Aims: Dapagliflozin(Dapa) improves glycemia by increasing glucosuria, but it enhances renal gluconeogenesis, thus reducing its efficacy. Resveratrol (RSV) inhibits hepatic gluconeogenesis by increasing insulin sensitivity. Our study aims to determine if RSV can reduce dapa-induced renal gluconeogenesis via modulating the PI3K/Akt/FoxO1 pathway.

Methods: Glucose produced via gluconeogenesis was tested by glucose assay kit. Changes in insulin signaling and gluconeogenic key enzymes were detected by RT-PCR and western blot.

Results: Dapa induced glucose production and the expression of gluconeogenic enzymes (PEPCK, G6Pase) via increasing the expression of FoxO1 in HK-2 cells. RSV treatment reversed all these findings by up-regulating pFoxO1 expression. The PI3K inhibitor LY294002 restained the pFoxO1 expression and subsequently inhibited PEPCK and G6Pase expression via PI3K/Akt-mediated FoxO1 inactivation.

Conclusion: Our data show that RSV ameliorates gluconeogenesis via modulating the PI3K-Akt-FoxO1-PEPCK/G6Pase pathway in dapa-treated HK-2 cells. This mechanism provides a basis for pharmaceutial intervention in order to achieve better hypoglycemic effect in future animal and human research.

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© 2020 by the American Diabetes Association
2020
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