Sirtuin 6 affects glucose reabsorption and gluconeogenesis in type 1 diabetes via FoxO1

Aim: The purpose of this study was to explore the expression changes of Sirtuin 6 in diabetic renal tissues and the molecular mechanisms affecting renal tubular gluconeogenesis and reabsorption. Methods: The type 1 diabetic C57BL/6 mice model as well as high glucose cultured proximal tubular cells and cell lines were established. Sirt6 siRNA, the SGLT2 inhibitor (dapagliflozin), and insulin were pre-treated to make Sirtuin 6 levels, gluconeogenesis, and reabsorption changes. Immunofluorescence was used for Sirtuin 6 renal localization, and molecular biological detection was adopted for transcription factors, FoxO1, transporters (SGLT2 and GLUT2) as well as rate-limiting enzyme. Nuclear/plasma proteins were extracted to detect Sirtuin 6 and FoxO1 levels in the subcellular structure. Results: Sirtuin 6 was decreased in STZ-induced diabetic renal outer medulla, and lower both in high glucoseinduced primary proximal tubular cells and cell lines. Sirtuin 6 reversed the glucose reabsorption and gluconeogenesis effect via regulating FoxO1 and affecting nuclear translocation of FoxO1 in high glucose-induced proximal tubular cells. Conclusion: Sirtuin 6 affects renal glucose reabsorption and gluconeogenesis in type 1 diabetes by regulating FoxO1 nuclear import.