Sodium–Glucose Cotransporter 2 Inhibitors Work as a “Regulator” of Autophagic Activity in Overnutrition Diseases

Kazuhiko Fukushima, Shinji Kitamura, Kenji Tsuji, Jun Wada

Research output: Contribution to journalReview articlepeer-review

14 Citations (Scopus)


Several large clinical trials have shown renal and cardioprotective effects of sodium–glucose cotransporter 2 (SGLT2) inhibitors in diabetes patients, and the protective mechanisms need to be elucidated. There have been accumulating studies which report that SGLT2 inhibitors ameliorate autophagy deficiency of multiple organs. In overnutrition diseases, SGLT2 inhibitors affect the autophagy via various signaling pathways, including mammalian target of rapamycin (mTOR), sirtuin 1 (SIRT1), and hypoxia-inducible factor (HIF) pathways. Recently, it turned out that not only stagnation but also overactivation of autophagy causes cellular damages, indicating that therapeutic interventions which simply enhance or stagnate autophagy activity might be a “double-edged sword” in some situations. A small number of studies suggest that SGLT2 inhibitors not only activate but also suppress the autophagy flux depending on the situation, indicating that SGLT2 inhibitors can “regulate” autophagic activity and help achieve the appropriate autophagy flux in each organ. Considering the complicated control and bilateral characteristics of autophagy, the potential of SGLT2 inhibitors as the regulator of autophagic activity would be beneficial in the treatment of autophagy deficiency.

Original languageEnglish
Article number761842
JournalFrontiers in Pharmacology
Publication statusPublished - Oct 21 2021


  • HIFs
  • SGLT2 inhibitor
  • SIRT1
  • autophagic cell death
  • autophagy
  • diabetic kidney disease
  • mTOR
  • secretory autophagy

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)


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