Hammes HP, Lochnit G, Schleicher ED,et al. (2010). Hyperglycemia impairs proteasome function by methylglyoxal. Diabetes, 59: 670-678
[146] Wolff SP, Jiang ZY, Hunt JV (1991). Protein glycation and oxidative stress in diabetes mellitus and ageing. Free Radic Biol Med, 10: 339-352
[147] Tomlinson DR, Gardiner NJ (2008). Glucose neurotoxicity. Nat Rev Neurosci, 9: 36-45
[148] Gawlowski T, Stratmann B, Stork I, Engelbrecht B, Brodehl A, Niehaus K,et al. (2009). Heat shock protein 27 modification is increased in the human diabetic failing heart. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme, 41: 594-599
[149] Schalkwijk CG, van Bezu J, van der Schors RC, Uchida K, Stehouwer CD, van Hinsbergh VW (2006). Heat-shock protein 27 is a major methylglyoxal-modified protein in endothelial cells. FEBS Lett, 580: 1565-1570
[150] Koga M, Murai J, Morita S, Saito H, Kasayama S (2013). Comparison of annual variability in HbA1c and glycated albumin in patients with type 1 vs. type 2 diabetes mellitus. Journal of diabetes and its complications, 27: 211-213
[151] Hayden MR, Tyagi SC (2002). Islet redox stress: the manifold toxicities of insulin resistance, metabolic syndrome and amylin derived islet amyloid in type 2 diabetes mellitus. JOP : Journal of the pancreas, 3: 86-108
[152] Munoz A, Costa M (2013). Nutritionally mediated oxidative stress and inflammation. Oxid Med Cell Longev, 2013: 610950
[153] Gao L, Mann GE (2009). Vascular NAD(P)H oxidase activation in diabetes: a double-edged sword in redox signalling. Cardiovasc Res, 82: 9-20
[154] Zhang M, Kho AL, Anilkumar N, Chibber R, Pagano PJ, Shah AM,et al. (2006). Glycated proteins stimulate reactive oxygen species production in cardiac myocytes: involvement of Nox2 (gp91phox)-containing NADPH oxidase. Circulation, 113: 1235-1243
[155] Newsholme P, Morgan D, Rebelato E, Oliveira-Emilio HC, Procopio J, Curi R,et al. (2009). Insights into the critical role of NADPH oxidase(s) in the normal and dysregulated pancreatic beta cell. Diabetologia, 52: 2489-2498
[156] Koulajian K, Desai T, Liu GC, Ivovic A, Patterson JN, Tang C,et al. (2013). NADPH oxidase inhibition prevents beta cell dysfunction induced by prolonged elevation of oleate in rodents. Diabetologia, 56: 1078-1087
[157] Weaver JR, Grzesik W, Taylor-Fishwick DA (2015). Inhibition of NADPH oxidase-1 preserves beta cell function. Diabetologia, 58: 113-121
[158] Mira ML, Martinho F, Azevedo MS, Manso CF (1991). Oxidative inhibition of red blood cell ATPases by glyceraldehyde. Biochim Biophys Acta, 1060: 257-261
[159] Wolff SP, Dean RT (1987). Glucose autoxidation and protein modification. The potential role of 'autoxidative glycosylation' in diabetes. Biochem J, 245: 243-250
[160] Nishikawa T, Araki E (2013). Mechanism-based antioxidant therapies promise to prevent diabetic complications? Journal of diabetes investigation, 4: 105-107
[161] Wolff SP (1993). Diabetes mellitus and free radicals. Free radicals, transition metals and oxidative stress in the aetiology of diabetes mellitus and complications. Br Med Bull, 49: 642-652
[162] Tiganis T (2011). Reactive oxygen species and insulin resistance: the good, the bad and the ugly. Trends in pharmacological sciences, 32: 82-89
[163] Bocci V, Zanardi I, Huijberts MS, Travagli V (2014). An integrated medical treatment for type-2 diabetes. Diabetes & metabolic syndrome, 8: 57-61
[164] Giacco F, Brownlee M (2010). Oxidative stress and diabetic complications. Circ Res, 107: 1058-1070
[165] Shaw A, Doherty MK, Mutch NJ, MacRury SM, Megson IL (2014). Endothelial cell oxidative stress in diabetes: a key driver of cardiovascular complications? Biochem Soc Trans, 42: 928-933
[166] Haldar SR, Chakrabarty A, Chowdhury S, Haldar A, Sengupta S, Bhattacharyya M (2015). Oxidative stress-related genes in type 2 diabetes: association analysis and their clinical impact. Biochem Genet, 53: 93-119
[167] Yan LJ (2009). Analysis of oxidative modification of proteins. Curr Protoc Protein Sci, Chapter 14: Unit14 14
[168] Ames BN, Shigenaga MK (1992). Oxidants are a major contributor to aging. Ann N Y Acad Sci, 663: 85-96
[169] Yan LJ, Sohal RS (1998). Mitochondrial adenine nucleotide translocase is modified oxidatively during aging. Proc Natl Acad Sci USA, 95: 12896-12901
[170] Yan LJ, Levine RL, Sohal RS (1997). Oxidative damage during aging targets mitochondrial aconitase. Proc. Natl. Acad. Sci. USA, 94: 11168-11172
[171] Starkov AA (2008). The role of mitochondria in reactive oxygen species metabolism and signaling. Ann N Y Acad Sci, 1147: 37-52
[172] Lenaz G (2012). Mitochondria and reactive oxygen species. Which role in physiology and pathology? Adv Exp Med Biol, 942: 93-136
[173] Pollegioni L, Molla G (2011). New biotech applications from evolved D-amino acid oxidases. Trends Biotechnol, 29: 276-283
[174] Fang J, Sawa T, Akaike T, Maeda H (2002). Tumor-targeted delivery of polyethylene glycol-conjugated D-amino acid oxidase for antitumor therapy via enzymatic generation of hydrogen peroxide. Cancer Res, 62: 3138-3143
[175] Haskew-Layton RE, Payappilly JB, Smirnova NA, Ma TC, Chan KK, Murphy TH,et al. (2010). Controlled enzymatic production of astrocytic hydrogen peroxide protects neurons from oxidative stress via an Nrf2-independent pathway. Proc Natl Acad Sci U S A, 107: 17385-17390
[176] Bando Y, Aki K (1991). Mechanisms of generation of oxygen radicals and reductive mobilization of ferritin iron by lipoamide dehydrogenase. J Biochem (Tokyo), 109: 450-454
[177] Sreider CM, Grinblat L, Stoppani AO (1990). Catalysis of nitrofuran redox-cycling and superoxide anion production by heart lipoamide dehydrogenase. Biochem Pharmacol, 40: 1849-1857
[178] Gazaryan IG, Krasnikov BF, Ashby GA, Thorneley RN, Kristal BS, Brown AM (2002). Zinc is a potent inhibitor of thiol oxidoreductase activity and stimulates reactive oxygen species production by lipoamide dehydrogenase. J Biol Chem, 277: 10064-10072
[179] Tahara EB, Barros MH, Oliveira GA, Netto LE, Kowaltowski AJ (2007). Dihydrolipoyl dehydrogenase as a source of reactive oxygen species inhibited by caloric restriction and involved in Saccharomyces cerevisiae aging. Faseb J, 21: 274-283
[180] Zhang Q, Zou P, Zhan H, Zhang M, Zhang L, Ge RS,et al. (2011). Dihydrolipoamide dehydrogenase and cAMP are associated with cadmium-mediated Leydig cell damage. Toxicol Lett, 205: 183-189
[181] Kareyeva AV, Grivennikova VG, Cecchini G, Vinogradov AD (2011). Molecular identification of the enzyme responsible for the mitochondrial NADH-supported ammonium-dependent hydrogen peroxide production. FEBS Lett, 585: 385-389
[182] Kareyeva AV, Grivennikova VG, Vinogradov AD (2012). Mitochondrial hydrogen peroxide production as determined by the pyridine nucleotide pool and its redox state. Biochim Biophys Acta
[183] Quinlan CL, Goncalves RL, Hey-Mogensen M, Yadava N, Bunik VI, Brand MD (2014). The 2-Oxoacid Dehydrogenase Complexes in Mitochondria Can Produce Superoxide/Hydrogen Peroxide at Much Higher Rates than Complex I. J Biol Chem
[184] Tretter L, Adam-Vizi V (2005). Alpha-ketoglutarate dehydrogenase: a target and generator of oxidative stress. Philos Trans R Soc Lond B Biol Sci, 360: 2335-2345
[185] Starkov AA, Fiskum G, Chinopoulos C, Lorenzo BJ, Browne SE, Patel MS,et al. (2004). Mitochondrial alpha-ketoglutarate dehydrogenase complex generates reactive oxygen species. J Neurosci, 24: 7779-7788
[186] Ambrus A, Tretter L, Adam-Vizi V (2009). Inhibition of the alpha-ketoglutarate dehydrogenase-mediated reactive oxygen species generation by lipoic acid. J Neurochem, 109 Suppl 1: 222-229
[187] Ambrus A, Torocsik B, Tretter L, Ozohanics O, Adam-Vizi V (2011). Stimulation of reactive oxygen species generation by disease-causing mutations of lipoamide dehydrogenase. Hum Mol Genet, 20: 2984-2995
[188] Manea A (2010). NADPH oxidase-derived reactive oxygen species: involvement in vascular physiology and pathology. Cell Tissue Res, 342: 325-339
[189] Bylund J, Brown KL, Movitz C, Dahlgren C, Karlsson A (2010). Intracellular generation of superoxide by the phagocyte NADPH oxidase: how, where, and what for? Free Radic Biol Med, 49: 1834-1845
[190] Harrison R (2004). Physiological roles of xanthine oxidoreductase. Drug Metab Rev, 36: 363-375
[191] Agarwal A, Banerjee A, Banerjee UC (2011). Xanthine oxidoreductase: a journey from purine metabolism to cardiovascular excitation-contraction coupling. Crit Rev Biotechnol, 31: 264-280
[192] Radi R (2013). Protein Tyrosine Nitration: Biochemical Mechanisms and Structural Basis of Functional Effects. Acc Chem Res, 46: 550-559
[193] Radi R, Cassina A, Hodara R, Quijano C, Castro L (2002). Peroxynitrite reactions and formation in mitochondria. Free Radic Biol Med, 33: 1451-1464
[194] Landino LM (2008). Protein thiol modification by peroxynitrite anion and nitric oxide donors. Methods Enzymol, 440: 95-109
[195] Singh IN, Sullivan PG, Hall ED (2007). Peroxynitrite-mediated oxidative damage to brain mitochondria: Protective effects of peroxynitrite scavengers. J Neurosci Res, 85: 2216-2223
[196] Alvarez B, Radi R (2003). Peroxynitrite reactivity with amino acids and proteins. Amino Acids, 25: 295-311
[197] Son SM (2012). Reactive oxygen and nitrogen species in pathogenesis of vascular complications of diabetes. Diabetes Metab J, 36: 190-198
[198] Stavniichuk R, Shevalye H, Lupachyk S, Obrosov A, Groves JT, Obrosova IG,et al. (2014). Peroxynitrite and protein nitration in the pathogenesis of diabetic peripheral neuropathy. Diabetes/metabolism research and reviews, 30: 669-678
[199] Hung LM, Huang JP, Liao JM, Yang MH, Li DE, Day YJ,et al. (2014). Insulin renders diabetic rats resistant to acute ischemic stroke by arresting nitric oxide reaction with superoxide to form peroxynitrite. J Biomed Sci, 21: 92
[200] Li Y, Qi J, Liu K, Li B, Wang H, Jia J (2010). Peroxynitrite-induced nitration of cyclooxygenase-2 and inducible nitric oxide synthase promotes their binding in diabetic angiopathy. Mol Med, 16: 335-342
[201] Liang JH, Li YN, Qi JS, Jia XX (2010). Peroxynitrite-induced protein nitration is responsible for renal mitochondrial damage in diabetic rat. J Endocrinol Invest, 33: 140-146
[202] Wu CH, Hsieh HT, Lin JA, Yen GC (2013). Alternanthera paronychioides protects pancreatic beta-cells from glucotoxicity by its antioxidant, antiapoptotic and insulin secretagogue actions. Food Chem, 139: 362-370
[203] Zhao WC, Zhang B, Liao MJ, Zhang WX, He WY, Wang HB,et al. (2014). Curcumin ameliorated diabetic neuropathy partially by inhibition of NADPH oxidase mediating oxidative stress in the spinal cord. Neurosci Lett, 560: 81-85
[204] Alam MM, Meerza D, Naseem I (2014). Protective effect of quercetin on hyperglycemia, oxidative stress and DNA damage in alloxan induced type 2 diabetic mice. Life Sci, 109: 8-14
[205] Niture NT, Ansari AA, Naik SR (2014). Anti-hyperglycemic activity of rutin in streptozotocin-induced diabetic rats: an effect mediated through cytokines, antioxidants and lipid biomarkers. Indian journal of experimental biology, 52: 720-727
[206] Erejuwa OO, Sulaiman SA, Wahab MS, Sirajudeen KN, Salleh MS, Gurtu S (2010). Antioxidant protection of Malaysian tualang honey in pancreas of normal and streptozotocin-induced diabetic rats. Annales d'endocrinologie, 71: 291-296
[207] Parveen K, Khan MR, Mujeeb M, Siddiqui WA (2010). Protective effects of Pycnogenol on hyperglycemia-induced oxidative damage in the liver of type 2 diabetic rats. Chem Biol Interact, 186: 219-227
[208] Ku CR, Lee HJ, Kim SK, Lee EY, Lee MK, Lee EJ (2012). Resveratrol prevents streptozotocin-induced diabetes by inhibiting the apoptosis of pancreatic beta-cell and the cleavage of poly (ADP-ribose) polymerase. Endocrine journal, 59: 103-109
[209] Chanpoo M, Petchpiboonthai H, Panyarachun B, Anupunpisit V (2010). Effect of curcumin in the amelioration of pancreatic islets in streptozotocin-induced diabetic mice. Journal of the Medical Association of Thailand = Chotmaihet thangphaet, 93 Suppl 6: S152-159
[210] Ding Y, Zhang Z, Dai X, Jiang Y, Bao L, Li Y,et al. (2013). Grape seed proanthocyanidins ameliorate pancreatic beta-cell dysfunction and death in low-dose streptozotocin- and high-carbohydrate/high-fat diet-induced diabetic rats partially by regulating endoplasmic reticulum stress. Nutrition & metabolism, 10: 51
[211] Ola MS, Aleisa AM, Al-Rejaie SS, Abuohashish HM, Parmar MY, Alhomida AS,et al. (2014). Flavonoid, morin inhibits oxidative stress, inflammation and enhances neurotrophic support in the brain of streptozotocin-induced diabetic rats. Neurol Sci, 35: 1003-1008
[212] Hirst J, Carroll J, Fearnley IM, Shannon RJ, Walker JE (2003). The nuclear encoded subunits of complex I from bovine heart mitochondria. Biochim Biophys Acta, 1604: 135-150
[213] Carroll J, Fearnley IM, Skehel JM, Shannon RJ, Hirst J, Walker JE (2006). Bovine complex I is a complex of 45 different subunits. J Biol Chem, 281: 32724-32727
[214] Carroll J, Ding S, Fearnley IM, Walker JE (2013). Post-translational modifications near the quinone binding site of mammalian complex I. J Biol Chem, 288: 24799-24808
[215] Andrews B, Carroll J, Ding S, Fearnley IM, Walker JE (2013). Assembly factors for the membrane arm of human complex I. Proc Natl Acad Sci U S A, 110: 18934-18939
[216] Hirst J (2013). Mitochondrial complex I. Annu Rev Biochem, 82: 551-575
[217] Murphy MP (2009). How mitochondria produce reactive oxygen species. Biochem J, 417: 1-13
[218] St-Pierre J, Buckingham JA, Roebuck SJ, Brand MD (2002). Topology of superoxide production from different sites in the mitochondrial electron transport chain. J Biol Chem, 277: 44784-44790
[219] Coughlan MT, Thorburn DR, Penfold SA, Laskowski A, Harcourt BE, Sourris KC,et al. (2009). RAGE-induced cytosolic ROS promote mitochondrial superoxide generation in diabetes. J Am Soc Nephrol, 20: 742-752
[220] Papa S, Sardanelli AM, Scacco S, Petruzzella V, Technikova-Dobrova Z, Vergari R,et al. (2002). The NADH: ubiquinone oxidoreductase (complex I) of the mammalian respiratory chain and the cAMP cascade. J Bioenerg Biomembr, 34: 1-10
[221] Hirst J, King MS, Pryde KR (2008). The production of reactive oxygen species by complex I. Biochem Soc Trans, 36: 976-980
[222] Bridges HR, Jones AJ, Pollak MN, Hirst J (2014). Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria. Biochem J, 462: 475-487
[223] Fontaine E (2014). Metformin and respiratory chain complex I: the last piece of the puzzle? Biochem J, 463: e3-5
[224] Matsuzaki S, Humphries KM (2015). Selective inhibition of deactivated mitochondrial complex I by biguanides. Biochemistry, 54: 2011-2021
[225] Hur JH, Bahadorani S, Graniel J, Koehler CL, Ulgherait M, Rera M,et al. (2013). Increased longevity mediated by yeast NDI1 expression in Drosophila intestinal stem and progenitor cells. Aging, 5: 662-681
[226] Cho J, Hur JH, Graniel J, Benzer S, Walker DW (2012). Expression of yeast NDI1 rescues a Drosophila complex I assembly defect. PLoS One, 7: e50644
[227] Marella M, Seo BB, Nakamaru-Ogiso E, Greenamyre JT, Matsuno-Yagi A, Yagi T (2008). Protection by the NDI1 gene against neurodegeneration in a rotenone rat model of Parkinson's disease. PLoS One, 3: e1433
[228] Santidrian AF, Matsuno-Yagi A, Ritland M, Seo BB, LeBoeuf SE, Gay LJ,et al. (2013). Mitochondrial complex I activity and NAD+/NADH balance regulate breast cancer progression. J Clin Invest, 123: 1068-1081
[229] Luo X, Li R, Yan LJ (2015). Roles of Pyruvate, NADH, and Mitochondrial Complex I in Redox Balance and Imbalance in β Cell Function and Dysfunction. Journal of diabetes research
[230] Brunmair B, Staniek K, Gras F, Scharf N, Althaym A, Clara R,et al. (2004). Thiazolidinediones, like metformin, inhibit respiratory complex I: a common mechanism contributing to their antidiabetic actions? Diabetes, 53: 1052-1059
[231] Sliwinska A, Drzewoski J (2015). Molecular Action of Metformin in Hepatocytes: an Updated Insight. Current diabetes reviews
[232] Owen MR, Doran E, Halestrap AP (2000). Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J, 348 Pt 3: 607-614
[233] Masini M, Anello M, Bugliani M, Marselli L, Filipponi F, Boggi U,et al. (2014). Prevention by metformin of alterations induced by chronic exposure to high glucose in human islet beta cells is associated with preserved ATP/ADP ratio. Diabetes research and clinical practice, 104: 163-170
[234] Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F (2012). Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond), 122: 253-270
[235] Pernicova I, Korbonits M (2014). Metformin--mode of action and clinical implications for diabetes and cancer. Nature reviews. Endocrinology, 10: 143-156
[236] Jenkins Y, Sun TQ, Markovtsov V, Foretz M, Li W, Nguyen H,et al. (2013). AMPK activation through mitochondrial regulation results in increased substrate oxidation and improved metabolic parameters in models of diabetes. PLoS One, 8: e81870
[237] Hinke SA, Martens GA, Cai Y, Finsi J, Heimberg H, Pipeleers D,et al. (2007). Methyl succinate antagonises biguanide-induced AMPK-activation and death of pancreatic beta-cells through restoration of mitochondrial electron transfer. Br J Pharmacol, 150: 1031-1043
[238] Hopson NE, Sack WA (1973). Cellular phosphorus changes under low-carbon stress. J Water Pollut Control Fed, 45: 85-96
[239] Kosanam H, Thai K, Zhang Y, Advani A, Connelly KA, Diamandis EP,et al. (2014). Diabetes induces lysine acetylation of intermediary metabolism enzymes in the kidney. Diabetes, 63: 2432-2439
[240] Frizzell N, Thomas SA, Carson JA, Baynes JW (2012). Mitochondrial stress causes increased succination of proteins in adipocytes in response to glucotoxicity. Biochem J, 445: 247-254
[241] Fritz KS, Galligan JJ, Hirschey MD, Verdin E, Petersen DR (2012). Mitochondrial acetylome analysis in a mouse model of alcohol-induced liver injury utilizing SIRT3 knockout mice. J Proteome Res, 11: 1633-1643
[242] Fritz KS, Green MF, Petersen DR, Hirschey MD (2013). Ethanol metabolism modifies hepatic protein acylation in mice. PLoS One, 8: e75868
[243] Verdin E, Ott M (2015). 50 years of protein acetylation: from gene regulation to epigenetics, metabolism and beyond. Nature reviews. Molecular cell biology, 16: 258-264
[244] Cohn RM, Roth KS (1996) Biochemistry and diabetes, Williams & Wilkins, Baltimore
[245] Paik WK, Pearson D, Lee HW, Kim S (1970). Nonenzymatic acetylation of histones with acetyl-CoA. Biochim Biophys Acta, 213: 513-522
[246] Ramponi G, Manao G, Camici G (1975). Nonenzymatic acetylation of histones with acetyl phosphate and acetyl adenylate. Biochemistry, 14: 2681-2685
[247] Baeza J, Smallegan MJ, Denu JM (2015). Site-specific reactivity of nonenzymatic lysine acetylation. ACS Chem Biol, 10: 122-128
[248] Wagner GR, Payne RM (2013). Widespread and enzyme-independent Nepsilon-acetylation and Nepsilon-succinylation of proteins in the chemical conditions of the mitochondrial matrix. J Biol Chem, 288: 29036-29045
[249] Muoio DM (2014). Metabolic inflexibility: when mitochondrial indecision leads to metabolic gridlock. Cell, 159: 1253-1262
[250] Morris BJ (2013). Seven sirtuins for seven deadly diseases of aging. Free Radic Biol Med, 56: 133-171
[251] Caton PW, Richardson SJ, Kieswich J, Bugliani M, Holland ML, Marchetti P,et al. (2013). Sirtuin 3 regulates mouse pancreatic beta cell function and is suppressed in pancreatic islets isolated from human type 2 diabetic patients. Diabetologia, 56: 1068-1077
[252] Michan S (2014). Calorie restriction and NAD(+)/sirtuin counteract the hallmarks of aging. Front Biosci (Landmark Ed), 19: 1300-1319
[253] Yang T, Sauve AA (2006). NAD metabolism and sirtuins: metabolic regulation of protein deacetylation in stress and toxicity. AAPS J, 8: E632-E643
[254] Wang Y (2014). Molecular Links between Caloric Restriction and Sir2/SIRT1 Activation. Diabetes Metab J, 38: 321-329
[255] Ramis MR, Esteban S, Miralles A, Tan DX, Reiter RJ (2015). Caloric restriction, resveratrol and melatonin: Role of SIRT1 and implications for aging and related-diseases. Mech Ageing Dev, 146-148C: 28-41
[256] Kincaid B, Bossy-Wetzel E (2013). Forever young: SIRT3 a shield against mitochondrial meltdown, aging, and neurodegeneration. Front Aging Neurosci, 5: 48
[257] Canto C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC,et al. (2009). AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature, 458: 1056-1060
[258] Kim HJ, Kim JH, Noh S, Hur HJ, Sung MJ, Hwang JT,et al. (2011). Metabolomic analysis of livers and serum from high-fat diet induced obese mice. J Proteome Res, 10: 722-731
[259] Jing E, Emanuelli B, Hirschey MD, Boucher J, Lee KY, Lombard D,et al. (2011). Sirtuin-3 (Sirt3) regulates skeletal muscle metabolism and insulin signaling via altered mitochondrial oxidation and reactive oxygen species production. Proc Natl Acad Sci U S A, 108: 14608-14613
[260] Hirschey MD, Shimazu T, Jing E, Grueter CA, Collins AM, Aouizerat B,et al. (2011). SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome. Mol Cell, 44: 177-190
[261] Wang RH, Kim HS, Xiao C, Xu X, Gavrilova O, Deng CX (2011). Hepatic Sirt1 deficiency in mice impairs mTorc2/Akt signaling and results in hyperglycemia, oxidative damage, and insulin resistance. J Clin Invest, 121: 4477-4490
[262] Cerutti R, Pirinen E, Lamperti C, Marchet S, Sauve AA, Li W,et al. (2014). NAD(+)-dependent activation of Sirt1 corrects the phenotype in a mouse model of mitochondrial disease. Cell Metab, 19: 1042-1049
[263] Balestrieri ML, Rizzo MR, Barbieri M, Paolisso P, D'Onofrio N, Giovane A,et al. (2015). Sirtuin 6 expression and inflammatory activity in diabetic atherosclerotic plaques: effects of incretin treatment. Diabetes, 64: 1395-1406
[264] de Kreutzenberg SV, Ceolotto G, Papparella I, Bortoluzzi A, Semplicini A, Dalla Man C,et al. (2010). Downregulation of the longevity-associated protein sirtuin 1 in insulin resistance and metabolic syndrome: potential biochemical mechanisms. Diabetes, 59: 1006-1015
[265] Hou X, Zeng H, He X, Chen JX (2015). Sirt3 is essential for apelin-induced angiogenesis in post-myocardial infarction of diabetes. J Cell Mol Med, 19: 53-61
[266] Herskovits AZ, Guarente L (2013). Sirtuin deacetylases in neurodegenerative diseases of aging. Cell Res, 23: 746-758
[267] Turkmen K, Karagoz A, Kucuk A (2014). Sirtuins as novel players in the pathogenesis of diabetes mellitus. World J Diabetes, 5: 894-900
[268] Hassa PO, Haenni SS, Elser M, Hottiger MO (2006). Nuclear ADP-ribosylation reactions in mammalian cells: where are we today and where are we going? Microbiol Mol Biol Rev, 70: 789-829
[269] Kaelin WG, Jr., McKnight SL (2013). Influence of metabolism on epigenetics and disease. Cell, 153: 56-69
[270] Mouchiroud L, Houtkooper RH, Auwerx J (2013). NAD(+) metabolism: a therapeutic target for age-related metabolic disease. Critical reviews in biochemistry and molecular biology, 48: 397-408
[271] Huynh FK, Hershberger KA, Hirschey MD (2013). Targeting sirtuins for the treatment of diabetes. Diabetes Manag (Lond), 3: 245-257
[272] Kitada M, Kume S, Kanasaki K, Takeda-Watanabe A, Koya D (2013). Sirtuins as possible drug targets in type 2 diabetes. Curr Drug Targets, 14: 622-636
[273] Lin H, Su X, He B (2012). Protein lysine acylation and cysteine succination by intermediates of energy metabolism. ACS Chem Biol, 7: 947-960
[274] Piroli GG, Manuel AM, Walla MD, Jepson MJ, Brock JW, Rajesh MP,et al. (2014). Identification of protein succination as a novel modification of tubulin. Biochem J, 462: 231-245
[275] Merkley ED, Metz TO, Smith RD, Baynes JW, Frizzell N (2014). The succinated proteome. Mass Spectrom Rev, 33: 98-109
[276] Yang M, Ternette N, Su H, Dabiri R, Kessler BM, Adam J,et al. (2014). The Succinated Proteome of FH-Mutant Tumours. Metabolites, 4: 640-654
[277] Blatnik M, Thorpe SR, Baynes JW (2008). Succination of proteins by fumarate: mechanism of inactivation of glyceraldehyde-3-phosphate dehydrogenase in diabetes. Ann N Y Acad Sci, 1126: 272-275
[278] Nagai R, Brock JW, Blatnik M, Baatz JE, Bethard J, Walla MD,et al. (2007). Succination of protein thiols during adipocyte maturation: a biomarker of mitochondrial stress. J Biol Chem, 282: 34219-34228
[279] Zheng L, Cardaci S, Jerby L, MacKenzie ED, Sciacovelli M, Johnson TI,et al. (2015). Fumarate induces redox-dependent senescence by modifying glutathione metabolism. Nat Commun, 6: 6001
[280] Yan LJ (2014). Positive oxidative stress in aging and aging-related disease tolerance. Redox Biology, 2: 165-169
[281] Yan LJ (2014). Protein Redox Modification as a Cellular Defense Mechanism against Tissue Ischemic Injury. Oxidative Medicine and Cellular Longevity, 2014: 12
[282] Winterbourn CC, Hampton MB (2008). Thiol chemistry and specificity in redox signaling. Free Radic Biol Med, 45: 549-561
[283] Ying J, Clavreul N, Sethuraman M, Adachi T, Cohen RA (2007). Thiol oxidation in signaling and response to stress: detection and quantification of physiological and pathophysiological thiol modifications. Free Radic Biol Med, 43: 1099-1108
[284] Forman HJ, Fukuto JM, Torres M (2004). Redox signaling: thiol chemistry defines which reactive oxygen and nitrogen species can act as second messengers. Am J Physiol Cell Physiol, 287: C246-256
[285] Fomenko DE, Marino SM, Gladyshev VN (2008). Functional diversity of cysteine residues in proteins and unique features of catalytic redox-active cysteines in thiol oxidoreductases. Molecules and cells, 26: 228-235
[286] Biswas S, Chida AS, Rahman I (2006). Redox modifications of protein-thiols: emerging roles in cell signaling. Biochem Pharmacol, 71: 551-564
[287] Cai Z, Yan LJ (2013). Protein oxidative modifications: Beneficial roles in disease and health. Journal of Biochemical and Pharmacological Research, 1: 15-26
[288] White H, Venkatesh B (2011). Clinical review: ketones and brain injury. Crit Care, 15: 219
[289] Cotter DG, Schugar RC, Crawford PA (2013). Ketone body metabolism and cardiovascular disease. Am J Physiol Heart Circ Physiol, 304: H1060-1076
[1] Tseng Chin-Hsiao. Metformin and the Risk of Dementia in Type 2 Diabetes Patients[J]. Aging and disease, 2019, 10(1): 37-48.
[2] Changhong Ren, Hang Wu, Dongjie Li, Yong Yang, Yuan Gao, Yunneng Jizhang, Dachuan Liu, Xunming Ji, Xuxiang Zhang. Remote Ischemic Conditioning Protects Diabetic Retinopathy in Streptozotocin-induced Diabetic Rats via Anti-Inflammation and Antioxidation[J]. Aging and disease, 2018, 9(6): 1122-1133.
[3] Maxime Fournet, Frederic Bonte, Alexis Desmouliere. Glycation Damage: A Possible Hub for Major Pathophysiological Disorders and Aging[J]. Aging and disease, 2018, 9(5): 880-900.
[4] Li Wenjun, Roy Choudhury Gourav, Winters Ali, Prah Jude, Lin Wenping, Liu Ran, Yang Shao-Hua. Hyperglycemia Alters Astrocyte Metabolism and Inhibits Astrocyte Proliferation[J]. Aging and disease, 2018, 9(4): 674-684.
[5] Yang Yao-Chih, Tsai Cheng-Yen, Chen Chien-Lin, Kuo Chia-Hua, Hou Chien-Wen, Cheng Shi-Yann, Aneja Ritu, Huang Chih-Yang, Kuo Wei-Wen. Pkcδ Activation is Involved in ROS-Mediated Mitochondrial Dysfunction and Apoptosis in Cardiomyocytes Exposed to Advanced Glycation End Products (Ages)[J]. Aging and disease, 2018, 9(4): 647-663.
[6] Zhang Jun, Liu Kaiyin, Elmadhoun Omar, Ji Xunming, Duan Yunxia, Shi Jingfei, He Xiaoduo, Liu Xiangrong, Wu Di, Che Ruiwen, Geng Xiaokun, Ding Yuchuan. Synergistically Induced Hypothermia and Enhanced Neuroprotection by Pharmacological and Physical Approaches in Stroke[J]. Aging and disease, 2018, 9(4): 578-589.
[7] Zhen Jie, Lin Tong, Huang Xiaochen, Zhang Huiqiang, Dong Shengqi, Wu Yifan, Song Linlin, Xiao Rong, Yuan Linhong. Association of ApoE Genetic Polymorphism and Type 2 Diabetes with Cognition in Non-Demented Aging Chinese Adults: A Community Based Cross-Sectional Study[J]. Aging and disease, 2018, 9(3): 346-357.
[8] Yan Tao, Venkat Poornima, Chopp Michael, Zacharek Alex, Yu Peng, Ning Ruizhuo, Qiao Xiaoxi, Kelley Mark R., Chen Jieli. APX3330 Promotes Neurorestorative Effects after Stroke in Type One Diabetic Rats[J]. Aging and disease, 2018, 9(3): 453-466.
[9] Zheng Hong, Wu Jinzi, Jin Zhen, Yan Liang-Jun. Potential Biochemical Mechanisms of Lung Injury in Diabetes[J]. Aging and disease, 2017, 8(1): 7-16.
[10] Salminen Antero,Kaarniranta Kai,Kauppinen Anu. Hypoxia-Inducible Histone Lysine Demethylases: Impact on the Aging Process and Age-Related Diseases[J]. A&D, 2016, 7(2): 180-200.
[11] João M N. Duarte. Metabolic Alterations Associated to Brain Dysfunction in Diabetes[J]. A&D, 2015, 6(5): 304-321.
[12] Yi Zhou,Rong Fang,Li-Hua Liu,Sheng-Di Chen,Hui-Dong Tang. Clinical Characteristics for the Relationship between Type-2 Diabetes Mellitus and Cognitive Impairment: A Cross-Sectional Study[J]. A&D, 2015, 6(4): 236-244.
[13] Ahmed H Abdelhafiz,Alan J Sinclair. Low HbA1c and Increased Mortality Risk-is Frailty a Confounding Factor?[J]. A&D, 2015, 6(4): 262-270.
[14] David Blokh,Ilia Stambler. Estimation of Heterogeneity in Diagnostic Parameters of Age-related Diseases[J]. Aging and Disease, 2014, 5(4): 218-225.
[15] Chandan Prasad,Victorine Imrhan,Francesco Marotta,Shanil Juma,Parakat Vijayagopal. Lifestyle and Advanced Glycation End Products (AGEs) Burden: Its Relevance to Healthy Aging[J]. Aging and Disease, 2014, 5(3): 212-217.
Full text



Copyright © 2014 Aging and Disease, All Rights Reserved.
Address: Aging and Disease Editorial Office 3400 Camp Bowie Boulevard Fort Worth, TX76106 USA
Fax: (817) 735-0408 E-mail:
Powered by Beijing Magtech Co. Ltd