Inhibition of the Na+-glucose transporter SGLT2 reduces glucose uptake and IFNγ release from activated human CD4+ T cells 2025 Jin et al

[Andy]

Glucose uptake in activated CD4+ T cells is essential for increased metabolic needs, synthesis of biomolecules and proliferation. Although, facilitated glucose transport is the predominant route for glucose entry at the time of activation, here we demonstrate role for the sodium-dependent glucose transporter SGLT2. By 72 h after activation, SGLT2 is expressed and functional in the human CD4+ T cells. SGLT2 inhibitors, phlorizin and empagliflozin decreased glucose uptake into the human CD4+ T cells compared to untreated cells. Phlorizin (25 μmol/L) reduced glycolysis at 5.6 mmol/L glucose and IFNγ levels at both 5.6 mmol/L and 16.7 mmol/L glucose.

In contrast, empagliflozin (0.5 μmol/L) only decreased IFNγ levels in 16.7 mmol/L glucose. GABA enhanced phlorizin inhibition at both 5.6 mmol/L and 16.7 mmol/L glucose in the presence of insulin. Insulin strengthens GABAA receptors signaling in CD4+ T cells. The results are consistent with expression of SGLT2 after activation of human CD4+ T cells, that facilitates concentrating glucose uptake into the cells, enabling enhanced release of inflammatory molecules like IFNγ. Importantly, inhibition of SGLT2 decreases IFNγ release.

Open access

 

[Jonathan Edwards]

So a link between glucose control and gamma interferon. There are probably links between everything but this is intriguing.

 

[jnmaciuch]

So a link between glucose control and gamma interferon. There are probably links between everything but this is intriguing.

I would guess that this is a very T-cell specific change, as the [edit: response to interferon can be quite variable]

But yes, interferons have been well known to modulate metabolism, it’s just a bit of a mess as to which specific part of metabolism in which direction in what cell type from which particular interferon.

[edit: at the risk of oversimplifying trends, it seems like generally parenchymal cells downregulate glucose uptake, most innate immune cells seem to upregulate (DCs and macrophages, at least), and adaptive is a bit of a crapshoot]