title: 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.
abstract: Recent evidence shows divergence between the concentrations of extracellular 70 kDa heat shock protein [eHSP70] and its intracellular concentrations [iHSP70] in people with type 2 diabetes (T2DM). A vital aspect regarding HSP70 physiology is its versatility to induce antagonistic actions, depending on the location of the protein. For example, iHSP70 exerts a powerful anti-inflammatory effect, while eHSP70 activates proinflammatory pathways. Increased eHSP70 is associated with inflammatory and oxidative stress conditions, whereas decreased iHSP70 levels are related to insulin resistance in skeletal muscle. Serum eHSP70 concentrations are positively correlated with markers of inflammation, such as C-reactive protein, monocyte count, and TNF-α, while strategies to enhance iHSP70 (e.g., heat treatment, chemical HSP70 inducers or coinducers, and physical exercise) are capable of reducing the inflammatory profile and the insulin resistance state. Here, we present recent findings suggesting that imbalances in the HSP70 status, described by the [eHSP70]/[iHSP70] ratio, may be determinant to trigger a chronic proinflammatory state that leads to insulin resistance and T2DM development. This led us to hypothesize that changes in this ratio value could be used as a biomarker for the management of the inflammatory response in insulin resistance and diabetes.
authors: Laboratory of Cellular Physiology, Department of Physiology, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, 90050-170 Porto Alegre, RS, Brazil.
authors: Mauricio
authors: M
authors: Krause
authors: Laboratory of Cellular Physiology, Department of Physiology, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, 90050-170 Porto Alegre, RS, Brazil ; National Institute of Science and Technology in Hormones and Women's Health (INCT-HSM), 90035-003 Porto Alegre, RS, Brazil ; Department of Life Sciences, Regional University of Northwestern Rio Grande do Sul State (UNIJUÍ), 98700-000 Ijuí, RS, Brazil.
authors: Thiago Gomes
authors: TG
authors: Heck
authors: Laboratory of Cellular Physiology, Department of Physiology, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, 90050-170 Porto Alegre, RS, Brazil ; National Institute of Science and Technology in Hormones and Women's Health (INCT-HSM), 90035-003 Porto Alegre, RS, Brazil.
authors: Aline
authors: A
authors: Bittencourt
authors: Laboratory of Cellular Physiology, Department of Physiology, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, 90050-170 Porto Alegre, RS, Brazil ; National Institute of Science and Technology in Hormones and Women's Health (INCT-HSM), 90035-003 Porto Alegre, RS, Brazil.
authors: Sofia Pizzato
authors: SP
authors: Scomazzon
authors: School of Biomedical Sciences, CHIRI Biosciences, Curtin University, Perth, WA 6845, Australia.
authors: Philip
authors: P
authors: Newsholme
authors: Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
authors: Rui
authors: R
authors: Curi
authors: Laboratory of Cellular Physiology, Department of Physiology, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, 90050-170 Porto Alegre, RS, Brazil ; National Institute of Science and Technology in Hormones and Women's Health (INCT-HSM), 90035-003 Porto Alegre, RS, Brazil.
authors: Paulo Ivo
authors: PI
authors: Homem de Bittencourt
mesh_terms: D003924:Diabetes Mellitus, Type 2 / Q000209:etiology*; D015444:Exercise; D018840:HSP70 Heat-Shock Proteins / Q000032:analysis / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000150:complications*; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000502:physiology; D009765:Obesity / Q000150:complications
chemical_list: D018840:HSP70 Heat-Shock Proteins