Experimental Models of Oxidative Stress Related to Cardiovascular Diseases and Diabetes

  • Maria D. Mesa
  • Concepcion M. Aguilera
  • Angel GilEmail author
Part of the Oxidative Stress in Applied Basic Research and Clinical Practice book series (OXISTRESS)


In this chapter we summarize the commonly used animal models employed in the study of cardiovascular diseases and diabetes, two of the most prevalent oxidative stress-induced diseases. A number of animal models of atherosclerosis support the notion that reactive oxygen and nitrogen species have a causal role in atherosclerosis and other vascular diseases. Experimental atherosclerosis is induced by specific lipid-rich diets or in genetically modified strains that cause hyperlipidemia and cardiovascular diseases. Rabbits are the animals most used for the study of atherosclerosis due to their facility to generate atherosclerosis with defined fat-enriched diets. Indeed, a myocardial infarction-prone derived from Watanabe LDL receptor-deficient rabbit strain is also used. Since mice are highly resistant to atherosclerosis, only genetically modified mice, such as the knock-out mouse for apo E, LDL receptor or both, have been used. In addition, reactive species also contribute to the pathogenesis of β-cell destruction in type 1 diabetes and β-dysfunction on type 2 diabetes. Alloxan induces the formation of reactive oxygen species and provokes β-cell death in type 1 and 2 diabetes mellitus, while streptozotocin involves DNA alkylation and fragmentation. Zucker rats are the most important animal models of genetic obesity and metabolic syndrome. Finally, genetically engineered diabetic models include transgenic and knock-out mice.


Atherosclerosis Animal models Cardiovascular diseases Diabetes Oxidative stress 


  1. 1.
    Davies KJ (1995). Oxidative stress: the paradox of aerobic life. Biochem Soc Symp 61:1–31.PubMedGoogle Scholar
  2. 2.
    Rees DA, Alcolado JC (2005). Animal models of diabetes mellitus. Diabet Med 22:359–370.PubMedCrossRefGoogle Scholar
  3. 3.
    Heistad DD, Wakisaka Y, Miller J, Chu Y, Pena-Silva R (2009). Novel aspects of oxidative stress in cardiovascular diseases. Circ J 73:201–207.PubMedCrossRefGoogle Scholar
  4. 4.
    Tedgui A, Mallat Z (2006). Cytokines in atherosclerosis: pathogenic and regulatory pathways. Physiol Rev 86:515–581.PubMedCrossRefGoogle Scholar
  5. 5.
    Beaudeux JL, Giral P, Bruckert E, Foglietti MJ, Chapman MJ (2004). Matrix metalloproteinases, inflammation and atherosclerosis: therapeutic perspectives. Clin Chem Lab Med 42:121–131.PubMedCrossRefGoogle Scholar
  6. 6.
    Shiomi M, Fan J (2008). Unstable coronary plaques and cardiac events in myocardial infarction-prone Watanabe heritable hyperlipidemic rabbits: questions and quandaries. Curr Opin Lipidol 19:631–636.PubMedCrossRefGoogle Scholar
  7. 7.
    Madamanchi NR, Hakim ZS, Runge MS (2005). Oxidative stress in atherogenesis and arterial thrombosis: the disconnect between cellular studies and clinical outcomes. J Thromb Haemost 3:254–267.PubMedCrossRefGoogle Scholar
  8. 8.
    Granada JF, Kaluza GL, Wilensky RL et al. (2009). Porcine models of coronary atherosclerosis and vulnerable plaque for imaging and interventional research. EuroIntervention 5:140–148.PubMedCrossRefGoogle Scholar
  9. 9.
    Fernandez ML, Volek JS (2006). Guinea pigs: a suitable animal model to study lipoprotein metabolism, atherosclerosis and inflammation. Nutr Metab (Lond) 27:3:17.Google Scholar
  10. 10.
    Yanni AE (2004). The laboratory rabbit: an animal model of atherosclerosis research. Lab Anim 38:246–256.PubMedCrossRefGoogle Scholar
  11. 11.
    Hayashi T, Fukuto JM, Ignaro LJ, Chadhuri G (1992). Basal release of nitric oxide from aortic rings is greater in female rabbits than in male rabbits: implications for atherosclerosis. Proceedings of the National Academy of Sciences of the United States of America 89:11259–11263.PubMedCrossRefGoogle Scholar
  12. 12.
    Pfister SL (2006). Aortic thromboxane receptor deficiency alters vascular reactivity in cholesterol-fed rabbits. Atherosclerosis 189:358–363.PubMedCrossRefGoogle Scholar
  13. 13.
    Zulli A, Buxton BF, Black MJ, Hare DL (2005). CD34 Class III positive cells are present in atherosclerotic plaques of the rabbit model of atherosclerosis. Histochem Cell Biol 124:517–522.PubMedCrossRefGoogle Scholar
  14. 14.
    Shakuto S, Oshima K, Tsuchiya E (2005). Glimepiride exhibits prophylactic effect on atherosclerosis in cholesterol-fed rabbits. Atherosclerosis 182:209–217.PubMedCrossRefGoogle Scholar
  15. 15.
    Zhang ZS, Jame AE, Huang Y et al. (2005). Quantification and characterization of aortic cholesterol in rabbits fed a high-cholesterol diet. Int J Food Sci Nutr 56:359–366.PubMedCrossRefGoogle Scholar
  16. 16.
    Ozer NK, Negis Y, Aytan N et al. (2006). Vitamin E inhibits CD36 scavenger receptor expression in hypercholesterolemic rabbits. Atherosclerosis 184:15–20.PubMedCrossRefGoogle Scholar
  17. 17.
    Juzwiak S, Wojcicki j, Mokrzycki K, et al. (2005). Effect of quercetin on experimental hyperlipidemia and atherosclerosis in rabbits. Pharmacol Rep 57:604–609.PubMedGoogle Scholar
  18. 18.
    Quiles JL, Mesa MD, Ramirez-Tortosa CL et al. (2002). Curcuma longa extract supplementation reduces oxidative stress and attenuates aortic fatty streak development in rabbits. Arterioscl Thromb Vasc Biol 22:1225–1231.PubMedCrossRefGoogle Scholar
  19. 19.
    Aguilera CM, Ramirez-Tortosa MC, Mesa MD, Ramirez-Tortosa CL, Gil A (2002). Sunflower, virgin olive and fish oils differentially affect the progression of aortic lesions in rabbits with experimental atherosclerosis. Atherosclerosis 162:335–344.PubMedCrossRefGoogle Scholar
  20. 20.
    Ramirez-Tortosa MC, Mesa MD, Aguilera MC et al. (1999). Oral administration of a turmeric extract inhibits LDL oxidation and has hypocholesterolemic effect in rabbits with experimental atherosclerosis. Atherosclerosis 147:371–378.PubMedCrossRefGoogle Scholar
  21. 21.
    Ramirez-Tortosa MC, Aguilera CM, Quiles JL, Gil A (1998). Influence of dietary lipids on lipoprotein composition and LDL Cu(2+)-induced oxidation in rabbits with experimental atherosclerosis. Biofactors 8:79–85.PubMedCrossRefGoogle Scholar
  22. 22.
    Quiles JL, Aguilera C, Mesa MD et al. (1998). An ethanolic-aqueous extract of Curcuma longa decreases the susceptibility of liver microsomes and mitochondria to lipid peroxidation in atherosclerotic rabbits. Biofactors 8:51–57.PubMedCrossRefGoogle Scholar
  23. 23.
    Mesa MD, Aguilera CM, Ramirez-Tortosa CL et al. (2003). Oral administration of a turmeric extract inhibits erythrocyte and liver microsome membrane oxidation in rabbits fed with an atherogenic diet. Nutrition 19:800–804.PubMedCrossRefGoogle Scholar
  24. 24.
    Ramirez-Tortosa MC, Quiles JL, Gil A, Mataix J (1997). Rabbit liver mitochondria coenzyme Q10 and hydroperoxide levels: an experimental model of atherosclerosis. Mol Aspects Med 18:233–236.CrossRefGoogle Scholar
  25. 25.
    Aguilera CM, Mesa MD, Ramirez-Tortosa MC, Quiles JL, Gil A (2003). Virgin oil and fish oils enhance the hepatic antioxidant defense system in atherosclerotic rabbits. Clin Nutr 22:379–384.PubMedCrossRefGoogle Scholar
  26. 26.
    Ramirez-Tortosa MC, Ramirez-Tortosa CL, Mesa MD et al. (2009). Curcumin ameliorates rabbits’ steatohepatitis via respiratory chain, oxidative stress, and TNF-alpha. Free Radic Biol Med 47:924–931.PubMedCrossRefGoogle Scholar
  27. 27.
    Watanabe Y (1980). Serial inbreeding of rabbits with hereditary hyperlipidemia (WHHL rabbit). Atherosclerosis 36:261–268.PubMedCrossRefGoogle Scholar
  28. 28.
    Shiomi M, Ito T, Yamada S, Kawashima S, Fan J (2003). Development of an animal model for spontaneous myocardial infarction (WHHLMI rabbit). Arterioscler Thromb Vasc Biol 23:1239–1244.PubMedCrossRefGoogle Scholar
  29. 29.
    Shiomi M, Ito T, Tsukada T et al. (1994). Cell composition of coronary and aortic atherosclerotic lesions in WHHL rabbits differ. Arterioscler Thromb 14:931–937.PubMedCrossRefGoogle Scholar
  30. 30.
    Ito T, Yamada S, Shiomi M (2004). Progression of coronary atherosclerosis relates to the onset of myocardial infarction in an animal model of spontaneous myocardial infarction (WHHLMI rabbits). Exp Anim 53:339–346.PubMedCrossRefGoogle Scholar
  31. 31.
    Aikawa M, Libby P (2004). The vulnerable atherosclerotic plaque, pathogenesis and therapeutic approach. Cardiovasc Pathol 13:125–138.PubMedCrossRefGoogle Scholar
  32. 32.
    Paigen B, Kovats SE, Chapman MH, Lin CY (1987). Characterization of a genetic difference in the platelet aggregation response of two inbred mouse strains, C57BL/6 and C3H/He. Atherosclerosis 64:181–190.PubMedCrossRefGoogle Scholar
  33. 33.
    Jawień J, Nastałek P, Korbut R (2004). Mouse models of experimental atherosclerosis. J Physiol Pharmacol 55:503–517.PubMedGoogle Scholar
  34. 34.
    Feig JE, Quick JS, Fisher EA (2009). The role of a murine transplantation model of atherosclerosis regression in drug discovery. Curr Opin Investig Drugs 10:232–238.PubMedGoogle Scholar
  35. 35.
    Singh V, Tiwari RL, Dikshit M, Barthwal MK (2009). Models to study atherosclerosis: a mechanistic insight. Curr Vasc Pharmacol 7:75–109.PubMedCrossRefGoogle Scholar
  36. 36.
    Zhang SH, Reddick RL, Piedrahita JA, Maeda N (1992). Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science 258:468–471.PubMedCrossRefGoogle Scholar
  37. 37.
    Palinski W, Ord VA, Plump AS, Breslow JL, Steinberg D, Witztum JL (1994). Apo E-deficient mice are a model of lipoprotein oxidation in atherogenesis. Demonstration of oxidation-specific epitopes in lesions and high titers of autoantibodies to malondialdehyde-lysine in serum. Arterioscler Thromb 14:605–616.PubMedCrossRefGoogle Scholar
  38. 38.
    Nakashima Y, Plump AS, Raines EW, Breslow JL, Ross R (1994). Apo E-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree. Arterioscler Thromb 14:133–140.PubMedCrossRefGoogle Scholar
  39. 39.
    Reddick RL, Zhang SH, Maeda N (1998). Aortic atherosclerotic plaque injury in apolipoprotein E deficient mice. Atherosclerosis 140:297–305.PubMedCrossRefGoogle Scholar
  40. 40.
    Ishibashi S, Herz J, Maeda N, Goldstein JL, Brown MS (1994). The two-receptor model of lipoprotein clearance: tests of the hypothesis in “knock-out” mice lacking the low density lipoprotein receptor, apolipoprotein E, or both proteins. Proc Natl Acad Sci USA 91:4431–4435.PubMedCrossRefGoogle Scholar
  41. 41.
    Sullivan PM, Mezdour H, Quarfordt SH, Maeda N (1998). Type III hyperlipoproteinemia and spontaneous atherosclerosis in mice resulting from gene replacement of mouse Apo E with human Apo E*2. J Clin Invest 102:130–135.PubMedCrossRefGoogle Scholar
  42. 42.
    Van den Maagdenberg AM, Hofker MH, Krimpenfort PJ et al. (1993). Transgenic mice carrying the apolipoprotein E3-Leiden gene exhibit hyperlipoproteinemia. J Biol Chem 268:10540–10545.PubMedGoogle Scholar
  43. 43.
    Hofker MH, van Vlijmen BJ, Havekes LM (1998). Transgenic mouse models to study the role of APO E in hyperlipidemia and atherosclerosis. Atherosclerosis 137:1–11.PubMedCrossRefGoogle Scholar
  44. 44.
    Wouters K, Shiri-Sverdlov R, van Gorp PJ, van Bilsen M, Hofker MH (2005). Understanding hyperlipidemia and atherosclerosis: lessons from genetically modified apo E and LDLr mice. Clin Chem Lab Med 43:470–479.PubMedCrossRefGoogle Scholar
  45. 45.
    Sullivan PM, Mezdour H, Aratani Y et al. (1997). Targeted replacement of the mouse apolipoprotein E gene with the common human APO E3 allele enhances diet-induced hypercholesterolemia and atherosclerosis. J Biol Chem 272:17972–17980.PubMedCrossRefGoogle Scholar
  46. 46.
    Nieswandt B, Aktas B, Moers A, Sachs UJ (2005). Platelets in atherothrombosis: lessons from mouse models. J Thromb Haemost 3:1725–1736.PubMedCrossRefGoogle Scholar
  47. 47.
    Srivastava N (2002). ATP binding cassette transporter A1--key roles in cellular lipid transport and atherosclerosis. Mol Cell Biochem 237:155–164.PubMedCrossRefGoogle Scholar
  48. 48.
    Wu X, Wang J, Fan J et al. (2006). Localized vessel expression of lipoprotein lipase in rabbits leads to rapid lipid deposition in the balloon-injured arterial wall. Atherosclerosis 187:65–73.PubMedCrossRefGoogle Scholar
  49. 49.
    Bailey EL, McCulloch J, Sudlow C, Wardlaw JM (2009). Potential animal models of lacunar stroke: a systematic review. Stroke 40:451–458.CrossRefGoogle Scholar
  50. 50.
    Dejongste MJ, Terhorst GJ, Foreman RD (2009). Basic research models for the study of underlying mechanisms of electrical neuromodulation and ischemic heart-brain interactions. Cleve Clin J Med76:41–46.Google Scholar
  51. 51.
    Lenzen S, Drinkgern J, Tiedge M (1996). Low antioxidant enzyme gene expression in pancreatic islets compared with various other mouse tissues. Free Radical Biol Med 20:463–466.CrossRefGoogle Scholar
  52. 52.
    Cnop M, Welsh N, Jonas JC et al. (2005). Mechanisms of pancreatic β-cell death in type 1 and type 2 diabetes: many differences, few similarities. Diabetes 54:97–107.CrossRefGoogle Scholar
  53. 53.
    Lenzen S (2008a). Oxidative stress: the vulnerable β-cell. Biochem Soc Trans 36:343–347.PubMedCrossRefGoogle Scholar
  54. 54.
    Chen J, Gusdon AM, Thayer TC, Mathews CE (2008). Role of increased ROS dissipation in prevention of T1D. Ann NY Acad Sci 1150:157–166.PubMedCrossRefGoogle Scholar
  55. 55.
    Eizirik DL, Mandrup-Poulsen T. (2001). A choice of death: the signal-transduction of immune-mediated β-cell apoptosis. Diabetologia 44:2115–2133.PubMedCrossRefGoogle Scholar
  56. 56.
    Diakogiannaki E, Dhayal S, Childs CE et al. (2007). Mechanisms involved in the cytotoxic and cytoprotective actions of saturated versus monounsaturated long chain fatty acids in pancreatic β-cells. J Endocrinol 194:283–291.PubMedCrossRefGoogle Scholar
  57. 57.
    Robertson R, Zhou H, Zhang T, Harmon JS (2007). Chronic oxidative stress as a mechanism for glucose toxicity of the β-cell in type 2 diabetes. Cell Biochem. Biophys 48:139–146.PubMedCrossRefGoogle Scholar
  58. 58.
    Shafrir E (1992) Animal models of non-insulin-dependent diabetes. Diabetes Metab Rev 8:179–208.PubMedCrossRefGoogle Scholar
  59. 59.
    Bailey CJ, Flatt PR (2003). Animal syndromes resembling type 2 diabetes. In: Pickup JC, Williams G eds. Textbook of Diabetes, 3rd edn, Vol. 1. Oxford: Blackwell Science 25:1–30.Google Scholar
  60. 60.
    Hansen BC (1989). Pathophysiology of obesity-associated type II diabetes (NIDDM): implications from longitudinal studies of non-human primates. Nutrition 5:48–50.PubMedGoogle Scholar
  61. 61.
    Tesch GH, Allen TJ (2007). Rodent models of streptozotocin-induced diabetic nephropathy. Nephrology (Carlton) 12:261–266.CrossRefGoogle Scholar
  62. 62.
    Lenzen S (2008b). The mechanisms of alloxan- and streptozotocin-induced diabetes. Diabetologia 51:216–226.PubMedCrossRefGoogle Scholar
  63. 63.
    Federiuk IF, Casey HM, Quinn MJ, Wood MD, Ward WK (2004). Induction of type-1 diabetes mellitus in laboratory rats by use of alloxan: route of administration, pitfalls, and insulin treatment. Comp Med 54:252–257.PubMedGoogle Scholar
  64. 64.
    Gurley SB, Clare SE, Snow KP et al. (2006). Impact of genetic background on nephropathy in diabetic mice. Am J Physiol Renal Physiol 290:214–222.CrossRefGoogle Scholar
  65. 65.
    Chen D, Wang MW (2005). Development and application of rodent models for type 2 diabetes. Diabetes Obes Metab 7:307–317.PubMedCrossRefGoogle Scholar
  66. 66.
    Portha B, Blondel O, Serradas P et al. (1989). The rat models of non-insulin dependent diabetes induced by neonatal streptozotocin. Diabetes Metab 15:61–75.Google Scholar
  67. 67.
    Reaven GM, Ho H (1991). Low-dose streptozotocin-induced diabetes in the spontaneously hypertensive rat. Metabolism 40:335–337.PubMedCrossRefGoogle Scholar
  68. 68.
    Iwase M (1991). A new animal model of non-insulin-dependent diabetes mellitus with hypertension: neonatal streptozotocin treatment in spontaneously hypertensive rats. Fukuoka Igaku Zasshi 82:415–427.PubMedGoogle Scholar
  69. 69.
    Van Zwieten PA, Kam KL, Pijl AJ et al. (1996). Hypertensive diabetic rats in pharmacological studies. Pharmacol Res 33:95–105.PubMedCrossRefGoogle Scholar
  70. 70.
    Luo J, Quan J, Tsai J et al. (1998). Nongenetic mouse models of non-insulin-dependent diabetes mellitus. Metabolism 47:663–668.PubMedCrossRefGoogle Scholar
  71. 71.
    Reed MJ, Meszaros K, Entes LJ et al. (2000). A new rat model of type 2 diabetes: the fat-fed, streptozotocin-treated rat. Metabolism 49:1390–1394.PubMedCrossRefGoogle Scholar
  72. 72.
    Etgen GJ, Oldham BA (2000). Profiling of Zucker diabetic fatty rats in their progression to the overt diabetic state. Metabolism 49:684–688.PubMedCrossRefGoogle Scholar
  73. 73.
    Aleixandre de Artiñano A, Castro MM (2009). Experimental rat models to study the metabolic syndrome. B J Nutr 1–9.Google Scholar
  74. 74.
    Pico C, Sánchez J, Oliver P, Palau A (2002). Leptin production by the stomach is up-regulated in obese (fa/fa) Zucker rats. Obesity Res 10, 932–938.CrossRefGoogle Scholar
  75. 75.
    Beck B (2000). Neuropeptides and obesity. Nutrition 16:916–923.PubMedCrossRefGoogle Scholar
  76. 76.
    Beck B, Richy S, Stricker-Krongrad A (2004). Feeding response to ghrelin agonist and antagonist in lean and obese Zucker rats. Life Sci 76:473–478.PubMedCrossRefGoogle Scholar
  77. 77.
    Peterson RG, Neel MA, Little LA, Kincaid JC, Eichberg J (1990). Zucker diabetic fatty as a model for non-insulin-dependent diabetes mellitus. ILAR News 32:16–19.Google Scholar
  78. 78.
    Slieker LJ, Sundell KL, Heath WF et al. (1992). Glucose transporter levels in tissues of spontaneously diabetic Zucker fa/fa rat (ZDF/drt) and viable yellow mouse (Avy/a). Diabetes 41:187–193.PubMedCrossRefGoogle Scholar
  79. 79.
    Kasiske BL, O’Donnell MP, Keane WF (1992). The Zucker rat model of obesity, insulin resistance, hyperlipidemia, and renal injury. Hypertension 19:110–115.CrossRefGoogle Scholar
  80. 80.
    Liao W, Angelin B, Rudling M (1997). Lipoprotein metabolism in the fat Zucker rat: reduced basal expression but normal regulation of hepatic low density lipoprotein receptors. Endocrinology 138:3276–3282.PubMedCrossRefGoogle Scholar
  81. 81.
    Lash JM, Sherman WM, Hamlin RL (1989). Capillary basement membrane thickness and capillary density in sedentary and trained obese Zucker rats. Diabetes 38:854–860.PubMedCrossRefGoogle Scholar
  82. 82.
    Kurtz TW, Morris RC, Pershadsingh HA (1989). The Zucker fatty rat as a genetic model of obesity and hypertension. Hypertension 13:896–901.PubMedCrossRefGoogle Scholar
  83. 83.
    De Gasparo M (2002). AT(1) and AT(2) angiotensin II receptors key features. Drugs 1:1–10.CrossRefGoogle Scholar
  84. 84.
    Picchi A, Gao X, Belmadani S et al. (2006). Tumor necrosis factor-alpha induces endothelial dysfunction in the prediabetic metabolic syndrome. Circ Res 99:69–77.PubMedCrossRefGoogle Scholar
  85. 85.
    Griffen SC, Wang J, German MS (2001). A genetic defect in betacell gene expression segregates independently from the fa locus in the ZDF rat. Diabetes 50:63–68.PubMedCrossRefGoogle Scholar
  86. 86.
    Tokuyama Y, Sturis J, DePaoli AM et al. (1995). Evolution of beta-cell dysfunction in the male Zucker diabetic fatty rat. Diabetes 44:1447–1457.PubMedCrossRefGoogle Scholar
  87. 87.
    Shimabukuro M, Ohneda M, Lee Y, Unger RH (1997). Role of nitric oxide in obesity-induced beta cell disease. J Clin Invest 100:290–295.PubMedCrossRefGoogle Scholar
  88. 88.
    Baudry A, Leroux L, Jackerott M, Joshi RL (2002). Genetic manipulation of insulin signaling, action and secretion in mice. EMBO Reports 4:323–328.CrossRefGoogle Scholar
  89. 89.
    Kawano K, Hirashima T, Mori S, Natori T (1994). OLETF (Otsuka Long-Evans Tokushima Fatty) rat: a new NIDDMrat strain. Diabetes Res Clin Pract 24:317–320.CrossRefGoogle Scholar
  90. 90.
    Bi S, Moran TH (2002). Actions of CCK in the controls of food intake and body weight: lessons from the CCK-A receptor deficient OLETF rat. Neuropeptides 36:171–181.PubMedCrossRefGoogle Scholar
  91. 91.
    Man ZW, Zhu M, Noma Y et al. (1997). Impaired beta-cell function and deposition of fat droplets in the pancreas as a consequence of hypertriglyceridemia in OLETF rat, a model of spontaneous NIDDM. Diabetes 46:1718–1724.PubMedCrossRefGoogle Scholar
  92. 92.
    Yanagita T, Nagao K (2008). Functional lipids and the prevention of the metabolic syndrome. Asia Pac J Clin Nutr 17:189–191.PubMedGoogle Scholar
  93. 93.
    Moran TH, Bi S (2006). Hyperphagia and obesity in OLETF rats lacking CCK-1 receptors. Philos Trans R Soc Lond B Biol Sci 361:1211–1218.PubMedCrossRefGoogle Scholar
  94. 94.
    Moran TH (2008). Unraveling the obesity of OLETF rats. Physiol Behav 22;94:71–78.Google Scholar
  95. 95.
    Baynes JW (1991). Role of oxidative stress in development of complications in diabetes, Diabetes 40:405–412.PubMedCrossRefGoogle Scholar
  96. 96.
    Nam SM, Lee MY, Koh JH et al. (2009). Effects of NADPH oxidase inhibitor on diabetic nephropathy in OLETF rats: the role of reducing oxidative stress in its protective property. Diabetes Res Clin Pract 83:176–182.PubMedCrossRefGoogle Scholar
  97. 97.
    Portha B, Lacraz G, Kergoat M et al. (2009). The GK rat beta-cell: a prototype for the ­diseased human beta-cell in type 2 diabetes? Mol Cell Endocrinol 297:73–85.PubMedCrossRefGoogle Scholar
  98. 98.
    Kowluru A (2008). Emerging roles for protein histidine phosphorylation in cellular signal transduction: lessons from the islet beta-cell. J Cell Mol Med 12:1885–1908.PubMedCrossRefGoogle Scholar
  99. 99.
    Lacraz G, Giroix MH, Kassis N et al. (2009). Islet endothelial activation and oxidative stress gene expression is reduced by IL-1Ra treatment in the type 2 diabetic GK rat. PLoS One 9;4:e6963.Google Scholar
  100. 100.
    Janssen U, Vassiliadou A, Riley SG, Phillips AO, Floege J (2004). The quest for a model of type II diabetes with nephropathy: the Goto Kakizaki rat. J Nephrol 7:769–773.Google Scholar
  101. 101.
    Yatoh S, Mizutani M, Yokoo T et al. (2006). Antioxidants and an inhibitor of advanced glycation ameliorate death of retinal microvascular cells in diabetic retinopathy. Diabetes Metab Res Rev 22:38–45.PubMedCrossRefGoogle Scholar
  102. 102.
    Coleman DL (1980). Lessons from studies with genetic forms of diabetes in the mouse. Metabolism 32:162–164.CrossRefGoogle Scholar
  103. 103.
    Kodama H, Fujita M, Yamazaki M, Yamaguchi I (1994). The possible role of age-related increase in the plasma glucagon/insulin ratio in the enhanced hepatic gluconeogenesis and hyperglycemia in genetically diabetic (C57BL/KsJ-db/db) mice. Jpn J Pharmacol 66:281–287.PubMedCrossRefGoogle Scholar
  104. 104.
    Mariappan N, Elks CM, Sriramula S et al. (2010). NF-{kappa}B-induced oxidative stress ­contributes to mitochondrial and cardiac dysfunction in type II diabetes. Cardiovasc Res. 85:473–483.Google Scholar
  105. 105.
    Allen TJ, Cooper ME, Lan HY (2004). Use of genetic mouse models in the study of diabetic nephropathy. Curr Diab Rep 4:435–440.PubMedCrossRefGoogle Scholar
  106. 106.
    Feliers D, Duraisamy S, Faulkner JL et al. (2001). Activation of renal signaling pathways in db/db mice with type 2 diabetes. Kidney Int 60:495–504.PubMedCrossRefGoogle Scholar
  107. 107.
    Coleman DL (1982). Obese and diabetes: two mutant genes causing diabetes–obesity syndromes in mice. Diabetes 31:1–6.PubMedCrossRefGoogle Scholar
  108. 108.
    Haluzik M, Colombo C, Gavrilova O et al. (2004). Genetic background (C57BL/6J versus FVB/N) strongly influences the severity of diabetes and insulin resistance in ob/ob mice. Endocrinology 145:3258–3264.PubMedCrossRefGoogle Scholar
  109. 109.
    Sainsbury A, Schwarzer C, Couzens M, Herzog H (2002). Y2 receptor deletion attenuates the type 2 diabetic syndrome of ob/ob mice. Diabetes 51:3420–3427.PubMedCrossRefGoogle Scholar
  110. 110.
    Bartels ED, Lauritsen M, Nielsen LB (2002). Hepatic expression of microsomal triglyceride transfer protein and in vivo secretion of triglyceride-rich lipoproteins are increased in obese diabetic mice. Diabetes 51:1233–1239.PubMedCrossRefGoogle Scholar
  111. 111.
    O’Harte FP, Mooney MH, Kelly CM, McKillop AM, Flatt PR (2001). Degradation and glycemic effects of His (7)-glucitol glucagon-like peptide-1(7–36) amide in obese diabetic ob/ob mice. Regul Pept 96:95–104.PubMedCrossRefGoogle Scholar
  112. 112.
    Gault VA, O’Harte FP, Harriott P et al. (2003). Effects of the novel (Pro3)GIP antagonist and exendin(9-39)amide on GIP- and GLP-1-induced cyclic AMP generation, insulin secretion and postprandial insulin release in obese diabetic (ob/ob) mice: evidence that GIP is the major physiological incretin. Diabetologia 46:222–230.PubMedGoogle Scholar
  113. 113.
    Rahimian R, Masih-Khan E, Lo M et al. (2001). Hepatic over-expression of peroxisome proliferator activated receptor gamma2 in the ob/ob mouse model of non-insulin dependent diabetes mellitus. Mol Cell Biochem 224: 29–37.PubMedCrossRefGoogle Scholar
  114. 114.
    Gum RJ, Gaede LL, Koterski SL et al. (2003). Reduction of protein tyrosine phosphatase 1B increases insulin-dependent signaling in ob/ob mice. Diabetes 52:21–28.PubMedCrossRefGoogle Scholar
  115. 115.
    Sonta T, Inoguchi T, Tsubouchi H et al. (2004). Evidence for contribution of vascular NAD(P)H oxidase to increased oxidative stress in animal models of diabetes and obesity. Free Radic Biol Med 37:115–123.PubMedCrossRefGoogle Scholar
  116. 116.
    Boudina S, Sena S, O’Neill BT et al. (2005). Reduced mitochondrial oxidative capacity and increased mitochondrial uncoupling impair myocardial energetics in obesity. Circulation 112:2686–2695.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Maria D. Mesa
  • Concepcion M. Aguilera
  • Angel Gil
    • 1
    Email author
  1. 1.Department of Biochemistry and Molecular Biology II, Institute of Nutrition and Food Technology “José Mataix”, Centre of Biomedical ResearchUniversity of GranadaGranadaSpain

Personalised recommendations