Effects of SGLT2 ablation or inhibition on corticosterone secretion in high-fat-fed mice: exploring a nexus with cytokine levels.

Aims/hypothesis: Despite recent therapeutic advances, achieving optimal glycaemic control remains a challenge in managing type 2 diabetes. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have emerged as effective treatments by promoting urinary glucose excretion. However, the full scope of their mechanisms extends beyond glycaemic control. At present, their immunometabolic effects remain elusive.

Methods: To investigate the effects of SGLT2 inhibition or deletion, we compared the metabolic and immune phenotype between high-fat-diet-fed control mice, mice treated chronically with dapagliflozin, and total-body Slc5a2-knockout mice.

Results: SGLT2-null mice exhibited better glucose tolerance and insulin sensitivity (blood glucose during IPGTT AUC 0-90 min 1175 ± 57.4 mmol/l × min, mean ± SEM) compared with control (AUC 0-90 min 1857 ± 117.9 mmol/l × min, p=0.05) or dapagliflozin-treated mice (AUC 0-90 min 1506 ± 68.72 mmol/l × min, p=0.09), independent of glycosuria and body weight. Moreover, SGLT2-null mice demonstrated physiological regulation of corticosterone secretion, with lower morning levels than control mice (p<0.01). Systemic cytokine profiling also unveiled significant alterations in inflammatory mediators, particularly IL-6. Furthermore, unbiased proteomic analysis demonstrated downregulation of acute-phase proteins and upregulation of glutathione-related proteins, suggesting a role in the modulation of antioxidant responses. Conversely, IL-6 treatment increased SGLT2 expression in human kidney HK2 cells, suggesting a role for cytokines in the effects of hyperglycaemia.

Conclusions/interpretation: Collectively, our data elucidate a potential interplay between SGLT2 activity, immune modulation and metabolic homeostasis, as well as a potential feedback loop between SGLT2 expression and cytokine concentration.