PS 10-13 HISTONE DEACETYLASE INHIBITION AMELIORATES HYPERGLYCEMIA THROUGH DOWN-REGULATION OF GLUCONEOGENESIS

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Abstract

Objective:

Diabetes mellitus (DM) is a chronic disease manifested by hyperglycemia and dyslipidemia. Histone deacetylase (HDAC) inhibitors have been emerged as new pharmacological approaches in the control of DM. However, the roles for HDAC inhibition in controlling DM are still elusive. We hypothesized that HDAC inhibition ameliorates hyperglycemia through down-regulation of gluconeogenesis in type II diabetic rats.

Design and Method:

Male normoglycemic Long-Evans-Tokushima-Otsuka (LETO) and hyperglycemic Otsuka Long-Evans Tokushima Fatty (OLETF) rats aged 14 weeks were administered sodium valproate (VPA, 0.71% w/v) dissolved in drinking water for 20 weeks during which the levels of blood glucose were analyzed at 13 and 19 weeks. Blood chemistry such as glycated hemoglobin HbA1c, triglyceride and cholesterol were analyzed. The expression of gluconeogenic genes such as glucose 6-phosphatase, phosphoenolpyruvate carboxykinase, fructose-1,6-biphosphatase and pyruvate carboxylase was measured by quantitative real-time polymerase chain reaction. Acetylation of forkhead box protein O1 (FOXO1), which is a master transcription factor for gluconeogenic genes, was determined by western blot with an anti-acetyl-lysine antibody after immunoprecipitation with an anti-FOXO1 antibody.

Results:

The levels of blood glucose, HbA1c, triglyceride and cholesterol as well as body weight, were greater in OLETF rats than those in LETO rats. VPA administration attenuated weight gain, blood glucose, HbA1c, triglyceride and cholesterol, as well as the expression of gluconeogenic genes in OLETF rats but not in LETO rats. VPA increased acetylation of FOXO1, decreasing its transcription activity for gluconeogenic genes.

Conclusions:

These results suggest that HDAC inhibition ameliorates hyperglycemia through down-regulation of gluconeogenesis in type II diabetic rats.

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