Download PDF
Exp Clin Endocrinol Diabetes 2012; 120(06): 329-334
DOI: 10.1055/s-0031-1298016
Article
© J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York

Increased DNA-Glycation in Type 2 Diabetic Patients: The Effect of Thiamine and Pyridoxine Therapy

F. C. Polizzi
1   İstanbul University, Cerrahpaşa Medical Faculty, Department of Biochemistry
,
G. Andican
1   İstanbul University, Cerrahpaşa Medical Faculty, Department of Biochemistry
,
E. Çetin
1   İstanbul University, Cerrahpaşa Medical Faculty, Department of Biochemistry
,
S. Civelek
1   İstanbul University, Cerrahpaşa Medical Faculty, Department of Biochemistry
,
V. Yumuk
2   Department of Internal Medicine
,
G. Burçak
1   İstanbul University, Cerrahpaşa Medical Faculty, Department of Biochemistry
› Author Affiliations
Further Information

Publication History

received 06 September 2011
first decision 25 November 2011

accepted 02 December 2011

Publication Date:
09 January 2012 (online)

Also available at
    Permissions and Reprints

Abstract

Background:

It is well known that advanced glycation plays an important role in the progression of diabetic complications. Although several studies have been done on protein glycation, studies related to DNA glycation is limited. The aim of this study is primarily to investigate DNA glycation in diabetes mellitus and secondarily to observe the effects of vitamins B1 and B6.

Materials and Methods:

Patients with diabetes (n=31) were divided into 2 groups as patients with nephropathy (n=17) and without nephro­pathy (n=14). The control group was recruited from age and sex matched healthy individuals (n=30). In the experimental groups, DNA glycation was measured in DNA isolated from leukocytes. HbA1c, thiamine pyrophosphate (TPP) and pyridoxal 5-phosphate (PLP) levels were determined in whole blood; glucose and insulin levels in plasma. Patients with nephropathy were further divided into 2 groups and were administered either vitamins B1 + B6 (n=6) or B6 (n=11), for 5 months. All the measurements were performed both before and after the vitamin administration period.

Results:

AGE-DNA levels were found significantly higher in diabetic patients (p<0.05) than the healthy controls. AGE-DNA and PLP levels were negatively correlated in control patients (r= − 0.361, p<0.05). The combined administration of B1 and B6 caused a significant decrease in AGE-DNA values (p<0.05).

Conclusion:

This study shows that the combined administration of vitamins B1 and B6 to diabetic nephropathy patients causes a decrease in DNA glycation in leukocytes. Importantly the administration of vitamin B6 alone did not have such an effect. To our knowledge, these are the first reported findings related to glycation of leukocyte nuclear DNA in diabetic nephropathy.

Key words

diabetes - diabetic nephropathy - DNA glycation - vitamin B1 - vitamin B6
 

  • References

  • 1 Amarnath V, Amarnath K, Amarnath K. Pyridoxamine and exteremely potent scavenger of 1,4 dicarbonyls. Chem Res Toxicol 2004; 17: 410-415
    CrossrefPubMedGoogle Scholar
  • 2 Andican G, Burçak G. Oxidative damage to nuclear DNA in streptozotocin-diabetic rat liver. Clin Exp Pharmacol Physiol 2005; 32 (08) 663-666
    CrossrefPubMedGoogle Scholar
  • 3 Barea F, Bonatto D. Relationships among carbohydrate intermediate metabolites and DNA damage and repair in yeast from a systems biology perspective. Mutat Res 2008; 642 (1-2) 43-56
    PubMedGoogle Scholar
  • 4 Baynes JW, Thorpe SR. Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes 1999; 48 (01) 1-9
    CrossrefPubMedGoogle Scholar
  • 5 Bloomgarden ZT. The European Association for the Study of Diabetes. Diabetes Care 2005; 28: 1250-1257
    CrossrefPubMedGoogle Scholar
  • 6 Bolton WK, Cattran DC, Williams ME. Randomized trial of an inhibitor of formation of advanced glycation end products in diabetic nephropathy. Am J Nephrol 2004; 24: 32-40
    CrossrefPubMedGoogle Scholar
  • 7 Booth AA, Khalifah RG, Hudson BG. Thiamine pyrophosphate and pyridoxamine inhibit the formation of antigenic advanced glycation end-products: comparison with aminoguanidine. Biochem Biophys Res Commun 1996; 220 (01) 113-119
    CrossrefPubMedGoogle Scholar
  • 8 Booth AA, Khalifah RG, Todd P et al. In vitro kinetic studies of formation of antigenic advanced glycation end products (AGEs). Novel inhibition of post-Amadori glycation pathways. J Biol Chem 1997; 272 (09) 5430-5437
    CrossrefPubMedGoogle Scholar
  • 9 Brownlee M, Cerami A, Vlassara H. Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. N Engl J Med 1988; 318 (20) 1315-1321
    CrossrefPubMedGoogle Scholar
  • 10 Bucala R, Model P, Cerami A. Modification of DNA by reducing sugars: a possible mechanism for nucleic acid aging and age-related dysfunction in gene expression. Proc Natl Acad Sci USA 1984; 81 (01) 105-109
    CrossrefPubMedGoogle Scholar
  • 11 Cohen G, Rudnicki M, Walter F et al. Glucose-modified proteins modulate essential functions and apoptosis of polymorphonuclear leukocytes. J Am Soc Nephrol 2001; 12 (06) 1264-1271
    PubMedGoogle Scholar
  • 12 Degenhardt TP, Alderson NL, Arrington DD et al. Pyridoxamine inhibits early renal disease and dyslipidemia in the streptozotocin-diabetic rat. Kidney Int 2002; 61 (03) 939-950
    CrossrefPubMedGoogle Scholar
  • 13 Dutta U, Cohenford MA, Dain JA. Nonenzymatic glycation of DNA nucleosides with reducing sugars. Anal Biochem 2005; 345 (02) 171-180
    CrossrefPubMedGoogle Scholar
  • 14 Feather MS, Flynn TG, Munro KA et al. Catalysis of reduction of carbohydrate 2-oxoaldehydes (osones) by mammalian aldose reductase and aldehyde reductase. Biochim Biophys Acta 1995; 1244: 10-16
    CrossrefPubMedGoogle Scholar
  • 15 Forbes JM, Fukami K, Cooper ME. Diabetic nephropathy: where hemodynamics meets metabolism. Exp Clin Endocrinol Diabetes 2007; 115 (02) 69-84
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 Kalousová M, Skrha J, Zima T. Advanced glycation end-products and advanced oxidation protein products in patients with diabetes mellitus. Physiol Res 2002; 51 (06) 597-604
    PubMedGoogle Scholar
  • 17 La Selva M, Beltramo E, Pagnozzi F. Thiamine corrects delayed replication and decreases production of lactate and AGEs in bovine retinal and human umbilical vein enddhotelial cells cultured under high glucose conditions. Diabetologia 1996; 39: 1263-1268
    CrossrefPubMedGoogle Scholar
  • 18 Li H, Nakamura S, Miyazaki S et al. N2-carboxyethyl-2′-deoxyguanosine, a DNA glycation marker, in kidneys and aortas of diabetic and uremic patients. Kidney Int 2006; 69 (02) 388-392
    CrossrefPubMedGoogle Scholar
  • 19 Li Y, Cohenford MA, Dutta U et al. In vitro nonenzymatic glycation of guanosine 5′-triphosphate by dihydroxyacetone phosphate. Anal Bioanal Chem 2008; 392 (06) 1189-1196
    CrossrefPubMedGoogle Scholar
  • 20 Lorenzi M, Montisano DF, Toledo S et al. High glucose induces DNA damage in cultured human endothelial cells. J Clin Inves 1986; 77: 322-325
    CrossrefPubMedGoogle Scholar
  • 21 Lo TW, Westwood ME, McLellan AC et al. Binding and modification of proteins by methylglyoxal under physiological conditions. A kinetic and mechanistic study with N alpha-acetylarginine, N alpha-acetylcysteine, and N alpha-acetyllysine, and bovine serum albumin. J Biol Chem 1994; 269: 32299-32305
    PubMedGoogle Scholar
  • 22 Miller SA, Dykes DD, Polesky HF. A salting out procedure for extracting DNA from human nucleated cells. Nucleic acids research 1988; 16: 1215
    CrossrefPubMedGoogle Scholar
  • 23 Nakamura S, Li H, Adijiang A et al. Pyridoxal phosphate prevents progression of diabetic nephropathy. Nephrol Dial Transplant 2007; 22 (08) 2165-2174
    CrossrefPubMedGoogle Scholar
  • 24 Nawroth PP, Rudofsky G, Humpert P. Have we understood diabetes? New tasks for diagnosis and therapy. Exp Clin Endocrinol Diabetes 2010; 118 (01) 1-3
    Article in Thieme ConnectPubMedGoogle Scholar
  • 25 Pomero F, Min AM, La Selva M et al. Benfothiamine is similar to thiamine in correcting endothelial cell defects induced by high glucose. Acta Diabetol 2001; 38: 135-138
    CrossrefPubMedGoogle Scholar
  • 26 Rabbani N, Thornalley PJ. Emerging role of thiamine therapy for prevention and treatment of early-stage diabetic nephropathy. Diabetes Obes Metab 2011; 13 (07) 577-583
    CrossrefPubMedGoogle Scholar
  • 27 Sacks DB. Carbohydrates. In: Burtis CA, Ashwood ER, Bruns DE. (eds.). Tıetz Texbook of Clinical Chemistry and Molecular Diagnostics. 4th ed. Elsevier Saunders; 2006: 886-888
    Google Scholar
  • 28 Said HM. Intestinal absorption of water-soluble vitamins in health and disease. Biochem J 2011; 437 (03) 357-372
    CrossrefPubMedGoogle Scholar
  • 29 Sengupta B, Uematsu T, Jacobsson P et al. Effect of glycation on the structure and dynamics of DNA: a critical spectroscopic approach. J Phys Chem B 2007; 111 (03) 646-651
    CrossrefPubMedGoogle Scholar
  • 30 Shangari N, Mehta R, O’brien PJ. Hepatocyte susceptibility to glyoxal is dependent on cell thiamin content. Chem Biol Interact 2007; 165 (02) 146-154
    CrossrefPubMedGoogle Scholar
  • 31 Shimoi K, Okitsu A, Green MH et al. Oxidative DNA damage induced by high glucose and its suppression in human umbilical vein endothelial cells. Mutat Res 2001; 480–481: 371-378
    PubMedGoogle Scholar
  • 32 Suzuki K, Koh YH, Mizuno H et al. Overexpression of aldehyde reductase protects PC12 cells from the cytotoxicity of methylglyoxal or 3-deoxyglucosone. J Biochem 1998; 123: 353-357
    CrossrefPubMedGoogle Scholar
  • 33 Tamae D, Lim P, Wuenschell GE et al. Mutagenesis and repair induced by the DNA advanced glycation end product N2-1-(carboxyethyl)-2’-deoxyguanosine in human cells. Biochemistry 2011; 50 (12) 2321-2329
    CrossrefPubMedGoogle Scholar
  • 34 Thornalley PJ. Pharmacology of methylglyoxal formation, modification of patients and nucleic acids and enzymatic detoxificaiton – a role in phatogenesis and antiproliferative chemotherapy. Gen Pharmacol 1996; 27: 565-573
    CrossrefPubMedGoogle Scholar
  • 35 Thornalley PJ, Jahan I, Ng R. Suppression of the accumulation of triosephosphates and increased formation of methylglyoxal in human red blood cells during hyperglycaemia by thiamine in vitro. J Biochem 2001; 129 (04) 543-549
    CrossrefPubMedGoogle Scholar
  • 36 Thornalley PJ. Protecting the genome:defence against nucleotide glycation and emerging role of glyoxalase I overexpression in multidrug resistance in cancer chemotherapy. Biochemical Society Transactions 2003; 31: 1372-1377
    CrossrefPubMedGoogle Scholar
  • 37 Thornalley PJ, Babaei Jadidi R, Al Ali H et al. High prevalence of low plasma thiamine concentration in diabetes linked to a marker of vascular disease. Diabetologia 2007; 50: 2164-2177
    CrossrefPubMedGoogle Scholar
  • 38 Thornalley PJ. Protein and nucleotide damage by glyoxal and methylglyoxal in physiological systems – role in ageing and disease. Drug Metabol Drug Interact 2008; 23: 125-150
    CrossrefPubMedGoogle Scholar
  • 39 Vlassara H, Bucala R, Striker L. Pathogenic effects of advanced glycosylation: biochemical, biologic, and clinical implications for diabetes and aging. Lab Invest 1994; 70 (02) 138-151
    PubMedGoogle Scholar
  • 40 Voziyan PA, Metz TO, Baynes JW et al. A post-Amadori inhibitor pyridoxamine also inhibits chemical modification of proteins by scavenging carbonyl intermediates of carbohydrate and lipid degradation. J Biol Chem 2002; 277 (05) 3397-3403
    CrossrefPubMedGoogle Scholar
  • 41 Wagner Z, Wittmann I, Mazák I et al. Nε-(carboxymethyl) lysine levels in patients with type 2 diabetes: role of renal function. Am J Kidney Dis 2001; 38 (04) 785-791
    CrossrefPubMedGoogle Scholar
  • 42 Wróbel K, Wróbel K, Garay-Sevilla ME et al. Novel analytical approach to monitoring advanced glycosylation end products in human serum with on-line spectrophotometric and spectrofluorometric detection in a flow system. Clin Chem 1997; 43 (09) 1563-1569
    PubMedGoogle Scholar
  • 43 Wuenschell GE, Tamae D, Cercillieux A et al. Mutagenic potential of DNA glycation: miscoding by (R)-and (S)-N2-(1-carboxyethyl)-2′-deoxyguanosine. Biochemistry 2010; 49 (09) 1814-1821
    CrossrefPubMedGoogle Scholar