Skip to main content
SpringerLink
Log in

Extra and intra cellular HSP70 levels in adults with and without metabolic disorders: a systematic review and meta-analysis

  • Original Article
  • Published:
Cell Stress and Chaperones Aims and scope

Abstract

Metabolic disorders, such as obesity, type 2 diabetes mellitus (T2DM), and metabolic syndrome (MS) are related to chronic pro-inflammatory conditions. Evidence suggests that heat shock proteins are linked to metabolic disorders. Intracellular HSP70 (iHSP70) is mandatory for normal insulin signalling, and proteostasis, and exerts a powerful anti-inflammatory role. On the other hand, the extracellular (eHSP72) is linked with a pro-inflammatory state and induces insulin resistance in humans. Then, we conducted a systematic review with meta-analysis to summarize the data of HSP70 in people with and without metabolic disorders. PubMed, Embase, Scopus, and Web of Science databases were used. Eligibility criteria included observational and baseline data of experimental studies that assessed iHSP70 and/or eHSP72 in adults with metabolic disorders and healthy people. The risk of bias was assessed by the Newcastle–Ottawa scale. Meta-analysis was performed using a random-effect model and the mean difference was estimated for eHSP72 and the standardized mean difference for iHSP70. A total of 11,255 articles were retrieved, 31 articles were assessed for eligibility and 15 were included for data extraction. There was no difference in eHSP72 between metabolic disorders and healthy controls (mean difference (MD) = 0.11; 95% confidence interval (CIs) = -0.05 to 0.27; I2 = 95%). Subgroup analysis showed higher levels of eHSP72 in T2DM people than healthy ones (MD = 0.32; 95% CIs = 0.17 to 0.47; I2 = 92%). For iHSP70 no difference was found (standardized mean difference (SMD) =—0.24; 95% CIs =—1.62 to 1.15; I2 = 86%). Our results suggest that eHSP72 levels may be dependent on metabolic condition and no difference in iHSP70 levels are attributed to high heterogeneity level between studies (PROSPERO REGISTRATION: CRD42022323514).

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

ADA:

American Diabetes Association

BMI:

Body mass index

Cis:

Confidence interval

CRP:

C-reactive protein

ELISA:

Enzyme-linked immunosorbent assay

HOMA-IR:

Homeostatic model of insulin resistance index

HSPs:

Heat shock proteins

HSP72:

Heat shock protein of 72 kilodaltons (kDa)

iHSP72:

Intracellular HSP72

eHSP72:

Extracellular HSP72

FC:

Flow citometry

IR:

Insulin resistance

IQR:

Interquartile range

IHC:

Immunohistochemistry

MD:

Mean difference

SMD:

Standardized mean difference

MS:

Metabolic syndrome

NCEP – ATP III:

National Cholesterol Education Program Adult Treatment Panel

PBMC:

Peripheral blood mononuclear cells

SAT:

Subcutaneous adipose tissue

SOMA scan:

Slow Of‑rate Modifed Aptamer- scan assay

TNF-α:

Tumor necrosis factor–alpha

T2DM:

Type 2 diabetes mellitus

WB:

Western blot

WC:

Waist circumference

References

  • Abubaker J, Tiss A, Abu-Farha M et al (2013) DNAJB3/HSP-40 cochaperone is downregulated in obese humans and is restored by physical exercise. PLoS ONE 8:e69217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Alberti KG, Eckel RH, Grundy SM et al (2009) Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 120:1640–1645

    Article  CAS  PubMed  Google Scholar 

  • Alemi H, Khaloo P, Rabizadeh S et al (2019) Association of extracellular heat shock protein 70 and insulin resistance in type 2 diabetes; independent of obesity and C-reactive protein. Cell Stress Chaperones 24:69–75

    Article  CAS  PubMed  Google Scholar 

  • Archer AE, Von Schulze AT, Geiger PC (2017) Exercise, heat shock proteins and insulin resistance. Philos Trans R Soc Lond B Biol Sci 19:1738. https://doi.org/10.1098/rstb.2016.0529

  • Armutcu F, Ataymen M, Atmaca H, Gurel A (2008) Oxidative stress markers, C-reactive protein and heat shock protein 70 levels in subjects with metabolic syndrome. Clin Chem Lab Med 46:785–790

    Article  CAS  PubMed  Google Scholar 

  • Atkin AS, Moin ASM, Nandakumar M et al (2021) Impact of severe hypoglycemia on the heat shock and related protein response. Sci Rep 11:17057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Chung J, Nguyen AK, Henstridge DC et al (2008) HSP72 protects against obesity-induced insulin resistance. Proc Natl Acad Sci U S A 105:1739–1744

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dasu MR, Devaraj S, Park S, Jialal I (2010) Increased toll-like receptor (TLR) activation and TLR ligands in recently diagnosed type 2 diabetic subjects. Diabetes Care 33:861–868

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Deeks JJ, Higgins JP, Altman DG (eds) (2019) Chapter 10: Analysing data and undertaking meta-analyses. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (eds) Cochrane Handbook for Systematic Reviews of Interventions version 6.3 (updated February 2022). Cochrane, 2022. Available from www.training.cochrane.org/handbook

  • de Lemos Muller CH, Rech A, Botton CE et al (2018) Heat-induced extracellular HSP72 release is blunted in elderly diabetic people compared with healthy middle-aged and older adults, but it is partially restored by resistance training. Exp Gerontol 111:180–187

    Article  PubMed  Google Scholar 

  • de Matos MA, Ottone Vde O, Duarte TC et al (2014) Exercise reduces cellular stress related to skeletal muscle insulin resistance. Cell Stress Chaperones 19:263–270

    Article  PubMed  Google Scholar 

  • de Oliveira AA, Mendoza VO, Rastogi S, Nunes KP (2022) New insights into the role and therapeutic potential of HSP70 in diabetes. Pharmacol Res 178:106173

    Article  PubMed  Google Scholar 

  • Geiger PC, Gupte AA (2011) Heat shock proteins are important mediators of skeletal muscle insulin sensitivity. Exerc Sport Sci Rev 39:34–42

    Article  PubMed  PubMed Central  Google Scholar 

  • Henstridge DC, Forbes JM, Penfold SA et al (2010) The relationship between heat shock protein 72 expression in skeletal muscle and insulin sensitivity is dependent on adiposity. Metabolism 59:1556–1561

    Article  CAS  PubMed  Google Scholar 

  • Higgins JPT, Eldridge S, Li T (2022) Chapter 23: Including variants on randomized trials. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (eds) Cochrane Handbook for Systematic Reviews of Interventions version 6.3. Cochrane. Available from www.training.cochrane.org/handbook

  • Islam A, Hait SH, Andrews-Shigaki B, Carus S, Deuster PA (2014) Plasma HSP70 levels correlate with health risk factors and insulin resistance in African American subjects. Exp Clin Endocrinol Diabetes 122:496–501

    Article  CAS  PubMed  Google Scholar 

  • Kampinga HH, Hageman J, Vos MJ et al (2009) Guidelines for the nomenclature of the human heat shock proteins. Cell Stress Chaperones 14:105–111

    Article  CAS  PubMed  Google Scholar 

  • Kavanagh K, Davis AT, Jenkins KA, Flynn DM (2016) Effects of heated hydrotherapy on muscle HSP70 and glucose metabolism in old and young vervet monkeys. Cell Stress Chaperones 21:717–725

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Koshy L, Jeemon P, Ganapathi S, Madhavan M, Urulangodi M, Sharma M, Harikrishnan S (2021) Association of South Asian-specific MYBPC3Δ25bp deletion polymorphism and cardiomyopathy: A systematic review and meta-analysis. Meta Gene 28:100883. https://doi.org/10.1016/j.mgene.2021.100883

  • Krause M, Keane K, Rodrigues-Krause J et al (2013) Elevated levels of extracellular heat-shock protein 72 (eHSP72) are positively correlated with insulin resistance in vivo and cause pancreatic beta-cell dysfunction and death in vitro. Clin Sci (lond) 126:739–752

    Article  Google Scholar 

  • Krause M, Heck TG, Bittencourt A et al (2015a) The chaperone balance hypothesis: the importance of the extracellular to intracellular HSP70 ratio to inflammation-driven type 2 diabetes, the effect of exercise, and the implications for clinical management. Mediators Inflamm 2015:249205

    Article  PubMed  PubMed Central  Google Scholar 

  • Krause M, Bock PM, Takahashi HK, Homem De Bittencourt PI Jr, Newsholme P (2015) The regulatory roles of NADPH oxidase, intra- and extra-cellular HSP70 in pancreatic islet function, dysfunction and diabetes. Clin Sci Lond 128:789–803

    Article  PubMed  Google Scholar 

  • Lee YS, Li P, Huh JY et al (2011) Inflammation is necessary for long-term but not short-term high-fat diet-induced insulin resistance. Diabetes 60:2474–2483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lopez-Lopez JA, Page MJ, Lipsey MW, Higgins JPT (2018) Dealing with effect size multiplicity in systematic reviews and meta-analyses. Res Synth Methods 9:336–351. https://doi.org/10.1002/jrsm.1310

  • Moin ASM, Nandakumar M, Kahal H, Sathyapalan T, Atkin SL, Butler AE (2021) Heat shock-related protein responses and inflammatory protein changes are associated with mild prolonged hypoglycemia. Cells 10:3109. https://doi.org/10.3390/cells10113109

  • Nahas EA, Nahas-Neto J, Orsatti CL et al (2014) The 60- and 70-kDa heat-shock proteins and their correlation with cardiovascular risk factors in postmenopausal women with metabolic syndrome. Cell Stress Chaperones 19:559–568

    Article  CAS  PubMed  Google Scholar 

  • Nakhjavani M, Morteza A, Khajeali L et al (2010) Increased serum HSP70 levels are associated with the duration of diabetes. Cell Stress Chaperones 15:959–964

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nakhjavani M, Morteza A, Asgarani F et al (2012) The dual behavior of heat shock protein 70 and asymmetric dimethylarginine in relation to serum CRP levels in type 2 diabetes. Gene 498:107–111

    Article  CAS  PubMed  Google Scholar 

  • Nakhjavani M, Morteza A, Nargesi AA, Mostafavi E, Esteghamati A (2013) Appearance of leptin-HSP70 correlation, in type 2 diabetes. Meta Gene 1:1–7

    Article  PubMed  PubMed Central  Google Scholar 

  • Oglesbee MJ, Herdman AV, Passmore GG, Hoffman WH (2005) Diabetic ketoacidosis increases extracellular levels of the major inducible 70-kDa heat shock protein. Clin Biochem 38:900–904

    Article  CAS  PubMed  Google Scholar 

  • O’Neill S, O’Driscoll L (2015) Metabolic syndrome: a closer look at the growing epidemic and its associated pathologies. Obes Rev 16:1–12

    Article  CAS  PubMed  Google Scholar 

  • Page MJ, Higgins JPT, Sterne JAC (2022) Chapter 13: Assessing risk of bias due to missing results in a synthesis. In: Higgins JPT TJ, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (eds) Cochrane Handbook for Systematic Reviews of Interventions version 6.3 (updated February 2022). Cochrane, 2022. Available from www.training.cochrane.org/handbook

  • Rodrigues-Krause J, Krause M, O’Hagan C et al (2012) Divergence of intracellular and extracellular HSP72 in type 2 diabetes: does fat matter? Cell Stress Chaperones 17:293–302

    Article  PubMed  PubMed Central  Google Scholar 

  • Saklayen MG (2018) The Global Epidemic of the Metabolic Syndrome. Curr Hypertens Rep 20:12

    Article  PubMed  PubMed Central  Google Scholar 

  • Simar D, Jacques A, Caillaud C (2012) Heat shock proteins induction reduces stress kinases activation, potentially improving insulin signalling in monocytes from obese subjects. Cell Stress Chaperones 17:615–621

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stroup DF, Berlin JA, Morton SC et al (2000) Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 283:2008–2012

    Article  CAS  PubMed  Google Scholar 

  • Tiss A, Khadir A, Abubaker J et al (2014) Immunohistochemical profiling of the heat shock response in obese non-diabetic subjects revealed impaired expression of heat shock proteins in the adipose tissue. Lipids Health Dis 13:106

    Article  PubMed  PubMed Central  Google Scholar 

  • Wells G, Shea B, O’connell D, Peterson J, Welch V, Losos M, Tugwell P (2014) The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Available from http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp

Download references

Acknowledgements

C.H.L.M. and H.T.S. were supported by scholarships from Brazilian National Council for Scientific and Technological Development (CNPq, Brazil). M.K. is a Research Productivity Fellow of the Brazilian National Council for Scientific and Technological Development (CNPq, Brazil).

Funding

This work was supported by The State of Rio Grande do Sul Foundation for Research Support (FAPERGS; grant #30791.434.41354.23112017—CHAMADA FAPERGS/Decit/SCTIE/ MS/CNPq/SESRS n. 03/2017 – PPSUS, to M.K.)

Author information

Authors and Affiliations

  1. Laboratório de Pesquisa em Inflamação, Metabolismo e Exercício (LAPIMEX) E Laboratório de Fisiologia Celular, Departamento de Fisiologia, Instituto de Ciências Básicas da Saúde, Universidade Federal Do Rio Grande Do Sul (UFRGS), Porto Alegre, RS, 90035-003, Brazil

    Carlos Henrique de Lemos Muller, Helena Trevisan Schroeder & Maurício Krause

  2. Programa de Pós-Graduação Em Ciências Do Movimento Humano, Escola de Educação Física, Fisioterapia E Dança (ESEFID), Universidade Federal Do Rio Grande Do Sul (UFRGS), Porto Alegre, RS, 90690-200, Brazil

    Josianne Rodrigues-Krause

  3. Department of Physical Education, Physical Activity, Sport and Health Research Group, Sogipa Faculty, Porto Alegre, RS, Brazil

    Josianne Rodrigues-Krause

Authors
  1. Carlos Henrique de Lemos Muller
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Helena Trevisan Schroeder
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Josianne Rodrigues-Krause
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maurício Krause
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.K., J.R-K and C.H.L.M. conceived and designed research. Funding acquisition: M.K. Data extraction and analysis: C.H.L.M., H.T.S. and J.R-K. Writing—original draft preparation: C.H.L.M., J.R-K. and M.K. All authors read and approved the manuscript.

Corresponding author

Correspondence to Maurício Krause.

Ethics declarations

Conflict of interest

No potential conflict of interest was reported by the author(s).

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

de Lemos Muller, C.H., Schroeder, H.T., Rodrigues-Krause, J. et al. Extra and intra cellular HSP70 levels in adults with and without metabolic disorders: a systematic review and meta-analysis. Cell Stress and Chaperones 28, 761–771 (2023). https://doi.org/10.1007/s12192-023-01368-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12192-023-01368-3

Keywords

Search

Navigation