There are human genes in the SLC A family and

There are 12 human genes in the SLC5A family, and 6 of these are expressed in human heart (Table 2). Little is known about SGLT proteins in the heart. Zhou et al. [56] reported the presence of SGLT1 mRNA in the human heart. Researchers have found that levels of SGLT1 mRNA in heart are approximately 10-fold greater than in kidney [56]. However, the cardiac function of SGLT1 protein, its cellular localization, and endothelin receptor antagonists were not investigated. Banerjee et al. [18] are the first researchers to report, that SGLT1 is highly expressed in human cardiac myocytes. The SGLT1 is predominantly localized in the sarcolemma, where it colocalizes with GLUT1, and is an important cardiac glucose transporter. In animal studies, authors have found, that levels of Sglt1 mRNA in murine heart, progressively increased from age 2 through 20weeks. Researchers suggest that SGLT1 plays a role in modulating the cardiac glucose uptake in response to hormonal stimuli [18]. Unfortunately, the expression of other SGLT proteins, their role and cellular localization in human or animal hearts, were not examined.
Insulin signaling in heart The increase in cardiac substrate uptake is due to two major stimuli: circulating insulin and elevated contractile activity. Insulin, that is synthesized and secreted from pancreatic β-cells is a well characterized stimulus which mediates GLUT4 translocation from the intracellular compartment to the plasma membrane. Insulin receptor (IR) has the tyrosine kinase activity. The binding of insulin to IR leads to autophosphorylation of insulin receptor. The activated IR subsequently binds to and phosphorylates multiple number of specific substrates including the insulin receptor substrate family proteins (IRS1–IRS4) and proto-oncogen Cbl [59], [60]. The Cbl pathway is described in adipocytes as phosphoinositide-3-kinase (PI3-K)-independent mechanism for insulin-mediated glucose uptake. It is discussed, whether this pathway is also in cardiomyocytes [9]. The PI3-K consists of two subunits: a catalytic subunit (p110) and a regulatory subunit (p85). Upon PI3-K activation, it catalyzes the phosphorylation of phosphoinositides to phosphatidylinositol-3,4,5-phosphate (PIP3). The PIP3 activates another kinase, phosphoinositide-dependent protein kinase 1 (PKD1), that phosphorylates serine/threonine protein kinase B (PKB/Akt) and the two atypical isoforms of protein kinase C: PKC λ and PKC ζ [61], [62], [63]. There are three isoforms of Akt: Akt-1, -2, and -3; however, Akt-2 isoform mediates the metabolic effect of insulin [64]. The activation of PKC λ and PKC ζ contributes to the insulin-induced translocation of GLUT4 however this pathway was described in adipocytes and skeletal muscles [65]. Another pathway of insulin-stimulated GLUT4 translocation was also characterized. In this pathway, Akt-2 phosphorylates AS160 (also known as TBC1D4), which is the Akt substrate [66], and inhibits its activity. The inhibition of AS160 is required for GLUT4 translocation, because AS160 was identified as a negative regulator of GLUT4 translocation. Phosphorylation of AS160, due to activation of insulin-dependent signaling, promotes its dissociation from GLUT4-containing vesicles [67]. The AS160 is a negative regulator of Rab GTPases. It promotes their guanoside diphosphate-bound (GDP) inactive form. Activation of AS160, due to its phosphorylation, inactivates its GTPase-activating function and enables the activation of Rab proteins. The substrates that are involved in insulin-stimulated GLUT4 translocation are Rab8, Rab10, and Rab14. In cardiomyocytes there are also other Rab proteins, such as Rab4a and Rab11a. Rab proteins are not substrates of AS160, but they participate in the GLUT4 vesicles trafficking [68], [69].
Translocation of GLUT4 in cardiomyocytes due to other stimuli Translocation of GLUT4 in cardiomyocytes is not only done by insulin, catecholamines stimulate GLUT4 translocation and also enhance glucose uptake [70] and the exercise [9]. It is good to note, that the pathway responsible for the stimulation of glucose uptake by exercise is distinct from that stimulated by insulin [9]. Catecholamines stimulate the above-mentioned process through α-adrenergic receptor stimulation [71]. However in the isolated rat perfused heart, α- and β-adrenergic stimulation increases glucose uptake and GLUT1 and GLUT4 translocation [72]. A-adrenergic stimulation of glucose uptake is mediated by PI3-K [73].