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

R Winkler, V Benz, M Clemenz, M Bloch… - Diabetes, 2012 - Am Diabetes Assoc
R Winkler, V Benz, M Clemenz, M Bloch, A Foryst-Ludwig, S Wardat, N Witte, M Trappiel…
Diabetes, 2012Am Diabetes Assoc
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' …
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.
Am Diabetes Assoc