1,1-Diethoxyethane increases insulin sensitivity and ameliorates obesity and dyslipidemia in mice fed high-fat diet

Alcoholic beverages have been concerned not only for gastronomic delight but also for certain impacts on health, such as obesity, diabetes, and cardiovascular diseases. In this study, we assessed the bioactive functions of 1,1-Diethoxyethane (1,1-DEE), a flavoring compound formed during the aging process of wine by flor yeast, using both cultured cell lines and a high-fat diet (HFD) mouse model. 1,1-DEE was identified in the batches of ethanol that induced oxidation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) using gel mobility shift assay and gas chromatography-mass spectrometry. PTEN was reversibly oxidized when exposed to 1,1-DEE, but 1,2-DEE did not induce PTEN oxidation. Mechanistically, 1,1-DEE treatment enhanced the production of mitochondrial reactive oxygen species, accompanying by oxidation of PTEN and subsequent activation of Akt signaling. 1,1-DEE treatment elevated Akt activation when combined with insulin, compared with insulin alone, and alleviated palmitate-induced insulin resistance in C2C12 myoblasts. Moreover, the oral administration of 1,1-DEE alleviated glucose intolerance and insulin resistance in HFD-fed mice. 1,1-DEE also mitigated HFD-induced body weight gain and hepatic dyslipidemia without reduction of food intake. Transcriptome analysis revealed significant genes involved in the improvement of insulin sensitivity and dyslipidemia. Thus, 1,1-DEE may serve as a promising therapeutic agent for the intervention of obesity, diabetes, and dyslipidemia.