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

  • Mol Cell Endocrinol. 2022 May 1;547:111597. doi: 10.1016/j.mce.2022.111597.
Che Bian  1 ,  Ruijing Zhang  2 ,  Yuxia Wang  1 ,  Jia Li  1 ,  Yuling Song  1 ,  Dan Guo  1 ,  Jing Gao  3 ,  Huiwen Ren  4
Affiliations
  • 1. Department of Endocrinology and Metabolism, The Fourth Affiliated Hospital of China Medical University, Shenyang, China.
  • 2. Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, Liaoning, China.
  • 3. Department of Gerontology, Xin Hua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
  • 4. Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, Liaoning, China. Electronic address: [email protected].
PMID: 35157928 DOI: 10.1016/j.mce.2022.111597
Abstract

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 glucose-induced 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.

Keywords
Gluconeogenesis; Glucose reabsorption; Sirtuin 6; Type 1 diabetes.
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