Histone Deacetylase 6 (HDAC6) Is an Essential Modifier of Glucocorticoid-Induced Hepatic Gluconeogenesis

  1. Ulrich Kintscher1
  1. 1Institute of Pharmacology, Charité Medical University, Center for Cardiovascular Research, Berlin, Germany
  2. 2Department of Endocrinology, Diabetes and Nutrition, Charité Medical University, Center for Cardiovascular Research, Berlin, Germany
  3. 3Institute of Laboratory Medicine, Charité Medical University, Center for Cardiovascular Research, Berlin, Germany
  4. 4Friedrich-Miescher-Institute for Biomedical Research, Basel, Switzerland
  1. Corresponding author: Ulrich Kintscher, ulrich.kintscher{at}


In the current study, we investigated the importance of histone deacetylase (HDAC)6 for glucocorticoid receptor–mediated effects on glucose metabolism and its potential as a therapeutic target for the prevention of glucocorticoid-induced diabetes. Dexamethasone-induced hepatic glucose output and glucocorticoid receptor translocation were analyzed in wild-type (wt) and HDAC6-deficient (HDAC6KO) mice. The effect of the specific HDAC6 inhibitor tubacin was analyzed in vitro. wt and HDAC6KO mice were subjected to 3 weeks’ dexamethasone treatment before analysis of glucose and insulin tolerance. HDAC6KO mice showed impaired dexamethasone-induced hepatic glucocorticoid receptor translocation. Accordingly, dexamethasone-induced expression of a large number of hepatic genes was significantly attenuated in mice lacking HDAC6 and by tubacin in vitro. Glucose output of primary hepatocytes from HDAC6KO mice was diminished. A significant improvement of dexamethasone-induced whole-body glucose intolerance as well as insulin resistance in HDAC6KO mice compared with wt littermates was observed. This study demonstrates that HDAC6 is an essential regulator of hepatic glucocorticoid-stimulated gluconeogenesis and impairment of whole-body glucose metabolism through modification of glucocorticoid receptor nuclear translocation. Selective pharmacological inhibition of HDAC6 may provide a future therapeutic option against the prodiabetogenic actions of glucocorticoids.

  • Received March 7, 2011.
  • Accepted November 25, 2011.

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  1. Diabetes vol. 61 no. 2 513-523
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