There is an overexpression of SGLT2 receptors in diabetic patients, which increases glucose reabsorption and thus, glycaemia [40]. target for treating diabetic patients and they have drawn tremendous attention over the last years. Interestingly and in contrast to SGLT2 receptor, that is mainly expressed in the kidneys, SGLT1 receptor is highly expressed in the human heart, with preferential location in the sarcolemma [11]. Its expression is also altered in diabetic and ischemic cardiomyopathy and it may be regulated by leptin [27]. While leptin stimulates the expression of cardiac SGLT1 mRNA, insulin seems to only stimulate its translocation to sarcolemma. Interestingly, at least in mice, cardiac SGLT1 expression has found to increase with age [27]. Functional SGLT1 is an oligomer, resulting from dimerization. At least 3 bands have been observed in human hearts: 2 bands of 70 and 140 kDa (that could (S)-Glutamic acid reflect dimerization), and also an intermediate (S)-Glutamic acid band, which its significance is unknown and could be related to post-translational modifications (i.e., phosphorylation) [27]. The expression of SGLT1 has been also found rat endothelial cells in skeletal muscle, brain and coronary arteries, where in is required for the action of insulin on glucose supply to myocytes [29]. However, this has not yet been confirmed in human endothelial cells [11]. Unlike GLUT1 and GLUT4, which expression (S)-Glutamic acid is down-regulated in diabetic hearts, SGLT1 expression is increased in individuals with end-stage cardiomyopathy secondary to T2DM and in obese mice [27]. In contrast, SGLT1 expression decreases in a mice model with T1DM [27]. It has been postulated that increased SGLT1 expression may be related to chronic hyperinsulinaemia in T2DM and/or and adaptive response to reduced GLUT1 and GLUT4 expression [27]. Insulin activates protein kinase C and phosphorylation of SGLT1, which increases the recruitment of SGLT1 transporter to the plasma membrane and thus, glucose uptake. Intestinal SGLT1 is modulated by dietary carbohydrate consumption. Following a high-glucose diet in animal models, SGLT1 activity and expression increase. Glucose appears to be a local rather than a systemic modulator since oral but not intravenous glucose administration enhances its expression [30]. 3.2. Impact of SGLT1 Inhibition on Ischemic Heart Disease Cardiac ischemia results in 2- to 3-fold increased glucose uptake and utilization [31], that seems to be protective at least partially, during acute injury. There is an upregulation of expression and translocation of GLUT1 and GLUT4 via PI3-K dependent manner and also through adenosine mono-phosphate activated protein kinase (AMPK) [32]. The phosphorylation (activation) of Akt by phosphatidylinositol 3-kinase (S)-Glutamic acid (PI3K) increases GLUT1/4 expression and may explain the cardioprotective effect of Akt on myocardial ischemia [23]. AMPK is the SIGLEC6 cell energy sensor that regulates cellular homeostasis during cardiac impairment. Hyperactivating mutation of AMKP in mice is associated with increased expression/activity of SGLT1 [11]. In addition, SGLT1 is also upregulated 2- to 3-fold in myocardial ischemia [27] and seems to be an adaptive response to injury give its association with the functional recovery in failing hearts after left ventricular assist device insertion [32]. This upregulation of SGLT1 receptors appears to be related to the activation of intracellular second messengers, ERK1/2 and mTOR [11]. Whether SGLT1 receptors exert protective or deleterious effects has not been yet determined. On one site, SGLT1 expression may be beneficial following acute myocardial ischemic injury since they facilitate glucose uptake, which is the only source of ATP through anaerobic glycolysis during ischemia. On the other side, chronic SGLT1 overexpression has been demonstrated to cause a phenotype similar to glycogen-storage cardiomyopathy [33,34]. Importantly a recent article has demonstrated that SGLT1-knockdown mice model was associated with reduced oxidative stress, myocardial necrosis and infarct size following ischemia-reperfusion (I/R) injury [35]. Specifically, during ischemia AMPK upregulates SGLT1 through ERK, and SGLT1 interacts with EGFR which in turn increases PKC and Nox2 activity and oxidative stress. Therefore, SLGLT1 may represent a novel therapeutic target for mitigating ischemiareperfusion injury for patients with ischemic heart disease and further trial should be addressed [36]. Nevertheless, acute treatment with dual SGLT1/SGLT2 inhibitors immediately after I/R injury has also been associated with exacerbated cardiac dysfunction in rats [37]. Given the absence of SGLT2 receptors in cardiac cells, this (S)-Glutamic acid effect may be linked to acute SGLT1 inhibition in the post-myocardial infarct setting. Moreover, I/R models treated.