Response to Glucose Deficiency with Sodium-Glucose Cotransporter 2 Inhibitors makes a Positive Impact on Heart and Kidney

Author(s): Yoshiyuki Hattori

Animal hibernation is a kind of starvation with some fat reserve. During early stage of starvation, gluconeogenesis, fatty acid oxidation and ketogenesis started in the liver which is a comparable condition in patients who are being treated with sodium-glucose cotransporter 2 inhibitors (SGLT2i). SGLT2i might exert a cardioprotective effect by change in cardiac excitation-contraction coupling as seen in hibernating animals, which prevents calcium overload and energy waste in myocardium. Modestly elevated circulating levels of the ketone β-hydroxybutyrate (βOHB) during treatment with SGLT2i causes different beneficial effects on organs and cells, depending on the succinyl-CoA:3-ketoacid CoA transferase (SCOT) level. In the failing heart, SCOT is highly expressed/up-regulated and thus βOHB may be an energy source apart from fat and glucose oxidation in myocardial mitochondria. On the other hand, SCOT is not highly expressed/down-regulated in the kidney and thus βOHB may translocate into nucleus and cause beneficial effects such as inhibition of inflammation, oxidative stress and fibrosis as an endogenous and specific inhibitor of class I histone deacetylases (HDACs) and the NLRP3 inflammasome. SGLT2i exert a direct renoprotective effect with restoration of tubulo-glomerular feedback and improving renal proximal tubule oxygenation. Other than that, various beneficial effects of SGLT2i might be caused by well-orchestrated pattern of systemic metabolic change against glucose starvation induced by SGLT2i.

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