Background:
Sodium glucose co-transporter 2 (SGLT2) in kidneys controls sodium and glucose reabsorption, and the newer class of anti-diabetic drugs, SGLT2 inhibitors (SGLT2i) lower glucose levels by increasing urinary glucose excretion. However, their responsiveness and effectiveness vary among patients with diabetes, with unclear underlying reasons. Chronic high salt intake impairs renal function, and it is crucial to assess whether excessive salt intake alters the efficacy of such drugs.
Methods
Seven-week-old male C57BL/6 mice were fed a 60% high-fat diet (HFD), while concurrently receiving either a 4% salt-supplemented diet or a vehicle for 4 weeks followed by multiple low doses of streptozotocin (STZ) injection to establish diet-induced type 2 diabetes (T2D) models. Subsequently, mice in each diet group received a daily gavage of either empagliflozin (SGLT2i, 10mg/kg BW) or a vehicle for 2 weeks. Glucose levels, glucose tolerance, and insulin sensitivity were monitored.
Results
We found that diabetic mice on a high-salt, high-fat diet treated with SGLT2 inhibitors displayed higher glucose levels compared to their non-salt diet counterparts. This was accompanied by significantly reduced urine glucose levels. In addition, consistent with the established findings, SGLT2i treatment increased LDL levels in the HFD-only T2D group; more strikingly, we observed further elevation of LDL levels in salt-treated mice, raising concerns over CVD risks.
Conclusion
This study, for the first time, demonstrates that high salt intake reduces the efficacy of SGLT2 inhibitors, highlighting a unrecognized physiological role of salt in metabolism. The identification of compromised efficacy of SGLT2i by high salt could potentially influence diabetes management by advising the necessary salt intake reduction for maximizing the benefits of SGLT-2 inhibitors in patients with T2D on SGLT2i. Overall, this research significantly contributes to our understanding of the multifaceted role of salt in both CVD and metabolism.