Abstract
Increased oxidative stress has been observed to contribute the development of insulin resistance. Oxidative stress is known to increase the conversion of deoxyguanosine (dG) to 8-hydroxy-2′-deoxyguanosine (8-OHdG). Human 8-oxoguanine glycosylase (hOGG1) is the key component responsible for the removal of 8-OHdG from oxidatively damaged DNA. The repair activity of the hOGG1 Ser326Cys gene variant has been demonstrated to be lower than that of the hOGG1 Ser/Ser genotype. Therefore, the possible association of the hOGG1 Ser326Cys gene variant with insulin sensitivity was investigated in 279 normal glucose-tolerant subjects without history of cancer. Allele frequency was 21.5% for the Ser/Ser genotype (n=60), 45.9% for the Ser/Cys genotype (n=128), and 32.6% for the Cys/Cys genotype (n=91). Subjects carrying the Cys/Cys genotype had significantly lower insulin sensitivity levels, assessed by homeostasis model assessment-insulin resistance (HOMA-IR), compared with the Ser/Ser and Ser/Cys genotypes (P<0.001 and P<0.001, respectively). In a multiple linear regression analysis, the Cys/Cys genotype was a significant determinant of HOMA-IR, independent of age, sex, body mass index, fasting plasma cholesterol, triglyceride, HDL cholesterol, LDL cholesterol, or hypertension. The present study indicates that the hOGG1 gene Cys/Cys variant is associated with a significant decrease in insulin sensitivity in subjects with normal glucose tolerance.
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References
Barbieri M, Bonafe M, Marfella R, Ragno E, Giugliano D, Franceschi C, Paolisso G (2002) LL-paraoxonase genotype is associated with a more severe degree of homeostasis model assessment IR in healthy subjects. J Clin Endocrinol Metab 87:222–225
Breen AP, Murphy JA (1995) Reactions of oxyl radicals with DNA. Free Radic Biol Med 18:1033–1077
Bruce CR, Carey AL, Hawley JA, Febbraio MA (2003) Intramuscular heat shock protein 72 and heme oxygenase-1 mRNA are reduced in patients with type 2 diabetes: evidence that insulin resistance is associated with a disturbed antioxidant defense mechanism. Diabetes 52:2338–2345
Bruner SD, Norman DP, Verdine GL (2000) Structural basis for recognition and repair of the endogenous mutagen 8-oxoguanine in DNA. Nature 403:859–866
Ceriello A, Quagliaro L, Piconi L, Assaloni RDRR, Maier A, Esposito K,Giugliano D (2004) Effect of postprandial hypertriglyceridemia and hyperglycemia on circulating adhesion molecules and oxidative stress generation and the possible role of simvastatin treatment. Diabetes 53:701–710
Deakin S, Leviev I, Nicaud V, Brulhart Meynet MC, Tiret L, James RW (2002) Paraoxonase-1 L55M polymorphism is associated with an abnormal oral glucose tolerance test and differentiates high risk coronary disease families. J Clin Endocrinol Metab 87:1268–1273
Evans JL, Goldfine ID, Maddux BA, Grodsky GM (2003) Are oxidative stress-activated signaling pathways mediators of insulin resistance and beta-cell dysfunction? Diabetes 52:1–8
Grundy SM (1999) Hypertriglyceridemia, insulin resistance, and the metabolic syndrome. Am J Cardiol 83:25F–29F
Haffner SM, Miettinen H, Stern M (1997) The homeostasis model in the San Antonio Heart Study. Diabetes care 20:1087–1092
Kohno T, Shinmura K, Tosaka M, Tani M, Kim SR, Sugimura H, Nohmi T, Kasai H, Yokota J (1998) Genetic polymorphisms and alternative splicing of the hOGG1 gene that is involved in the repair of 8-hydroxyguanine in damaged DNA. Oncogene 16:3219–3225
Lee AJ, Hodges NJ, Chipman JK (2005) Interindividual variability in response to sodium dichromate-induced oxidative DNA damage: role of the Ser326Cys polymorphism in the DNA-repair protein of 8-oxo-7,8-dihydro-2′-deoxyguanosine DNA glycosylase 1. Cancer Epidemiol Biomarkers Prev 14:497–505
Leviev I, Kalix B, Brulhart MMC, James RW (2001) The paraoxonase PON1 promoter polymorphism C(−107)T is associated with increased serum glucose concentrations in non-diabetic patients. Diabetologia 44:1177–1183
Maddux BA, See W, Lawrence JCJ, Goldfine AL, Goldfine ID, Evans JL (2001) Protection against oxidative stress-induced insulin resistance in rat L6 muscle cells by micromolar concentrations of alpha-lipoic acid. Diabetes 50:404–410
Moller DE, Bjorbek C, Vidal-Puig A (1996) Candidate gene for insulin resistance. Diabetes Care 19:396–400
Norbury CJ, Hickson ID (2001) Cellular responses to DNA damage. Annu Rev Pharmacol Toxicol 41:367–401
Ogihara T, Asano T, Katagiri H, Sakoda H, Anai M, Shojima NOH, Fujishiro M, Kushiyama A, Fukushima Y, Kikuchi M, Noguchi N, Aburatani H, Gotoh Y, Komuro I, Fujita T (2004) Oxidative stress induces insulin resistance by activating the nuclear factor-kappa B pathway and disrupting normal subcellular distribution of phosphatidylinositol 3-kinase. Diabetologia 47:794–805
Paolisso G, Tagliamonte MR, Rizzo MR, Giugliano D (1999) Advancing age and insulin resistance: new facts about an ancient history. Eur J Clin Invest 29:758–769
Pleiner J, Schaller G, Mittermayer F, Bayerle-Eder M, Roden M, Wolzt M (2002) FFA-induced endothelial dysfunction can be corrected by vitamin C. J Clin Endocrinol Metab 87:2913–2917
Rudich A, Tirosh A, Potashnik R, Hemi R, Kanety H, Bashan N (1998) Prolonged oxidative stress impairs insulin-induced GLUT4 translocation in 3T3-L1 adipocytes. Diabetes 47:1562–1569
Rudich A, Tirosh A, Potashnik R, Khamaisi M, Bashan N (1999) Lipoic acid protects against oxidative stress induced impairment in insulin stimulation of protein kinase B and glucose transport in 3T3-L1 adipocytes. Diabetologia 42:949–957
Talior I, Yarkoni M, Bashan N, Eldar-Finkelman H (2003) Increased glucose uptake promotes oxidative stress and PKC-delta activation in adipocytes of obese insulin-resistant mice. Am J Physiol Endocrinol Metab 285:E295–E302
Tretter L, Adam-Vizi V (2000) Inhibition of Krebs cycle enzymes by hydrogen peroxide: a key role of [alpha]-ketoglutarate dehydrogenase in limiting NADH production under oxidative stress. J Neurosci 20:8972–8979
Acknowledgments
This study was supported in part by Grants DOC 93-HP-1101 from the Department of Health, Taiwan. We are grateful to Prof. Ming-Tsang Wu for his statistical advice and critical comments.
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Wang, CL., Hsieh, MC., Hsin, SC. et al. The hOGG1 Ser326Cys gene polymorphism is associated with decreased insulin sensitivity in subjects with normal glucose tolerance. J Hum Genet 51, 124–128 (2006). https://doi.org/10.1007/s10038-005-0335-8
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DOI: https://doi.org/10.1007/s10038-005-0335-8
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