Human cardiomyocytes express high level of Na⁺/glucose cotransporter 1 (SGLT1)

Abstract

We have quantitatively measured gene expression for the sodium-dependent glucose cotransporters 1 and 2 (SGLT1 and SGLT2) in 23 human tissues using the method of real time PCR. As predicted, our results revealed that the expression of SGLT1 was very high in the small intestine (1.2E + 6 molecules/microg total RNA) relative to that in the kidney (3E + 4 molecules/microg total RNA). Surprisingly, we observed that the expression of SGLT1 in human heart was unexpectedly high (3.4E + 5 molecules/microg total RNA), approximately 10-fold higher than that observed in kidney tissue. DNA sequencing confirmed that the PCR amplified fragment was indeed the human SGLT1 gene. Moreover, in situ hybridization studies using a digoxigenin (DIG)-labeled antisense cRNA probe corresponding to human SGLT1 cDNA confirm that human cardiomyocytes express SGLT1 mRNA. In contrast, the expression of SGLT2 in human tissues appears to be ubiquitous, with levels ranging from 6.7E + 4 molecules/microg total RNA (in skeletal muscle) to 3.2E + 6 molecules/microg total RNA (in kidney), levels 10-100-fold higher than the expression of SGLT1 in the same tissues. Our finding that human cardiomyocytes express high levels of SGLT1 RNA suggests that SGLT1 may have a functional role in cardiac glucose transport. Since several SGLT inhibitors are currently in development as potential anti-diabetic agents, it may be important to assess the functional consequences of inhibition of SGLT1 in the heart.

SGLT2 Mediates Glucose Reabsorption in the Early Proximal Tubule

“…1,[5][6][7] This concept is based on mRNA and transport studies in isolated nephron segments and membrane vesicles from various tissue zones of rat and rabbit kidneys. 6 -14 Real-time PCR suggested SGLT2 mRNA expression in many human tissues, 15 but, because of the lack of good antibodies (Ab), the implication for extrarenal protein expression of SGLT2 is unclear. Another low-affinity Na ϩ -D-glucose co-transporter named NaGLT1 was cloned from rat, 2 which has no amino acid sequence similarity to transporters of the SGLT family and does not transport D-galactose, as has been described for SGLT2.…”

The Sweet Pee Model for Sglt2 Mutation

“…Two major SGLT transporters exist in the kidneys, SGLT1 and SGLT2, which differ in their affinity, substrate specificity, and tissue expression. Whereas SGLT1 is more widely expressed and is found in the small intestine, the distal (S2, S3) segments of the renal proximal tubule, and in cardiomyocytes, 1,2 SGLT2 is expressed only in the apical brush border of the S1 and S2 portion of the proximal renal tubule. SGLT1 is a high-affinity (K 0.5 ϭ 0.…”

“…4,5 Familial renal glucosuria describes patients with a rare mutation in the solute carrier family 5, member 2 (SLC5A2) gene that encodes for a 75-kD sodium-glucose cotransporter 2 (SGLT2). Patients with this disorder manifest a variable degree of glucosuria, depending on the type of mutation and the number of alleles affected; massive glucosuria of 169 g/1.73 m 2 per d has been reported, 6 yet most of them remain euglycemic and have no other major health sequela. 7 Given the apparent benign nature of loss of function of SGLT2 and its restricted renal expression, it follows that SGLT inhibition might be a valuable treatment for diabetes to enhance renal glucose excretion and thereby improve glycemic control.…”

Inhibitor Binding in the Human Renal Low- and High-Affinity Na+/Glucose Cotransporters

“…In addition, the newer compounds are more selective for SGLT2 than SGLT1, thus minimizing potential side effects associated with the broad tissue distribution of SGLT1. Besides intestine and kidney, SGLT1 is found in other organs and tissues, including blood-brain barrier and heart (Zhou et al, 2003;Elfeber et al, 2004;Tazawa et al, 2005). In diabetic animal models, inhibition of SGLT2 produces glucosuria, followed by a normalization of blood glucose levels and a consequent improve-ment in insulin resistance and renal damage (Asano et al, 2004;Katsuno et al, 2007).…”