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Renal glucose transporters: novel targets for hyperglycemia management

Nature Reviews Nephrology volume 6, pages 307–311 (2010)Cite this article

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Abstract

The naturally occurring substance phlorizin has long been recognized to block the reabsorption of glucose from the glomerular ultrafiltrate into the systemic circulation. The poor oral bioavailability and adverse effects associated with this agent, however, have prevented its use in clinical practice and restricted its use to that of a physiological tool. The development of novel agents that are able to block the principal glucose transporter in the kidney has allowed the inhibition of renal glucose reabsorption to be re-evaluated as a therapeutic tool in patients with diabetes mellitus. This Perspectives article summarizes current knowledge pertaining to glucose transport in the kidney and describes the evidence regarding glucose transport blockade as a novel target for the management of hyperglycemia in the context of existing treatment strategies.

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Figure 1: Glucose reabsorption in the proximal tubule.

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References

  1. Wright, E. M., Hirayama, B. A. & Loo, D. F. Active sugar transport in health and disease. J. Intern. Med. 261, 32–43 (2007).

    Article  CAS  Google Scholar 

  2. Bakris, G. L., Fonseca, V. A., Sharma, K. & Wright, E. M. Renal sodium-glucose transport: role in diabetes mellitus and potential clinical implications. Kidney Int. 75, 1272–1277 (2009).

    Article  CAS  Google Scholar 

  3. Wright, E. M. Renal Na(+)-glucose cotransporters. Am. J. Physiol. Renal Physiol. 280, F10–F18 (2001).

    Article  CAS  Google Scholar 

  4. Mogensen, C. E. Maximum tubular reabsorption capacity for glucose and renal hemodynamics during rapid hypertonic glucose infusion in normal and diabetic subjects. Scand. J. Clin. Lab. Invest. 28, 101–109 (1971).

    Article  CAS  Google Scholar 

  5. Vestri, S. et al. Changes in sodium or glucose filtration rate modulate expression of glucose transporters in renal proximal tubular cells of rat. J. Membr. Biol. 182, 105–112 (2001).

    Article  CAS  Google Scholar 

  6. Marks, J., Carvou, N. J., Debnam, E. S., Srai, S. K. & Unwin, R. J. Diabetes increases facilitative glucose uptake and GLUT2 expression at the rat proximal tubule brush border membrane. J. Physiol. 553, 137–145 (2003).

    Article  CAS  Google Scholar 

  7. Rahmoune, H. et al. Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes. Diabetes 54, 3427–3434 (2005).

    Article  CAS  Google Scholar 

  8. Freitas, H. S. et al. Na(+) -glucose transporter-2 messenger ribonucleic acid expression in kidney of diabetic rats correlates with glycemic levels: involvement of hepatocyte nuclear factor-1alpha expression and activity. Endocrinology 149, 717–724 (2008).

    Article  CAS  Google Scholar 

  9. Ackermann, T. F. et al. SGK1-sensitive renal tubular glucose reabsorption in diabetes. Am. J. Physiol. Renal Physiol. 296, F859–F866 (2009).

    Article  CAS  Google Scholar 

  10. Palmada, M. et al. SGK1 kinase upregulates GLUT1 activity and plasma membrane expression. Diabetes 55, 421–427 (2006).

    Article  CAS  Google Scholar 

  11. Koro, C. E., Bowlin, S. J., Bourgeois, N. & Fedder, D. O. Glycemic control from 1988 to 2000 among US adults diagnosed with type 2 diabetes: a preliminary report. Diabetes Care 27, 17–20 (2004).

    Article  Google Scholar 

  12. Singh, D. K., Winocour, P. & Farrington, K. Mechanisms of disease: the hypoxic tubular hypothesis of diabetic nephropathy. Nat. Clin. Pract. Nephrol. 4, 216–226 (2008).

    Article  CAS  Google Scholar 

  13. Calado, J. et al. Familial renal glucosuria: SLC5A2 mutation analysis and evidence of salt-wasting. Kidney Int. 69, 852–855 (2006).

    Article  CAS  Google Scholar 

  14. Jabbour, S. A. & Goldstein, B. J. Sodium glucose co-transporter 2 inhibitors: blocking renal tubular reabsorption of glucose to improve glycaemic control in patients with diabetes. Int. J. Clin. Pract. 62, 1279–1284 (2008).

    Article  CAS  Google Scholar 

  15. Wilding, J. et al. A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus insulin sensitizers: applicability of a novel insulin-independent treatment. Diabetes Care 32, 1656–1662 (2009).

    Article  CAS  Google Scholar 

  16. [No authors listed] Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 352, 837–853 (1998).

  17. Santer, R. et al. Molecular analysis of the SGLT2 gene in patients with renal glucosuria. J. Am. Soc. Nephrol. 14, 2873–2882 (2003).

    Article  CAS  Google Scholar 

  18. Geerlings, S. E., Brouwer, E. C., Gaastra, W., Verhoef, J. & Hoepelman, A. I. Effect of glucose and pH on uropathogenic and non-uropathogenic Escherichia coli: studies with urine from diabetic and non-diabetic individuals. J. Med. Microbiol. 48, 535–539 (1999).

    Article  CAS  Google Scholar 

  19. Geerlings, S. E. et al. Asymptomatic bacteriuria may be considered a complication in women with diabetes. Diabetes Mellitus Women Asymptomatic Bacteriuria Utrecht Study Group. Diabetes Care 23, 744–749 (2000).

    Article  CAS  Google Scholar 

  20. List, J. F., Woo, V., Morales, E., Tang, W. & Fiedorek, F. T. Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care 32, 650–657 (2009).

    Article  CAS  Google Scholar 

  21. Rossetti, L., Smith, D., Shulman, G. I., Papachristou, D. & DeFronzo, R. A. Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats. J. Clin. Invest. 79, 1510–1515 (1987).

    Article  CAS  Google Scholar 

  22. Blondel, O., Bailbe, D. & Portha, B. Insulin resistance in rats with non-insulin-dependent diabetes induced by neonatal (5 days) streptozotocin: evidence for reversal following phlorizin treatment. Metabolism 39, 787–793 (1990).

    Article  CAS  Google Scholar 

  23. Kahn, B. B., Shulman, G. I., DeFronzo, R. A., Cushman, S. W. & Rossetti, L. Normalization of blood glucose in diabetic rats with phlorizin treatment reverses insulin-resistant glucose transport in adipose cells without restoring glucose transporter gene expression. J. Clin. Invest. 87, 561–570 (1991).

    Article  CAS  Google Scholar 

  24. Pollock, C. A., Lawrence, J. R. & Field, M. J. Tubular sodium handling and tubuloglomerular feedback in experimental diabetes mellitus. Am. J. Physiol. 260, F946–F952 (1991).

    CAS  PubMed  Google Scholar 

  25. Vallon, V., Richter, K., Blantz, R. C., Thomson, S. & Osswald, H. Glomerular hyperfiltration in experimental diabetes mellitus: potential role of tubular reabsorption. J. Am. Soc. Nephrol. 10, 2569–2576 (1999).

    CAS  PubMed  Google Scholar 

  26. Malatiali, S., Francis, I. & Barac-Nieto, M. Phlorizin prevents glomerular hyperfiltration but not hypertrophy in diabetic rats. Exp. Diabetes Res. 2008, 305403 (2008).

    Article  Google Scholar 

  27. Turk, E., Zabel, B., Mundlos, S., Dyer, J. & Wright, E. M. Glucose/galactose malabsorption caused by a defect in the Na+/glucose cotransporter. Nature 350, 354–356 (1991).

    Article  CAS  Google Scholar 

  28. Wells, R. G. et al. Cloning of a human kidney cDNA with similarity to the sodium-glucose cotransporter. Am. J. Physiol. 263, F459–F465 (1992).

    CAS  PubMed  Google Scholar 

  29. Zhou, L. et al. Human cardiomyocytes express high level of Na+/glucose cotransporter 1 (SGLT1). J. Cell Biochem. 90, 339–346 (2003).

    Article  CAS  Google Scholar 

  30. Santer, R. & Calado, J. Familial renal glucosuria and SGLT2: from a mendelian trait to a therapeutic target. Clin. J. Am. Soc. Nephrol. 5, 133–141 (2010).

    Article  CAS  Google Scholar 

  31. Scholl-Bürgi, S., Santer, R. & Ehrich, J. H. Long-term outcome of renal glucosuria type 0: the original patient and his natural history. Nephrol. Dial. Transplant. 19, 2394–2396 (2004).

    Article  Google Scholar 

  32. Washburn, W. N. Development of the renal glucose reabsorption inhibitors: a new mechanism for the pharmacotherapy of diabetes mellitus type 2. J. Med. Chem. 52, 1785–1794 (2009).

    Article  CAS  Google Scholar 

  33. Arakawa, K. et al. Improved diabetic syndrome in C57BL/KsJ-db/db mice by oral administration of the Na(+)-glucose cotransporter inhibitor T-1095. Br. J. Pharmacol. 132, 578–586 (2001).

    Article  CAS  Google Scholar 

  34. Oku, A. et al. T-1095, an inhibitor of renal Na+-glucose cotransporters, may provide a novel approach to treating diabetes. Diabetes 48, 1794–1800 (1999).

    Article  CAS  Google Scholar 

  35. Ueta, K. et al. Long-term treatment with the Na+-glucose cotransporter inhibitor T-1095 causes sustained improvement in hyperglycemia and prevents diabetic neuropathy in Goto-Kakizaki rats. Life Sci. 76, 2655–2668 (2005).

    Article  CAS  Google Scholar 

  36. Marsenic, O. Glucose control by the kidney: an emerging target in diabetes. Am. J. Kidney Dis. 53, 875–883 (2009).

    Article  CAS  Google Scholar 

  37. Katsuno, K. et al. Sergliflozin, a novel selective inhibitor of low-affinity sodium glucose cotransporter (SGLT2), validates the critical role of SGLT2 in renal glucose reabsorption and modulates plasma glucose level. J. Pharmacol. Exp. Ther. 320, 323–330 (2007).

    Article  CAS  Google Scholar 

  38. Fujimori, Y. et al. Sergliflozin etabonate, a selective SGLT2 inhibitor, improves glycemic control in streptozotocin-induced diabetic rats and Zucker fatty rats. Eur. J. Pharmacol. 609, 148–154 (2009).

    Article  CAS  Google Scholar 

  39. Fujimori, Y. et al. Remogliflozin etabonate, in a novel category of selective low-affinity sodium glucose cotransporter (SGLT2) inhibitors, exhibits antidiabetic efficacy in rodent models. J. Pharmacol. Exp. Ther. 327, 268–276 (2008).

    Article  CAS  Google Scholar 

  40. Harrington, W. W. et al. Remogliflozin etabonate, a potent and selective sodium-dependent glucose transporter 2 antagonist, produced sustained metabolic effects in Zucker diabetic fatty rats. In 68th Scientific Sessions of the American Diabetes Association. San Francisco, California (2008).

    Google Scholar 

  41. Han, S. et al. Dapagliflozin, a selective SGLT2 inhibitor, improves glucose homeostasis in normal and diabetic rats. Diabetes 57, 1723–1729 (2008).

    Article  CAS  Google Scholar 

  42. Meng, W. et al. Discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. J. Med. Chem. 51, 1145–1149 (2008).

    Article  CAS  Google Scholar 

  43. Komoroski, B. et al. Dapagliflozin, a novel SGLT2 inhibitor, induces dose-dependent glucosuria in healthy subjects. Clin. Pharmacol. Ther. 85, 520–526 (2009).

    Article  CAS  Google Scholar 

  44. Brooks, A. M. & Thacker, S. M. Dapagliflozin for the treatment of type 2 diabetes. Ann. Pharmacother. 43, 1286–1293 (2009).

    Article  CAS  Google Scholar 

  45. Wancewicz, E. V. et al. Long term safety and efficacy of ISIS 388626, an optimized SGLT2 antisense inhibitor, in multiple diabetic and euglycemic species. In 68th Scientific Sessions of the American Diabetes Association. San Francisco, California (2008).

    Google Scholar 

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  1. Renal Research Laboratory, Kolling Institute of Medical Research, Sydney Medical School, University of Sydney, Royal North Shore Hospital, St Leonards, 2065, NSW, Australia

    Amanda Mather & Carol Pollock

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Correspondence to Carol Pollock.

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Competing interests

C. Pollock has declared associations with the following companies: AstraZeneca and Boehringer Ingelheim. A. Mather has declared an association with Boehringer Ingelheim.

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Mather, A., Pollock, C. Renal glucose transporters: novel targets for hyperglycemia management. Nat Rev Nephrol 6, 307–311 (2010). https://doi.org/10.1038/nrneph.2010.38

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