Diabetic ketoacidosis increases extracellular levels of the major inducible 70-kDa heat shock protein Michael J. Oglesbee a, * , Anne V. Herdman b , Gregory G. Passmore c , William H. Hoffman d a Department of Veterinary Biosciences, The Ohio State University, 1925 Coffey Road, Columbus, OH 43210, USA b Department of Pathology, Medical College of Georgia, 1120 15th Street, Augusta, GA 30912, USA c Department of Biomedical and Radiological Technologies, Medical College of Georgia, 1120 15th Street, Augusta, GA 30912, USA d Department of Pediatrics, Medical College of Georgia, 1120 15th Street, Augusta, GA 30912, USA Received 24 February 2005; received in revised form 20 May 2005; accepted 26 May 2005 Available online 11 July 2005 Abstract Objectives: Diabetic ketoacidosis (DKA) represents a metabolic stress whose treatment induces a systemic proinflammatory cytokine profile and accentuates life-threatening acute complications. The present study determined whether serum levels of the major inducible 70- kDa heat shock protein (Hsp72), a modulator of cytokine expression, were influenced by DKA and its treatment. Design and methods: Serum levels of Hsp72 and glucose were measured in five adolescents with type 1 diabetes mellitus (T1DM) prior to, during and following correction of severe DKA. Samples from nine relatively euglycemic T1DM patients served as controls. Results: DKA pre-treatment samples showed significant elevation in Hsp72 (40.8 T 6.9 ng/mL) relative to euglycemic T1DM controls (33.6 T 3.2 ng/mL) ( P < 0.05). Treatment resulted in a decline in Hsp72 to control levels within 24 h, with Hsp72 and glucose levels being tightly correlated (r = 0.9258). Conclusion: Extracellular Hsp72 is increased by DKA, paralleling changes in serum glucose levels. D 2005 The Canadian Society of Clinical Chemists. All rights reserved. Keywords: Diabetic ketoacidosis; Blood glucose; Hsp72 protein Introduction Heat shock proteins (Hsp’s) are grouped into families according to their molecular mass and consist of both constitutive and stress-inducible members. The 70-kDa family contains one of the most highly inducible isoforms, Hsp72, a protein that is minimally expressed in the cytosol and nucleus of all cells under normal physiologic con- ditions. Loss of cellular homeostasis is a potent signal for Hsp72 induction, where the chaperone functions of Hsp72 stabilize protein metabolism within the cell, thereby enhancing cell survival. Elevations in intracellular Hsp72 (iHsp72) levels can persist long after the induction stimulus occurs, these levels enhancing cellular resistance to other- wise noxious stimuli. Cells protected in this manner are considered pre-conditioned [1]. Hsp72 is also present in the extracellular environment (eHsp72), being released from necrotic cells [2] or produced by cells in response to various forms of acute sublethal stress [3]. Extracellular Hsp72 then acts as a danger signal to the organism, activating the immune system and stimulating a proinflammatory response [4–7]. Quantitative or qualitative changes in Hsp72 expression thus have the potential to modulate expression of a diverse array of diseases, given the far-reaching biological activities of intracellular and extracellular Hsp72 and the fact that Hsp72 induction is common to many forms of stress. The present work tested the hypothesis that eHsp72 is elevated in patients with type 1 diabetes mellitus (T1DM) during the metabolic crisis of diabetic ketoacidosis (DKA), and that levels change as a consequence of reversing the acidosis and regulating the blood glucose levels. Hsp72 is 0009-9120/$ - see front matter D 2005 The Canadian Society of Clinical Chemists. All rights reserved. doi:10.1016/j.clinbiochem.2005.05.011 * Corresponding author. Fax: +1 614 292 6473. E-mail address: oglesbee.1@osu.edu (M.J. Oglesbee). Clinical Biochemistry 38 (2005) 900 – 904