Inhibitors Of Glut

Research to identify and characterize glucose transport inhibitors that may protect against the development of DN is in its infancy. Certainly, many different drugs and food constituents have the potential to regulate glucose transporter expression, and some examples are mentioned here with references for more in-depth reading.

Captopril has been shown to inhibit a high-glucose-induced increase in GLUT1-mediated glucose transport in retinal endothelial cells (85). A role for Captopril inhibition of MC glucose transport will need to be investigated because this could identify a new and important nonhemodynamic protective effect of an angiotensin-converting enzyme (ACE) inhibitor on the kidney. The mechanism by which Captopril achieves this effect in retinal endothelial cells is not yet known, although it does not appear to result from a change in overall GLUT1 expression (85).

The flavanoids and isoflavones (e.g., genestein, quercetin, and others) are tyrosine kinase inhibitors known to inhibit glucose transport via their effects on GLUT1 (86). At least part of the affect results from their binding to an ATP-binding site in GLUT1, thereby impairing its transport capacity (86). One article has been published in which the isoflavone quercetin was given to diabetic rats and prevented the development of DN (87). Although the beneficial effect of quercetin was attributed to inhibition of ROS, the effect of this compound to inhibit glucose uptake into the mesangial cells and glomeruli was not assessed. Certainly, future studies should address the effectiveness of chemical inhibition of glucose transporters to prevent DN, because suppression of MC GLUT1 has provided protection against ECM production in vitro (33), and preliminary data indicates that transgenic suppression of MC GLUT1 in vivo is protective against the development of diabetic glomerulosclerosis in mice (41). Methylxanthines as well have been shown in nonrenal cells to inhibit glucose transport via GLUT1, and their avoidance has been recommended in patients with the GLUT1 deficiency syndrome in which a congenital deficiency of GLUT1 leads to hypoglycorrhachia, seizure activity, and motor abnormalities (88-90). The latter example also indicates that excessive systemic inhibition of GLUT1 could have adverse consequences. Therefore, a more selective inhibition of glucose transporters in the kidney would be desirable in screening for drugs with the potential to inhibit glomerular ECM production by interfering with GLUT1-mediated glucose uptake.

The drug, rhein, an anthraquinone derived from rhubarb, which historically was used as an herbal remedy for various ailments in China, has also been effective in blocking TGFP1-induced GLUT1 and glucose transport in cultured MCs (91). The inhibitory effect of rhein on glucose transport has been known for many years in nonrenal tumor cells (92). The effectiveness of rhein to prevent DN is currently under investigation.

Finally, pentobarbital is a known suppressant of GLUT1 in nonrenal tissues such as the brain (26), however its potential to suppress GLUT1 in the kidney has not yet been investigated.

0 0

Post a comment