American Journal of Kidney Diseases
Volume 53, Issue 5 , Pages 875-883 , May 2009

Glucose Control by the Kidney: An Emerging Target in Diabetes

  • Olivera Marsenic, MD

      Affiliations

    • Corresponding Author InformationAddress correspondence to Olivera Marsenic, MD, Children's Hospital of Philadelphia, 34th St and Civic Center Blvd, Philadelphia, PA 19104

Received 25 September 2008 ,Accepted 18 December 2008.

References 

  1. Stumvoll M, Chintalapudi U, Perriello G, Welle S, Gutierrez O, Gerich J. Uptake and release of glucose by the human kidney (Postabsorptive rates and responses to epinephrine). J Clin Invest. 1995;96:2528–2533
  2. Meyer C, Dostou JM, Welle SL, Gerich JE. Role of human liver, kidney, and skeletal muscle in postprandial glucose homeostasis. Am J Physiol Endocrinol Metab. 2002;282:E419–E427
  3. Gerich JE. Physiology of glucose homeostasis. Diabetes Obes Metab. 2000;2:345–350
  4. Thorens B. Glucose transporters in the regulation of intestinal, renal, and liver glucose fluxes. Am J Physiol. 1996;270(Pt 1):G541–G553
  5. Wright EM, Hirsch JR, Loo DD, Zampighi GA. Regulation of Na+/glucose cotransporters. J Exp Biol. 1997;200(Pt 2):287–293
  6. Gerich JE, Meyer C, Woerle HJ, Stumvoll M. Renal gluconeogenesis: Its importance in human glucose homeostasis. Diabetes Care. 2001;24:382–391
  7. Meyer C, Woerle HJ, Dostou JM, Welle SL, Gerich JE. Abnormal renal, hepatic, and muscle glucose metabolism following glucose ingestion in type 2 diabetes. Am J Physiol Endocrinol Metab. 2004;287:E1049–E1056
  8. Guder WG, Ross BD. Enzyme distribution along the nephron. Kidney Int. 1984;26:101–111
  9. Vandewalle A, Wirthensohn G, Heidrich HG, Guder WG. Distribution of hexokinase and phosphoenolpyruvate carboxykinase along the rabbit nephron. Am J Physiol. 1981;240:F492–F500
  10. Schoolwerth AC, Smith BC, Culpepper RM. Renal gluconeogenesis. Miner Electrolyte Metab. 1988;14:347–361
  11. Conjard A, Martin M, Guitton J, Baverel G, Ferrier B. Gluconeogenesis from glutamine and lactate in the isolated human renal proximal tubule: Longitudinal heterogeneity and lack of response to adrenaline. Biochem J. 2001;360(Pt 2):371–377
  12. Meyer C, Stumvoll M, Dostou J, Welle S, Haymond M, Gerich J. Renal substrate exchange and gluconeogenesis in normal postabsorptive humans. Am J Physiol Endocrinol Metab. 2002;282:E428–E434
  13. Biava C, Grossman A, West M. Ultrastructural observations on renal glycogen in normal and pathologic human kidneys. Lab Invest. 1966;15(Pt 2):330–356
  14. Landau BR, Wahren J, Chandramouli V, Schumann WC, Ekberg K, Kalhan SC. Contributions of gluconeogenesis to glucose production in the fasted state. J Clin Invest. 1996;98:378–385
  15. Meyer C, Stumvoll M, Nadkarni V, Dostou J, Mitrakou A, Gerich J. Abnormal renal and hepatic glucose metabolism in type 2 diabetes mellitus. J Clin Invest. 1998;102:619–624
  16. Eid A, Bodin S, Ferrier B, et al. Intrinsic gluconeogenesis is enhanced in renal proximal tubules of Zucker diabetic fatty rats. J Am Soc Nephrol. 2006;17:398–405
  17. Wright EM. Renal Na(+)-glucose cotransporters. Am J Physiol Renal Physiol. 2001;280:F10–F18
  18. Zelikovic I. Aminoaciduria and glycosuria. In:  Avner ED,  Harmon WE,  Niaudet P editor. Pediatric Nephrology. (ed 5). Philadelphia, PA: Lippincott Williams & Wilkins; 2004;p. 701–772
  19. Moe OW, Wright SH, Palacín M. Renal handling of organic solutes. In:  Brenner BM editors. Brenner and Rector's The Kidney. (ed 8). Philadelphia, PA: Saunders Elsevier; 2008;p. 214–247
  20. Silverman M, Turner RJ. Glucose transport in the renal proximal tubule. In:  Windhager EE editors. Handbook of Physiology. New York, NY: Oxford University; 1992;p. 2017–2038
  21. Wright EM, Hirayama BA, Loo DF. Active sugar transport in health and disease. J Intern Med. 2007;261:32–43
  22. Brown GK. Glucose transporters: Structure, function and consequences of deficiency. J Inherit Metab Dis. 2000;23:237–246
  23. Wright EM, Turk E. The sodium/glucose cotransport family SLC5. Pflugers Arch. 2004;447:510–518
  24. Lee YJ, Han HJ. Regulatory mechanisms of Na(+)/glucose cotransporters in renal proximal tubule cells. Kidney Int Suppl. 2007;106:S27–S35
  25. Takata K, Kasahara T, Kasahara M, Ezaki O, Hirano H. Localization of Na(+)-dependent active type and erythrocyte/HepG2-type glucose transporters in rat kidney: Immunofluorescence and immunogold study. J Histochem Cytochem. 1991;39:287–298
  26. Tazawa S, Yamato T, Fujikura H, et al. SLC5A9/SGLT4, a new Na+-dependent glucose transporter, is an essential transporter for mannose, 1,5-anhydro-d-glucitol, and fructose. Life Sci. 2005;76:1039–1050
  27. Chen J, Feder J, Neuhaus I, Whaley JM. Tissue expression profiling of the sodium-glucose co-transporter (SGLT) family: Implication for targeting SGLT2 in type 2 diabetes patients. [abstract 2493-PO] 2008;American Diabetes Association, San Francisco, USA, 6-10 June
  28. Isaji M. Sodium-glucose cotransporter inhibitors for diabetes. Curr Opin Investig Drugs. 2007;8:285–292
  29. Santer R, Kinner M, Lassen CL, et al. Molecular analysis of the SGLT2 gene in patients with renal glucosuria. J Am Soc Nephrol. 2003;14:2873–2882
  30. van den Heuvel LP, Assink K, Willemsen M, Monnens L. Autosomal recessive renal glucosuria attributable to a mutation in the sodium glucose cotransporter (SGLT2). Hum Genet. 2002;111:544–547
  31. Calado J, Soto K, Clemente C, Correia P, Rueff J. Novel compound heterozygous mutations in SLC5A2 are responsible for autosomal recessive renal glucosuria. Hum Genet. 2004;114:314–316
  32. Francis J, Zhang J, Farhi A, Carey H, Geller DS. A novel SGLT2 mutation in a patient with autosomal recessive renal glucosuria. Nephrol Dial Transplant. 2004;19:2893–2895
  33. Kleta R, Stuart C, Gill FA, Gahl WA. Renal glucosuria due to SGLT2 mutations. Mol Genet Metab. 2004;82:56–58
  34. Scholl-Burgi S, Santer R, Ehrich JH. Long-term outcome of renal glucosuria type O: The original patient and his natural history. Nephrol Dial Transplant. 2004;19:2394–2396
  35. Magen D, Sprecher E, Zelikovic I, Skorecki K. A novel missense mutation in SLC5A2 encoding SGLT2 underlies autosomal-recessive renal glucosuria and aminoaciduria. Kidney Int. 2005;67:34–41
  36. Calado J, Loeffler J, Sakallioglu O, et al. Familial renal glucosuria: SLC5A2 mutation analysis and evidence of salt-wasting. Kidney Int. 2006;69:852–855
  37. Turk E, Zabel B, Mundlos S, Dyer J, Wright EM. Glucose/galactose malabsorption caused by a defect in the Na+/glucose cotransporter. Nature. 1991;350:354–356
  38. Manz F, Bickel H, Brodehl J, et al. Fanconi-Bickel syndrome. Pediatr Nephrol. 1987;1:509–518
  39. Santer R, Steinmann B, Schaub J. Fanconi-Bickel syndrome—A congenital defect of facilitative glucose transport. Curr Mol Med. 2002;2:213–227
  40. Dominguez JH, Camp K, Maianu L, Feister H, Garvey WT. Molecular adaptations of GLUT1 and GLUT2 in renal proximal tubules of diabetic rats. Am J Physiol. 1994;266(Pt 2):F283–F290
  41. Chin E, Zamah AM, Landau D, et al. Changes in facilitative glucose transporter messenger ribonucleic acid levels in the diabetic rat kidney. Endocrinology. 1997;138:1267–1275
  42. Kamran M, Peterson RG, Dominguez JH. Overexpression of GLUT2 gene in renal proximal tubules of diabetic Zucker rats. J Am Soc Nephrol. 1997;8:943–948
  43. Marks J, Carvou NJ, Debnam ES, Srai SK, Unwin RJ. Diabetes increases facilitative glucose uptake and GLUT2 expression at the rat proximal tubule brush border membrane. J Physiol. 2003;553(Pt 1):137–145
  44. Schaan BD, Irigoyen MC, Bertoluci MC, et al. Increased urinary TGF-beta1 and cortical renal GLUT1 and GLUT2 levels: Additive effects of hypertension and diabetes. Nephron Physiol. 2005;100:43–50
  45. Rahmoune H, Thompson PW, Ward JM, Smith CD, Hong G, Brown J. Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes. Diabetes. 2005;54:3427–3434
  46. Laukkanen O, Lindstrom J, Eriksson J, et al. Polymorphisms in the SLC2A2 (GLUT2) gene are associated with the conversion from impaired glucose tolerance to type 2 diabetes: The Finnish Diabetes Prevention Study. Diabetes. 2005;54:2256–2260
  47. Farber SJ, Berger EY, Earle DP. Effect of diabetes and insulin of the maximum capacity of the renal tubules to reabsorb glucose. J Clin Invest. 1951;30:125–129
  48. Mogensen CE. Maximum tubular reabsorption capacity for glucose and renal hemodynamics during rapid hypertonic glucose infusion in normal and diabetic subjects. Scand J Clin Lab Invest. 1971;28:101–109
  49. Ehrenkranz JR, Lewis NG, Kahn CR, Roth J. Phlorizin: A review. Diabetes Metab Res Rev. 2005;21:31–38
  50. Adachi T, Yasuda K, Okamoto Y, et al. T-1095, a renal Na+-glucose transporter inhibitor, improves hyperglycemia in streptozotocin-induced diabetic rats. Metabolism. 2000;49:990–995
  51. Katsuno K, Fujimori Y, Takemura Y, 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. 2007;320:323–330
  52. Oku A, Ueta K, Arakawa K, et al. Correction of hyperglycemia and insulin sensitivity by T-1095, an inhibitor of renal Na+-glucose cotransporters, in streptozotocin-induced diabetic rats. Jpn J Pharmacol. 2000;84:351–354
  53. Turner RJ, Silverman M. Interaction of phlorizin and sodium with the renal brush-border membrane d-glucose transporter: Stoichiometry and order of binding. J Membr Biol. 1981;58:43–55
  54. Ueta K, Ishihara T, Matsumoto Y, 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. 2005;76:2655–2668
  55. Yasuda K, Okamoto Y, Nunoi K, et al. Normalization of cytoplasmic calcium response in pancreatic beta-cells of spontaneously diabetic GK rat by the treatment with T-1095, a specific inhibitor of renal Na+-glucose co-transporters. Horm Metab Res. 2002;34:217–221
  56. Han S, Hagan DL, Taylor JR, et al. Dapagliflozin, a selective SGLT2 inhibitor, improves glucose homeostasis in normal and diabetic rats. Diabetes. 2008;57:1723–1729
  57. Meng W, Ellsworth BA, Nirschl AA, 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. 2008;51:1145–1149
  58. Kanai Y, Lee WS, You G, Brown D, Hediger MA. The human kidney low affinity Na+/glucose cotransporter SGLT2 (Delineation of the major renal reabsorptive mechanism for d-glucose). J Clin Invest. 1994;93:397–404
  59. Panayotova-Heiermann M, Loo DD, Wright EM. Kinetics of steady-state currents and charge movements associated with the rat Na+/glucose cotransporter. J Biol Chem. 1995;270:27099–27105
  60. Oku A, Ueta K, Arakawa K, et al. T-1095, an inhibitor of renal Na+-glucose cotransporters, may provide a novel approach to treating diabetes. Diabetes. 1999;48:1794–1800
  61. Washburn WN, Sher PM, Wu G. Preparation of O-aryl glucosides as antidiabetic agents and SGLT2 inhibitors (U.S. Patent 6683056). Chem Abstr. 2001;135:273163A;(abstr)
  62. Washburn WN. Preparation of O-pyrazole glucoside SGLT2 inhibitors as antidiabetic agents (PCT Int. Appl. WO/2003/020737). Chem Abstr. 2003;138:21784A;(abstr)
  63. Komoroski B, Brenner E, Li L, et al. Dapagliflozin (BMS-512148), a selective inhibitor of the sodium-glucose uptake transporter 2 (SGLT2), reduces fasting serum glucose and glucose excursion in type 2 diabetes mellitus patients over 14 days. Diabetes. 2007;56:49A;(abstr)
  64. Wolters Kluwer Health Research & Development Insight database. http://bi.adisinsight.com/login/login.aspxAccessed December 8, 2008

 Originally published online as doi:10.1053/j.ajkd.2008.12.031 on March 27, 2009.

PII: S0272-6386(09)00148-6

doi: 10.1053/j.ajkd.2008.12.031

American Journal of Kidney Diseases
Volume 53, Issue 5 , Pages 875-883 , May 2009

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