Why the study?
Does SGLT2 inhibition with dapagliflozin modulate sympathetic nervous system activity in high-fat diet-fed mice?
Does SGLT2 inhibition with dapagliflozin modulate sympathetic nervous system activity in high-fat diet-fed mice?
This preclinical study provides early evidence of cross-talk between the sympathetic nervous system and SGLT2 regulation, suggesting a potential mechanism for the cardiovascular and renal benefits of SGLT2 inhibitors.
May indicate sympathetic modulation by SGLT2 inhibition in obese models; hypothesis-generating and requires human validation.
BACKGROUND: The sympathetic nervous system (SNS) regulates glucose metabolism in various organs including the kidneys. The sodium glucose cotransporter 2 (SGLT2) mediates glucose reabsorption in renal proximal tubules and its inhibition has been shown to improve glucose control, cardiovascular and renal outcomes. We hypothesized that SNS-induced alterations of glucose metabolism may be mediated via regulation of SGLT2. METHOD: We used human renal proximal tubule cells to investigate the effects of noradrenaline on SGLT2 regulation. Mice fed a high-fat diet were oral gavaged with dapagliflozin and the expression of noradrenaline and tyrosine hydroxylase was measured in the kidney and heart. RESULTS: Noradrenaline treatment resulted in a pronounced increase in SGLT2 and interleukin (IL)-6 expression in HK2 cells and promoted translocation of SGLT2 to the cell surface. In vivo, dapagliflozin treatment resulted in marked glucosuria in high-fat diet-fed mice. SGLT2 inhibition significantly reduced high-fat diet-induced elevations of tyrosine hydroxylase and noradrenaline in the kidney and heart. We also aimed to assess the levels of hypertension-related cytokines in the kidneys of our mice treated with and without dapagliflozin. Excitingly, we demonstrate that SGLT2 inhibition with dapagliflozin promoted a trend towards reduced tumour necrosis factor-alpha and elevated IL-1β protein levels in the kidney. CONCLUSION: Our in-vitro and in-vivo studies provide first evidence for an important cross-talk between the SNS and SGLT2 regulation that may not only account for SNS-induced alterations of glucose metabolism but potentially contribute to cardiovascular and renal protection observed with SGLT2 inhibitors.
No takes yet. Share an insight, caveat, or question.
Matthews et al. (2017) studied this question.
Synapse has enriched 3 closely related papers on similar clinical questions. Consider them for comparative context: