Molecular and Cellular Biochemistry

, Volume 365, Issue 1–2, pp 343–350 | Cite as

Accelerated aging as evidenced by increased telomere shortening and mitochondrial DNA depletion in patients with type 2 diabetes

  • Finny Monickaraj
  • Sankaramoorthy Aravind
  • Kuppan Gokulakrishnan
  • Chandrakumar Sathishkumar
  • Paramasivam Prabu
  • Durai Prabu
  • Viswanathan Mohan
  • Muthuswamy Balasubramanyam


Although shortened telomeres were shown associated with several risk factors of diabetes, there is lack of data on their relationship with mitochondrial dysfunction. Therefore, we compared the relationship between telomere length and mitochondrial DNA (mtDNA) content in patients with type 2 diabetes mellitus (T2DM; n = 145) and in subjects with normal glucose tolerance (NGT; n = 145). Subjects were randomly recruited from the Chennai Urban Rural Epidemiology Study. mtDNA content and telomere length were assessed by Real-Time PCR. Malonodialdehyde, a marker of lipid peroxidation was measured by thiobarbituric acid reactive substances (TBARS) using fluorescence methodology. Adiponectin levels were measured by radioimmunoassay. Oxidative stress as determined by lipid peroxidation (TBARS) was significantly (p < 0.001) higher in patients with T2DM compared to NGT subjects. In contrast, the mean telomere length, adiponectin and mtDNA content were significantly (p < 0.001) lower in patients with T2DM compared to NGT subjects. Telomere length was positively correlated with adiponectin, HDL, mtDNA content and good glycemic/lipid control and negatively correlated with adiposity and insulin resistance. On regression analysis, shortened telomeres showed significant association with T2DM even after adjusting for waist circumference, insulin resistance, triglyceride, HDL, adiponectin, mtDNA & TBARS. mtDNA depletion showed significant association with T2DM after adjusting for waist circumference and adiponectin but lost its significance when further adjusted for telomere length, TBARS and insulin resistance. Our study emphasizes the clustering of accelerated aging features viz., shortened telomeres, decreased mtDNA content, hypoadiponectinemia, low HDL, and increased oxidative stress in Asian Indian type 2 diabetes patients.


Telomere shortening mtDNA depletion Oxidative stress Type 2 diabetes 


  1. 1.
    Curtis R, Geesaman BJ, DiStefano PS (2005) Ageing and metabolism: drug discovery opportunities. Nat Rev Drug Discov 4:569–580PubMedCrossRefGoogle Scholar
  2. 2.
    Morley JE (2008) Diabetes and aging: epidemiologic overview. Clin Geriatr Med 24:395–405PubMedCrossRefGoogle Scholar
  3. 3.
    Wei YH, Lee HC (2002) Oxidative stress, mitochondrial DNA mutation, and impairment of antioxidant enzymes in aging. Exp Biol Med (Maywood) 227:671–682Google Scholar
  4. 4.
    Rhee DB, Ghosh A, Lu J et al (2011) Factors that influence telomeric oxidative base damage and repair by DNA glycosylase OGG1. DNA Repair (Amst) 10:34–44CrossRefGoogle Scholar
  5. 5.
    Kanvah S, Schuster GB (2005) The sacrificial role of easily oxidizable sites in the protection of DNA from damage. Nucleic Acids Res 33:5133–5138PubMedCrossRefGoogle Scholar
  6. 6.
    Ceriello A, Ihnat M (2010) Oxidative stress is, convincingly, the mediator of the dangerous effects of glucose variability. Diabet Med 27:968PubMedCrossRefGoogle Scholar
  7. 7.
    Calvert PA, Liew TV, Gorenne I et al (2011) Leukocyte telomere length is associated with high-risk plaques on virtual histology intravascular ultrasound and increased proinflammatory activity. Arterioscler Thromb Vasc Biol 31:2157–2164PubMedCrossRefGoogle Scholar
  8. 8.
    Jeanclos E, Krolewski A, Skurnick J et al (1998) Shortened telomere length in white blood cells of patients with IDDM. Diabetes 47:482–486PubMedCrossRefGoogle Scholar
  9. 9.
    Adaikalakoteswari A, Balasubramanyam M, Mohan V (2005) Telomere shortening occurs in Asian Indian Type 2 diabetic patients. Diabet Med 22:1151–1156PubMedCrossRefGoogle Scholar
  10. 10.
    Sampson MJ, Winterbone MS, Hughes JC et al (2006) Monocyte telomere shortening and oxidative DNA damage in type 2 diabetes. Diabetes Care 29:283–289PubMedCrossRefGoogle Scholar
  11. 11.
    Adaikalakoteswari A, Balasubramanyam M, Ravikumar R et al (2007) Association of telomere shortening with impaired glucose tolerance and diabetic macroangiopathy. Atherosclerosis 195:83–89PubMedCrossRefGoogle Scholar
  12. 12.
    Zee RY, Castonguay AJ, Barton NS et al (2010) Mean leukocyte telomere length shortening and type 2 diabetes mellitus: a case-control study. Transl Res 155:166–169PubMedCrossRefGoogle Scholar
  13. 13.
    Al-Attas OS, Al-Daghri NM, Alokail MS et al (2010) Adiposity and insulin resistance correlate with telomere length in middle-aged Arabs: the influence of circulating adiponectin. Eur J Endocrinol 163:601–607PubMedCrossRefGoogle Scholar
  14. 14.
    Salpea KD, Talmud PJ, Cooper JA et al (2010) Association of telomere length with type 2 diabetes, oxidative stress and UCP2 gene variation. Atherosclerosis 209:42–50PubMedCrossRefGoogle Scholar
  15. 15.
    Wu H, Yu Z, Qi Q et al (2011) Joint analysis of multiple biomarkers for identifying type 2 diabetes in middle-aged and older Chinese: a cross-sectional study. BMJ Open 1:e000191PubMedCrossRefGoogle Scholar
  16. 16.
    Deepa M, Pradeepa R, Rema M et al (2003) The Chennai Urban Rural Epidemiology Study (CURES)—Study design and Methodology (Urban Component) (CURES—1). J Assoc Physicians India 51:863–870PubMedGoogle Scholar
  17. 17.
    Alberti KG, Zimmet PZ (1998) Definition diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus, provisional report of a WHO Consultation. Diabet Med 15:539–553PubMedCrossRefGoogle Scholar
  18. 18.
    Kochl S, Niederstatter H, Parson W (2005) DNA extraction and quantitation of forensic samples using the phenol-chloroform method and real-time PCR. Methods Mol Biol 297:13–30PubMedGoogle Scholar
  19. 19.
    Cawthon RM (2002) Telomere measurement by quantitative PCR. Nucleic Acids Res 30:e47PubMedCrossRefGoogle Scholar
  20. 20.
    Yagi K (1976) A simple fluorometric assay for lipoperoxide in blood plasma. Biochem Med 15:212–216PubMedCrossRefGoogle Scholar
  21. 21.
    Serra V, Grune T, Sitte N et al (2000) Telomere length as a marker of oxidative stress in primary human fibroblast cultures. Ann N Y Acad Sci 908:327–330PubMedCrossRefGoogle Scholar
  22. 22.
    Mulder H (2010) Is shortening of telomeres the missing link between aging and the type 2 diabetes epidemic? Aging 2:634–636PubMedGoogle Scholar
  23. 23.
    Kuhlow D, Florian S, von Figura G et al (2010) Telomerase deficiency impairs glucose metabolism and insulin secretion. Aging 2:650–658PubMedGoogle Scholar
  24. 24.
    Guo N, Parry EM, Li LS et al (2011) Short telomeres compromise β-cell signaling and survival. PLoS ONE 6:e17858PubMedCrossRefGoogle Scholar
  25. 25.
    Slagboom PE, Droog S, Boomsma DI (1994) Genetic determination of telomere size in humans: a twin study of three age groups. Am J Hum Genet 55:876–882PubMedGoogle Scholar
  26. 26.
    Atzmon G, Cho M, Cawthon RM et al (2010) Evolution in health and medicine Sackler colloquium: genetic variation in human telomerase is associated with telomere length in Ashkenazi centenarians. Proc Natl Acad Sci USA 26(Suppl 1):1710–1717CrossRefGoogle Scholar
  27. 27.
    Shen Q, Zhang Z, Yu L et al (2011) Common variants near TERC are associated with leukocyte telomere length in the Chinese Han population. Eur J Hum Genet 19:721–723PubMedCrossRefGoogle Scholar
  28. 28.
    Cassidy A, De Vivo I, Liu Y et al (2010) Associations between diet, lifestyle factors, and telomere length in women. Am J Clin Nutr 91:1273–1280PubMedCrossRefGoogle Scholar
  29. 29.
    Joeng KS, Song EJ, Lee KJ et al (2004) Long lifespan in worms with long telomeric DNA. Nat Genet 36:607–611PubMedCrossRefGoogle Scholar
  30. 30.
    Xu F, Zhou X, Shen F et al (2012) Decreased peripheral blood mitochondrial DNA content is related to HbA(1c), fasting plasma glucose level and age of onset in type 2 diabetes mellitus. Diabet Med (in press)Google Scholar
  31. 31.
    Morgantini C, Natali A, Boldrini B et al (2011) Anti-inflammatory and antioxidant properties of HDLs are impaired in type 2 diabetes. Diabetes 60:2617–2623PubMedCrossRefGoogle Scholar
  32. 32.
    Harte AL, da Silva NF, Miller MA et al (2012) Telomere length attrition, a marker of biological senescence, is inversely correlated with triglycerides and cholesterol in south asian males with type 2 diabetes mellitus. Exp Diab Res (in press)Google Scholar
  33. 33.
    Bakker SJ, IJzerman RG, Teerlink T et al (2000) Cytosolic triglycerides and oxidative stress in central obesity: the missing link between excessive atherosclerosis, endothelial dysfunction, and beta-cell failure? Atherosclerosis 148:17–21PubMedCrossRefGoogle Scholar
  34. 34.
    Croteau DL, Stierum RH, Bohr VA (1999) Mitochondrial DNA repair pathways. Mutat Res 434:137–148PubMedGoogle Scholar
  35. 35.
    Szendroedi J, Phielix E, Roden M (2011) The role of mitochondria in insulin resistance and type 2 diabetes mellitus. Nat Rev Endocrinol 8:92–103PubMedCrossRefGoogle Scholar
  36. 36.
    Michel S, Wanet A, De Pauw A et al (2012) Crosstalk between mitochondrial (dys)function and mitochondrial abundance. J Cell Physiol 227:2297–2310Google Scholar
  37. 37.
    Song J, Oh JY, Sung YA et al (2001) Peripheral blood mitochondrial DNA content is related to insulin sensitivity in offspring of type 2 diabetic patients. Diabetes Care 24:865–869PubMedCrossRefGoogle Scholar
  38. 38.
    el-Sharnooby JA, Ahmed LM (2003) Potential relationship between peripheral blood mitochondrial DNA content and insulin resistance and secretion in offspring of type 2 diabetic patients. Egypt J Immunol 10:57–66PubMedGoogle Scholar
  39. 39.
    Morino K, Petersen KF, Shulman GI (2006) Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction. Diabetes 55:S9–S15PubMedCrossRefGoogle Scholar
  40. 40.
    Wong J, McLennan SV, Molyneaux L et al (2009) Mitochondrial DNA content in peripheral blood monocytes: relationship with age of diabetes onset and diabetic complications. Diabetologia 52:1953–1961PubMedCrossRefGoogle Scholar
  41. 41.
    Hsieh CJ, Weng SW, Liou CW et al (2011) Tissue-specific differences in mitochondrial DNA content in type 2 diabetes. Diabetes Res Clin Pract 92:106–110PubMedCrossRefGoogle Scholar
  42. 42.
    Lee HK, Song JH, Shin CS et al (1998) Decreased mitochondrial DNA content in peripheral blood precedes the development of non-insulin-dependent diabetes mellitus. Diabetes Res Clin Pract 42:161–167PubMedCrossRefGoogle Scholar
  43. 43.
    Lee JE, Park H, Ju YS et al (2009) Higher mitochondrial DNA copy number is associated with lower prevalence of microalbuminuria. Exp Mol Med 41:253–258PubMedCrossRefGoogle Scholar
  44. 44.
    Park SY, Choi GH, Choi HI et al (2005) Depletion of mitochondrial DNA causes impaired glucose utilization and insulin resistance in L6 GLUT4myc myocytes. J Biol Chem 280:9855–9864PubMedCrossRefGoogle Scholar
  45. 45.
    Mohan V, Deepa R, Pradeepa R et al (2005) Association of low adiponectin levels with the metabolic syndrome—the Chennai Urban Rural Epidemiology Study (CURES-4). Metabolism 54:476–481PubMedCrossRefGoogle Scholar
  46. 46.
    Wasim H, Al-Daghri NM, Chetty R et al (2006) Relationship of serum adiponectin and resistin to glucose intolerance and fat topography in South-Asians. Cardiovasc Diabetol 5:10PubMedCrossRefGoogle Scholar
  47. 47.
    Ryu HK, Yu SY, Park JS et al (2010) Hypoadiponectinemia is strongly associated with metabolic syndrome in Korean type 2 diabetes patients. J Am Coll Nutr 29:171–178PubMedGoogle Scholar
  48. 48.
    Lam KS, Xu A (2005) Adiponectin: protection of the endothelium. Curr Diab Rep 5:254–259PubMedCrossRefGoogle Scholar
  49. 49.
    Sandhya N, Gokulakrishnan K, Ravikumar R et al (2010) Association of hypoadiponectinemia with hypoglutathionemia in NAFLD subjects with and without type 2 diabetes. Dis Markers 29:213–221PubMedGoogle Scholar
  50. 50.
    Deng G, Long Y, Yu YR et al (2010) Adiponectin directly improves endothelial dysfunction in obese rats through the AMPK–eNOS pathway. Int J Obes 34:165–171CrossRefGoogle Scholar
  51. 51.
    Essick EE, Ouchi N, Wilson RM et al (2011) Adiponectin mediates cardioprotection in oxidative stress-induced cardiac myocyte remodeling. Am J Physiol Heart Circ Physiol 301:H984–H993PubMedCrossRefGoogle Scholar
  52. 52.
    Antonopoulos AS, Lee R, Margaritis M et al (2011) Adiponectin as a regulator of vascular redox state: therapeutic implications. Recent Pat Cardiovasc Drug Discov 6:78–88PubMedCrossRefGoogle Scholar
  53. 53.
    Detopoulou P, Panagiotakos DB, Chrysohoou C et al (2010) Dietary antioxidant capacity and concentration of adiponectin in apparently healthy adults: the ATTICA study. Eur J Clin Nutr 64:161–168PubMedCrossRefGoogle Scholar
  54. 54.
    Landrier JF, Gouranton E, El Yazidi C et al (2009) Adiponectin expression is induced by vitamin E via a peroxisome proliferator-activated receptor gamma-dependent mechanism. Endocrinology 150:5318–5325PubMedCrossRefGoogle Scholar
  55. 55.
    Chang J, Li Y, Huang Y et al (2010) Adiponectin prevents diabetic premature senescence of endothelial progenitor cells and promotes endothelial repair by suppressing the p38 MAP kinase/p16INK4A signaling pathway. Diabetes 59:2949–2959PubMedCrossRefGoogle Scholar
  56. 56.
    Passos JF, Saretzki G, von Zglinicki T (2007) DNA damage in telomeres and mitochondria during cellular senescence: is there a connection? Nucleic Acids Res 35:7505–7513PubMedCrossRefGoogle Scholar
  57. 57.
    Civitarese AE, Ukropcova B, Carling S et al (2006) Role of adiponectin in human skeletal muscle bioenergetics. Cell Metab 4:75–87PubMedCrossRefGoogle Scholar
  58. 58.
    Iwabu M, Yamauchi T, Okada-Iwabu M et al (2010) Adiponectin and AdipoR1 regulate PGC-1alpha and mitochondria by Ca(2+) and AMPK/SIRT1. Nature 464:1313–1319PubMedCrossRefGoogle Scholar
  59. 59.
    Koh EH, Park JY, Park HS et al (2007) Essential role of mitochondrial function in adiponectin synthesis in adipocytes. Diabetes 56:2973–2981PubMedCrossRefGoogle Scholar
  60. 60.
    Sahin E, Colla S, Liesa M et al (2011) Telomere dysfunction induces metabolic and mitochondrial compromise. Nature 470:359–365PubMedCrossRefGoogle Scholar
  61. 61.
    Joseph A, Joanisse DR, Baillot RG et al (2012) Mitochondrial dysregulation in the pathogenesis of diabetes: potential for mitochondrial biogenesis-mediated interventions. Exp Diab Res (in press)Google Scholar
  62. 62.
    Jheng HF, Tsai PJ, Guo SM et al (2012) Mitochondrial fission contributes to mitochondrial dysfunction and insulin resistance in skeletal muscle. Mol Cell Biol 32:309–319PubMedCrossRefGoogle Scholar
  63. 63.
    Kelly DP (2011) Ageing theories unified. Nature 470:342–343PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2012

Authors and Affiliations

  • Finny Monickaraj
    • 1
  • Sankaramoorthy Aravind
    • 1
  • Kuppan Gokulakrishnan
    • 1
  • Chandrakumar Sathishkumar
    • 1
  • Paramasivam Prabu
    • 1
  • Durai Prabu
    • 1
  • Viswanathan Mohan
    • 1
  • Muthuswamy Balasubramanyam
    • 1
  1. 1.Department of Cell and Molecular BiologyMadras Diabetes Research Foundation and Dr. Mohan’s Diabetes Specialities Centre, WHO Collaborating Centre for Non-Communicable Diseases Prevention and Control, IDF Centre of EducationChennaiIndia

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