Cell Stress and Chaperones

, Volume 15, Issue 6, pp 959–964 | Cite as

Increased serum HSP70 levels are associated with the duration of diabetes

  • Manouchehr NakhjavaniEmail author
  • Afsaneh Morteza
  • Leila Khajeali
  • Alireza Esteghamati
  • Omid Khalilzadeh
  • Firouzeh Asgarani
  • Tiago F. Outeiro
Original Paper


The evolutionary conserved family of heat shock proteins (HSP) is responsible for protecting cells against different types of stress, including oxidative stress. Although the levels of HSPs can be readily measured in blood serum, the levels of HSP70 in patients with different durations of diabetes have not been studied before. We quantified serum HSP70 levels in a healthy control group (n = 36) and two groups of type 2 diabetic patients, defined as newly diagnosed diabetes (n = 36) and patients with diabetes duration of more than 5 years (n = 37). The clinical characteristics and biochemical parameters were evaluated in the studied population. We found that serum HSP70 levels were significantly higher in patients with diabetes when compared with controls (p < 0.001) and it was higher in patients with disease for more than 5 years than in newly diagnosed patients (p < 0.001). Serum HSP70 was inversely correlated with fasting blood sugar in patients with diabetes for more than 5 years (r = −0.500, p = 0.002), positively correlated with the history of hypertension in newly diagnosed patients (p < 0.001), and positively correlated with age in patients with diabetes (r = 0.531, p = 0.001). Serum level of HSP70 is significantly higher in patients with diabetes and correlates with the duration of disease. Higher HSP70 in prolonged diabetes versus newly diagnosed diabetes may be an indicator of metabolic derangement in the course of diabetes.


HSP70 Type2 diabetes Diabetes duration 


  1. Asea A (2008) Hsp70: a chaperokine. Novartis Found Symp 291:173–179, discussion 179–183, 221–174CrossRefPubMedGoogle Scholar
  2. Atalay M, Oksala N, Lappalainen J, Laaksonen DE, Sen CK, Roy S (2009) Heat shock proteins in diabetes and wound healing. Curr Protein Pept Sci 10:85–95CrossRefPubMedGoogle Scholar
  3. Atalay M, Oksala NKJ, Laaksonen DE, Khanna S, Nakao C, Lappalainen J, Roy S, Hnninen O, Sen CK (2004) Exercise training modulates heat shock protein response in diabetic rats. J Appl Physiol 97:605–611CrossRefPubMedGoogle Scholar
  4. Bhatia S, Shukla R, Venkata Madhu S, Kaur Gambhir J, Madhava Prabhu K (2003) Antioxidant status, lipid peroxidation and nitric oxide end products in patients of type 2 diabetes mellitus with nephropathy. Clin Biochem 36:557–562CrossRefPubMedGoogle Scholar
  5. Bouassida KZ, Chouchane L, Jellouli K, Cherif S, Haddad S, Gabbouj S, Danguir J (2004) Polymorphism of stress protein HSP70-2 gene in Tunisians: susceptibility implications in type 2 diabetes and obesity. Diabetes Metab 30:175–180CrossRefGoogle Scholar
  6. Calabrese V, Mancuso C, Sapienza M, Puleo E, Calafato S, Cornelius C, Finocchiaro M, Mangiameli A, Di Mauro M, Stella AM, Castellino P (2007) Oxidative stress and cellular stress response in diabetic nephropathy. Cell Stress Chaperones 12:299–306CrossRefPubMedGoogle Scholar
  7. Calderwood SK, Murshid A, Prince T (2009) The shock of aging: molecular chaperones and the heat shock response in longevity and aging—a mini-review. Gerontology 55:550–558CrossRefPubMedGoogle Scholar
  8. Csermely P (2008) The biology of extracellular molecular chaperones. Chair's introduction. Novartis Foundation Symposium 291:1–2CrossRefPubMedGoogle Scholar
  9. American Diabetes Association (2009) Diagnosis and classification of diabetes mellitus. Diabetes Care 32(Suppl 1):S62–S67CrossRefGoogle Scholar
  10. Febbraio MA, Ott P, Nielsen HB, Steensberg A, Keller C, Krustrup P, Secher NH, Pedersen BK (2002) Exercise induces hepatosplanchnic release of heat shock protein 72 in humans. J Physiol 544:957–962CrossRefPubMedGoogle Scholar
  11. Fortes MB, Whitham M (2009) No endogenous circadian rhythm in resting plasma Hsp72 concentration in humans. Cell Stress Chaperones 14:273–280CrossRefPubMedGoogle Scholar
  12. Gruden G, Bruno G, Chaturvedi N, Burt D, Pinach S, Schalkwijk C, Stehouwer CD, Witte DR, Fuller JH, Cavallo-Perin P (2009) ANTI-HSP60 and ANTI-HSP70 antibody levels and micro/macrovascular complications in type 1 diabetes: the EURODIAB Study. J Intern Med 266:527–536CrossRefPubMedGoogle Scholar
  13. Hooper PL (2007) Insulin signaling, GSK-3, heat shock proteins and the natural history of type 2 diabetes mellitus: a hypothesis. Metab Syndr Relat Disord 5:220–230CrossRefPubMedGoogle Scholar
  14. Hooper PL, Hooper JJ (2004) Is low-heat shock protein 70 a primary or a secondary event in the development of atherosclerosis? Hypertension 43:e18–e19, author reply e18-19CrossRefPubMedGoogle Scholar
  15. Hooper PL, Hooper PL (2009) Inflammation, heat shock proteins, and type 2 diabetes. Cell Stress and Chaperones 14:113–115CrossRefPubMedGoogle Scholar
  16. Hunter-Lavin C, Hudson PR, Mukherjee S, Davies GK, Williams CP, Harvey JN, Child DF, Williams JH (2004) Folate supplementation reduces serum hsp70 levels in patients with type 2 diabetes. Cell Stress Chaperones 9:344–349CrossRefPubMedGoogle Scholar
  17. Ireland HE, Leoni F, Altaie O, Birch CS, Coleman RC, Hunter-Lavin C, Williams JH (2007) Measuring the secretion of heat shock proteins from cells. Methods 43:176–183CrossRefPubMedGoogle Scholar
  18. Jafarnejad A, Bathaie SZ, Nakhjavani M, Hassan MZ (2008) Investigation of the mechanisms involved in the high-dose and long-term acetyl salicylic acid therapy of type I diabetic rats. J Pharmacol Exp Ther 324:850–857CrossRefPubMedGoogle Scholar
  19. Kavanagh K, Zhang L, Wagner JD (2009) Tissue-specific regulation and expression of heat shock proteins in type 2 diabetic monkeys. Cell stress & chaperones 14:291–299CrossRefGoogle Scholar
  20. Lappalainen Z, Lappalainen J, Oksala NK, Laaksonen DE, Khanna S, Sen CK, Atalay M (2008) Exercise training and experimental diabetes modulate heat shock protein response in brain. Scand J Med Sci Sports (in press)Google Scholar
  21. Li G, Ali IS, Currie RW (2006) Insulin induces myocardial protection and Hsp70 localization to plasma membranes in rat hearts. Am J Physiol Heart Circ Physiol 291:H1709–1721CrossRefPubMedGoogle Scholar
  22. Li JX, Tang BP, Sun HP, Feng M, Cheng ZH, Niu WQ (2009) Interacting contribution of the five polymorphisms in three genes of Hsp70 family to essential hypertension in Uygur ethnicity. Cell Stress Chaperones 14:355–362CrossRefPubMedGoogle Scholar
  23. Mayer MP, Bukau B (2005) Hsp70 chaperones: cellular functions and molecular mechanism. Cell Mol Life Sci 62:670–684CrossRefPubMedGoogle Scholar
  24. Molvarec A, Prohaszka Z, Nagy B, Szalay J, Fust G, Karadi I, Rigo J Jr (2006) Association of elevated serum heat-shock protein 70 concentration with transient hypertension of pregnancy, preeclampsia and superimposed preeclampsia: a case-control study. Hum Hypertens 20:780–786CrossRefGoogle Scholar
  25. Njemini R, Demanet C, Mets T (2004) Inflammatory status as an important determinant of heat shock protein 70 serum concentrations during aging. Biogerontology 5:31–38CrossRefPubMedGoogle Scholar
  26. Njemini R, Lambert M, Demanet C, Vanden Abeele M, Vandebosch S, Mets T (2003) The induction of heat shock protein 70 in peripheral mononuclear blood cells in elderly patients: a role for inflammatory markers. Hum Immunol 64:575–585PubMedGoogle Scholar
  27. Oglesbee MJ, Herdman AV, Passmore GG, Hoffman WH (2005) Diabetic ketoacidosis increases extracellular levels of the major inducible 70-kDa heat shock protein. J Biomed Biotechnol 38:900–904Google Scholar
  28. Oksala NK, Lappalainen J, Laaksonen DE, Khanna S, Kaarniranta K, Sen CK, Atalay M (2007) Alpha-lipoic acid modulates heat shock factor-1 expression in streptozotocin-induced diabetic rat kidney. Antioxid Redox Signal 9:497–506CrossRefPubMedGoogle Scholar
  29. Oksala NKJ, Laaksonen DE, Lappalainen J, Khanna S, Nakao C, Hanninen O, Sen CK, Atalay M (2006) Heat shock protein 60 response to exercise in diabetes. Effects of a-lipoic acid supplementation. J Diabetes Complications 20:257–261CrossRefPubMedGoogle Scholar
  30. Pandey KB, Mishra N, Rizvi SI (2009) Protein oxidation biomarkers in plasma of type 2 diabetic patients. Clin Biochem 23:23Google Scholar
  31. Patti ME, Butte AJ, Crunkhorn S, Cusi K, Berria R, Kashyap S, Miyazaki Y, Kohane I, Costello M, Saccone R, Landaker EJ, Goldfine AB, Mun E, DeFronzo R, Finlayson J, Kahn CR, Mandarino LJ (2003) Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: potential role of PGC1 and NRF1. Proceedings of the National Academy of Sciences of the United States of America 100:8466–8471CrossRefPubMedGoogle Scholar
  32. Pockley AG, Calderwood SK, Multhoff G (2009) The atheroprotective properties of Hsp70: a role for Hsp70-endothelial interactions? Cell Stress Chaperones 14:545–553CrossRefPubMedGoogle Scholar
  33. Pockley AG, Georgiades A, Thulin T, de Faire U, Frostegard J (2003) Serum heat shock protein 70 levels predict the development of atherosclerosis in subjects with established hypertension. Hypertension 42:235–238CrossRefPubMedGoogle Scholar
  34. Shan YX, Yang TL, Mestril R, Wang PH (2003) Hsp10 and Hsp60 suppress ubiquitination of insulin-like growth factor-1 receptor and augment insulin-like growth factor-1 receptor signaling in cardiac muscle: implications on decreased myocardial protection in diabetic cardiomyopathy. J Biol Chem 278:45492–45498CrossRefPubMedGoogle Scholar
  35. Shinohara T, Takahashi N, Ooie T, Hara M, Shigematsu S, Nakagawa M, Yonemochi H, Saikawa T, Yoshimatsu H (2006) Phosphatidylinositol 3-kinase-dependent activation of akt, an essential signal for hyperthermia-induced heat-shock protein 72, is attenuated in streptozotocin-induced diabetic heart. Diabetes 55:1307–1315CrossRefPubMedGoogle Scholar
  36. Soti C, Nagy E, Giricz Z, Vigh L, Csermely P, Ferdinandy P (2005) Heat shock proteins as emerging therapeutic targets. Br J Pharmacol 146:769–780CrossRefPubMedGoogle Scholar
  37. Vince RV, Oliver K, Midgley AW, McNaughton LR, Madden LA (2009) In vitro heat shock of human monocytes results in a proportional increase of inducible Hsp70 expression according to the basal content. Amino Acids 38:1423–1428CrossRefPubMedGoogle Scholar
  38. Wei W, Liu Q, Tan Y, Liu L, Li X, Cai L (2009) Oxidative stress, diabetes, and diabetic complications. Hemoglobin 33:370–377CrossRefPubMedGoogle Scholar
  39. Wright E Jr, Scism-Bacon JL, Glass LC (2006) Oxidative stress in type 2 diabetes: the role of fasting and postprandial glycaemia. Int J Clin Pract 60:308–314CrossRefPubMedGoogle Scholar
  40. Yabunaka N, Ohtsuka Y, Watanabe I, Noro H, Fujisawa H, Agishi Y (1995) Elevated levels of heat-shock protein 70 (HSP70) in the mononuclear cells of patients with non-insulin-dependent diabetes mellitus. Diabetes Res Clin Pract 30:143–147CrossRefPubMedGoogle Scholar
  41. Zhang X, He M, Cheng L, Chen Y, Zhou L, Zeng H, Pockley AG, Hu FB, Wu T (2008) Elevated heat shock protein 60 levels are associated with higher risk of coronary heart disease in Chinese. Circulation 118:2687–2693CrossRefPubMedGoogle Scholar

Copyright information

© Cell Stress Society International 2010

Authors and Affiliations

  • Manouchehr Nakhjavani
    • 1
    Email author
  • Afsaneh Morteza
    • 1
  • Leila Khajeali
    • 1
  • Alireza Esteghamati
    • 1
  • Omid Khalilzadeh
    • 1
  • Firouzeh Asgarani
    • 1
  • Tiago F. Outeiro
    • 2
    • 3
  1. 1.Endocrinology and Metabolism Research Center (EMRC), Vali-Asr HospitalTehran University of Medical SciencesTehranIran
  2. 2.Cell and Molecular Neuroscience UnitInstituto de Medicina MolecularLisbonPortugal
  3. 3.Instituto de Fisiologia, Faculdade de MedicinaUniversidade de LisboaLisboaPortugal

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