Abstract
We propose that type 2 diabetes results from a vicious cycle of metabolically induced inflammation, impaired insulin responsiveness, and subsequent loss of homeostatic signaling. A crucial and previously under-recognized event contributing to this loss of homeostasis is a reduction in heat shock proteins (HSPs, or stress proteins). The central causal pathways of this cycle are the following: (a) obesity-driven inflammation promotes insulin resistance; (b) impaired insulin signaling in turn reduces the expression of HSPs, leaving tissues vulnerable to damage and allowing the accumulation of harmful proteins aggregates; and (c) resulting damage to the pancreatic beta-cell leads to further losses in insulin signaling, while a decline in anti-inflammatory HSPs allows inflammation to expand unhindered. Obesity and sedentary lifestyle perpetuate this cycle, while dieting and exercise forestall it by raising HSPs, reducing inflammation, and improving insulin signaling. Because HSP expression carries substantial metabolic costs, it is likely that an evolutionary history of high activity levels and resource scarcity selected for more conservative HSP expression than is appropriate for our current environment of caloric abundance.
References
Atalay M, Oksala NKJ, Laaksonen DE, Khanna S, Nakao C, Lappalainen J, Roy S, Hänninen O, Sen CK (2004) Exercise training modulates heat shock protein response in diabetic rats. J Appl Physiol 97:605–611, doi:10.1152/japplphysiol.01183.2003
Bitar MS, Farook T, John B, Francis IM (1999) Heat-shock protein 72/73 and impaired wound healing in diabetic and hypercortisolemic states. Surgery 125:594–601
Brown I (2007) Heat shock proteins and protection of the nervous system. Ann NY Acad Sci 1113:147–158, doi:10.1196/annals.1391.032
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, doi:10.2337/diabetes.52.9.2338
Chu B, Zhong R, Soncin F, Stevenson MA, Calderwood SK (1998) Transcriptional activity of heat shock factor 1 at 37 degrees C is repressed through phosphorylation on two distinct serine residues by glycogen synthase kinase 3 and protein kinases C alpha and C zeta. J Biol Chem 273:18640–18646, doi:10.1074/jbc.273.29.18640
Chung J, Nguyen AK, Henstridge DC, Holmes AG, Chan MH, Mesa JL, Lancaster GI, Southgate RJ, Bruce CR, Duffy SJ, Horvath I, Mestril R, Watt MJ, Hooper PL, Kingwell BA, Vigh L, Hevener A, Febbraio MA (2008) HSP72 protects against obesity-induced insulin resistance. Proc Nat Acad Sci 105:1739–1744, doi:10.1073/pnas.0705799105
Ferrándiz ML, Devesa I (2008) Inducers of heme oxygenase-1. Curr Pharm Des 14:473–486, doi:10.2174/138161208783597399
Gabai VL, Meriin AB, Mosser DD, Caron AW, Rits S, Shifrin VI, Sherman MY (1997) Hsp70 prevents activation of stress kinases: a novel pathway of cellular thermotolerance. J Biol Chem 272:18033–18037, doi:10.1074/jbc.272.29.18033
Hayden MR, Tyagi SC, Kerklo MM, Nicolls MR (2005) Type 2 diabetes mellitus as a conformational disease. JOP 6:287–302
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 5:220–230, doi:10.1089/met.2007.0005
Hotamışlıgil GS (2006) Inflammation and metabolic disorders. Nature 444:860–867, doi:10.1038/nature05485
Kavanagh K, Nelson C, Jenkins KA, Zhang L, Flynn DM, Butler PC, Wagner JD (2008) Decreased chaperone protein HSP70 in diabetic monkeys results from hyperglycemia-associated impairment of heat shock factor-1 induction and activation. Diabetes 57, suppl 1, A535, 1930. (Abstract)
Li M, Kim DH, Tsenovoy PL, Peterson SJ, Rezzani R, Rodella LF, Aronow WS, Ikehara S, Abraham NG (2008) Treatment of obese diabetes mice with a heme oxygenase inducer reduces visceral and subcutaneous adiposity, increases adiponectin levels, and improves insulin sensitivity and glucose tolerance. Diabetes 57:1526–1535, doi:10.2337/db07-1764
Lu A, Ran RQ, Clark J, Reilly M, Nee A, Sharp FR (2002) 17-beta-estradiol induces heat shock proteins in brain arteries and potentiates ischemic heat shock protein induction in glia and neurons. J Cereb Blood Flow Metab 22:183–195, doi:10.1097/00004647-200202000-00006
Özcan U, Yılmaz E, Özcan L, Furuhashi M, Vaillancourt E, Smith RO, Görgün CZ, Hotamışlıgil GS (2006) Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 313:1137–1140, doi:10.1126/science.1128294
Park J, Liu AY (2001) JNK phosphorylates the HSF1 transcriptional activation domain: role of JNK in the regulation of the heat shock response. J Cell Biochem 82:326–338, doi:10.1002/jcb.1163
Ren M, Leng Y, Jeong MR, Leeds PR, Chuang DM (2004) Valproic acid reduces brain damage induced by transient focal cerebral ischemia in rats: potential roles of histone deacetylase inhibition and heat shock protein induction. J Neurochem 89:1358–1367, doi:10.1111/j.1471-4159.2004.02406.x
Salazar M, Rojo AI, Velasco D, de Sagarra RM, Cuadrado A (2006) Glycogen synthase kinase-3beta inhibits the xenobiotic and antioxidant cell response by direct phosphorylation and nuclear exclusion of the transcription factor Nrf2. J Biol Chem 281:14841–14851, doi:10.1074/jbc.M513737200
Shoelson SE, Lee J, Goldfine AB (2006) Inflammation and insulin resistance. J Clin Invest 116:1793–1801, doi:10.1172/JCI29069
Stice JP, Knowlton AA (2008) Estrogen, NFkappaB and the Heat Shock Response. Mol Med 14:517–527
Wigmore SJ, Sangster K, McNally SJ, Harrison EM, Ross JA, Fearon KCH, Garden OJ (2007) De-repression of heat shock transcription factor-1 in interleukin-6-treated hepatocytes is mediated by down regulation of glycogen synthase kinase 3beta and MAPK/ERK-1. Int J Mol Med 19:413–420
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Hooper, P.L., Hooper, P.L. Inflammation, heat shock proteins, and type 2 diabetes. Cell Stress and Chaperones 14, 113–115 (2009). https://doi.org/10.1007/s12192-008-0073-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12192-008-0073-x