Abstract
Type 2 diabetes mellitus (T2DM) is a chronic disease manifested by hyperglycemia. It is essential to effectively control hyperglycemia to prevent complications of T2DM. Here, we hypothesize that repression of transcriptional activity of forkhead box O1 (FoxO1) via histone deacetylase inhibitors (HDACi) ameliorates hyperglycemia in T2DM rats. Methods: Male Long-Evans Tokushima Otsuka (LETO) and Otsuka Long-Evans Tokushima Fatty (OLETF) rats aged 14 weeks were administered sodium valproate (VPA, 0.71% w/v) dissolved in water for 20 weeks. Electrophoretic mobility shift assay (EMSA) and luciferase assay were performed for elucidation of transcriptional regulation through acetylation of FoxO1 by HDACi. Results: VPA attenuated blood glucose levels in accordance with a decrease in the expression of gluconeogenic genes in hyperglycemic OLETF rats. It has been shown that HDAC class I-specific and HDAC class IIa-specific inhibitors, as well as pan-HDAC inhibitors decrease FoxO1 enrichment at the cis-element of target gene promoters. Mutations in FoxO1 prevent its acetylation, thereby increasing its transcriptional activity. HDAC3 and HDAC4 interact with FoxO1, and knockdown of HDAC3, HDAC4, or their combination increases FoxO1 acetylation, thereby decreasing the expression of gluconeogenic genes. Conclusions: These results indicate that HDACi attenuates the transcriptional activity of FoxO1 by impeding deacetylation, thereby ameliorating hyperglycemia in T2DM rats.
Highlights
It is estimated that 371 million people have diabetes mellitus, and 1.5 million Americans are newly diagnosed with diabetes every year [1]
To determine how VPA reduces blood glucose levels, we investigated the expression of gluconeogenic genes in the liver of rats
These results suggest that interactions between forkhead box O1 (FoxO1) and the insulin response element (IRE) are stronger under hyperglycemic conditions than those under euglycemic conditions, and Histone deacetylases (HDACs) inhibitors impede these interactions
Summary
It is estimated that 371 million people have diabetes mellitus, and 1.5 million Americans are newly diagnosed with diabetes every year [1]. Type II diabetes mellitus (T2DM), which is caused by increased insulin resistance and decreased insulin secretion, accounts for 90–95% of people with diabetes [3]. Insulin decreases hepatic glucose production during states of nutrient abundance by activating the AKT Ser/Thr kinase and subsequent phosphorylation of FoxO1, thereby inhibiting nuclear translocation and increasing glucose uptake in peripheral tissues [4,5]. Dysfunction of these hormones leads to hyperglycemia (high glucose levels), which is a major symptom of diabetes mellitus
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