Figure 3.

Potential molecular mechanisms of SGLT2 inhibitors on iron homeostasis, mitochondrial function, and cardiac microvasculature in diabetic cardiomyopathy. SGLT2Is can reduce cardiomyocyte sodium (Na⁺) and calcium (Ca²⁺) by inhibition of NHE activity in cardiomyocytes. In addition, SGLT2Is also regulate Ca²⁺ through enhancing SERCA2α function and CaMKII activation. SGLT2Is can enhance mitochondrial function by improvement of mitochondrial fusion–fission proteins, such as Mfn1:Mfn2 ratio and Fis1, as well as Drp1, which is dependent of AMPK activation. Activation of the PGC1α–NRF1–Tfam signaling pathway by SGLT2Is play a crucial role in regulation of mitochondrial biogenesis in the diabetic heart. Microcirculation can be improved by SGLT2Is by eNOS phosphorylation and NO-dependent improvement of endothelial function. All these changes have beneficial effects on attenuation of cardiac stiffness and diastolic dysfunction