The DOI matches its Crossref record; 44 of the 44 references it cites were found in a registry or an index.
The Na+/Glucose Cotransporter Inhibitor Canagliflozin Activates AMPK by Inhibiting Mitochondrial Function and Increasing Cellular AMP Levels
Open accessAbstract
Canagliflozin, dapagliflozin, and empagliflozin, all recently approved for treatment of type 2 diabetes, were derived from the natural product phlorizin. They reduce hyperglycemia by inhibiting glucose reuptake by sodium/glucose cotransporter (SGLT) 2 in the kidney, without affecting intestinal glucose uptake by SGLT1. We now report that canagliflozin also activates AMPK, an effect also seen with phloretin (the aglycone breakdown product of phlorizin), but not to any significant extent with dapagliflozin, empagliflozin, or phlorizin. AMPK activation occurred at canagliflozin concentrations measured in human plasma in clinical trials and was caused by inhibition of Complex I of the respiratory chain, leading to increases in cellular AMP or ADP. Although canagliflozin also inhibited cellular glucose uptake independently of SGLT2, this did not account for AMPK activation. Canagliflozin also inhibited lipid synthesis, an effect that was absent in AMPK knockout cells and that required phosphorylation of acetyl-CoA carboxylase (ACC) 1 and/or ACC2 at the AMPK sites. Oral administration of canagliflozin activated AMPK in mouse liver, although not in muscle, adipose tissue, or spleen. Because phosphorylation of ACC by AMPK is known to lower liver lipid content, these data suggest a potential additional benefit of canagliflozin therapy compared with other SGLT2 inhibitors.
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Role of AMP-Activated Protein Kinase in Mechanism of Metformin Action
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Self-citationAMPK: An Energy-Sensing Pathway with Multiple Inputs and Outputs
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Lytvyn, Y., Bjornstad, P., Udell, J. A., Lovshin, J. A., & Cherney, D. Z. I. (2017) · Circulation · doi:10.1161/circulationaha.117.030012 · Cited by 459
Renoprotective effects of sodium-glucose cotransporter-2 inhibitors
Heerspink, H. J. L., Kosiborod, M., Inzucchi, S. E., & Cherney, D. Z. I. (2018) · Kidney International · doi:10.1016/j.kint.2017.12.027 · Cited by 393
Ketone bodies: from enemy to friend and guardian angel
Kolb, H., Kempf, K., Röhling, M., Lenzen-Schulte, M., Schloot, N. C., & Martin, S. (2021) · BMC Medicine · doi:10.1186/s12916-021-02185-0 · Cited by 361
The actions of SGLT2 inhibitors on metabolism, renal function and blood pressure
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Metadata
- Authors
- Hawley, S. A., Ford, R. J., Smith, B. K., Gowans, G. J., Mancini, S. J., Pitt, R. D., Day, E. A., Salt, I. P., Steinberg, G. R., & Hardie, D. G.
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2016-07-05
- Volume
- 65
- Issue
- 9
- Pages
- 2784-2794
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2467821377
- Cited by
- 391
- References
- 44
- FWCI
- 11.29
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- CoChat. (2026). Citation check: The Na+/Glucose Cotransporter Inhibitor Canagliflozin Activates AMPK by Inhibiting Mitochondrial Function and Increasing Cellular AMP Levels. https://app.cochat.ai/papers/10.2337/db16-0058
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- Hawley, S. A., Ford, R. J., Smith, B. K., Gowans, G. J., Mancini, S. J., Pitt, R. D., Day, E. A., Salt, I. P., Steinberg, G. R., & Hardie, D. G. (2016). The Na+/Glucose Cotransporter Inhibitor Canagliflozin Activates AMPK by Inhibiting Mitochondrial Function and Increasing Cellular AMP Levels. Diabetes. https://doi.org/10.2337/db16-0058
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