Analysis of the SGLT2-independent off-target dapagliflozin activity using model organism Caenorhabditis elegans

Flozins, an emerging class of antidiabetic agents, selectively target the SGLT2 sodium/glucose cotransporter in the renalproximal tubule, thereby preventing glucose reabsorption and reducing hyperglycemia. Beyond lowering glucose levels, flozins exhibitsignificant benefits in heart failure and chronic kidney disease. This expanded therapeutic utility is noteworthy, particularly given the absenceof SGLT2 expression in cardiac tissue, suggesting the involvement of additional targets or mechanisms affected by flozins.

Here, we utilized Caenorhabditis elegans as a model organism devoid of an SGLT2 orthologue to analyze the off-targetactivity of flozins, specifically following dapagliflozin treatment. Glucose-fed worms were treated with dapagliflozin, and lifespan analyseswere performed. Transcriptomic profiling was conducted to compare glucose- and dapagliflozin-treated worms with glucose-only-treatedcontrols. In vivo glucose transport was assessed using the fluorescent glucose analogue 2-NBDG. Additionally, smvt-1 (sodium-dependentmultivitamin transporter) expression was downregulated to evaluate its role in dapagliflozin-mediated effects.

Although C. elegans lacks an SGLT2 orthologue, dapagliflozin remarkably mirrored observations from murine models by significantlyprolonging lifespan under glucose-fed conditions. Transcriptomic analyses revealed gene expression profiles closely resemblingthose observed in mammalian systems. Furthermore, we observed that dapagliflozin inhibits glucose transport in vivo, as demonstratedby reduced 2-NBDG uptake. Notably, this inhibitory effect was abolished upon downregulation of smvt-1, indicating its involvement indapagliflozin-mediated glucose transport inhibition.

Our findings suggest that dapagliflozin exerts SGLT2-independent effects on glucose transport and longevity. In C. elegans, the sodium-dependent multivitamin transporter SMVT-1 represents a relevant target of dapagliflozin, providing insight into potentialalternative mechanisms underlying the pleiotropic benefits of flozins observed in mammals.