TABLE 1.
Proposed effects of SGLT2 inhibitors on autophagy deficiency in each organ/cell and disease.
| Organ/cell | Disease/stress | Proposed mechanisms |
|---|---|---|
| Kidney | ||
| Proximal tubular cell | Obesity | AMPK/mTOR signaling (Fukushima et al., 2020) |
| Improvement of lysosomal capacity (Fukushima et al., 2020) | ||
| DKD | AMPK/mTOR signaling (Lee et al., 2019) | |
| Podocyte | DKD | Beclin1 activation (Korbut et al., 2020) |
| (No mention on cell) | Obesity | AMPK/mTOR signaling (Jaikumkao et al., 2021) |
| Heart | Diabetic hearts | Cardiotoxic lipids reduction and AMPK activation (Aragon-Herrera et al., 2019) |
| Inhibiting microRNA-30d expression (Zhang et al., 2020) | ||
| DOX cardiomyopathy | Beclin1/toll-like receptor 9/SIRT3 axis (Wang et al., 2020) | |
| SNT-induced cardiac dysfunction | AMPK–mTOR signaling pathway (Ren et al., 2021) | |
| Myocardial infarction | Beclin1 suppression via NHE1 inhibition (Jiang et al., 2021) a | |
| Myocardial infarction of diabetic hearts | Increase of BNIP3 expression (Mizuno et al., 2018) | |
| Liver | ||
| Hepatocyte | Hepatic steatosis in type 2 DM | AMPK/mTOR signaling and Beclin1 activation (Li et al., 2021) |
| NAFLD | AMPK/mTOR signaling and suppression of SREBP1c (Nasiri-Ansari et al., 2021) | |
| Hepatic macrophage | NAFLD | AMPK/mTOR signaling (Meng et al., 2021) |
| Colon | Inflammatory bowel disease | AMPK/mTOR signaling pathway and Beclin1 activation (Arab et al., 2021) |
| Nerve system striatum | Huntington’s disease | Suppression of glycolysis, apoptosis, and inflammation (El-Sahar et al., 2020) |
| Immune cells | Lipopolysaccharide induction | Inhibiting intracellular glucose metabolism resulting in AMPK activation and p62 increase (Xu et al., 2018) |
| HepG2 cell | DOX induction | Promoting ULK1 serine 757 phosphorylation (Zhong et al., 2020) a |
Proposed effects of SGLT2 inhibitors on autophagy deficiency in each organ/cell and disease. AMPK, AMP-activated protein kinase; BNIP3, BCL2-interacting protein 3; DKD, diabetic kidney disease; DM, diabetes mellitus; DOX, doxorubicin; mTOR, mammalian target of rapamycin; NAFLD, nonalcoholic fatty liver disease; NHE1, Na+/H+ exchanger 1; SIRT3, sirtuin 3; SNT, sunitinib; SREBP1c, sterol regulatory element–binding protein 1c; ULK1, Unc-51–like autophagy-activating kinase 1.
a
Indicates the suppression effects of overactivated autophagy, and all the others are the activation effects of stagnated autophagy.