1932

Abstract

The kidneys in normoglycemic humans filter 160–180 g of glucose per day (∼30% of daily calorie intake), which is reabsorbed and returned to the systemic circulation by the proximal tubule. Hyperglycemia increases the filtered and reabsorbed glucose up to two- to three-fold. The sodium glucose cotransporter SGLT2 in the early proximal tubule is the major pathway for renal glucose reabsorption. Inhibition of SGLT2 increases urinary glucose and calorie excretion, thereby reducing plasma glucose levels and body weight. The first SGLT2 inhibitors have been approved as a new class of antidiabetic drugs in type 2 diabetes mellitus, and studies are under way to investigate their use in type 1 diabetes mellitus. These compounds work independent of insulin, improve glycemic control in all stages of diabetes mellitus in the absence of clinically relevant hypoglycemia, and can be combined with other antidiabetic agents. By lowering blood pressure and diabetic glomerular hyperfiltration, SGLT2 inhibitors may induce protective effects on the kidney and cardiovascular system beyond blood glucose control.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-med-051013-110046
2015-01-14
2024-03-29
Loading full text...

Full text loading...

/deliver/fulltext/med/66/1/annurev-med-051013-110046.html?itemId=/content/journals/10.1146/annurev-med-051013-110046&mimeType=html&fmt=ahah

Literature Cited

  1. 1. International Diabetes Federation 2013. IDF diabetes atlas, 6th. http://www.idf.org/diabetesatlas
  2. DeFronzo RA.2.  2009. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 58:773–95 [Google Scholar]
  3. 3. The Diabetes Control and Complications Trial Research Group 1993. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N. Engl. J. Med. 329:977–86 [Google Scholar]
  4. 4. American Diabetes Association 2014. Standards of medical care in diabetes—2014. Diabetes Care 37:S14–80 [Google Scholar]
  5. Kahn SE, Haffner SM, Heise MA. 5.  et al. 2006. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N. Engl. J. Med. 355:2427–43 [Google Scholar]
  6. Gerstein HC, Miller ME, Byington RP. 6.  et al. 2008. Effects of intensive glucose lowering in type 2 diabetes. N. Engl. J. Med. 358:2545–59 [Google Scholar]
  7. Mogensen CE.7.  1971. Maximum tubular reabsorption capacity for glucose and renal hemodynamics during rapid hypertonic glucose infusion in normal and diabetic subjects. Scand. J. Clin. Lab. Invest. 28:101–9 [Google Scholar]
  8. Farber SJ, Berger EY, Eaerle DP. 8.  1951. Effect of diabetes and insulin on the maximum capacity of the renal tubules to reabsorb glucose. J. Clin. Invest. 30:125–29 [Google Scholar]
  9. Santer R, Calado J. 9.  2010. Familial renal glucosuria and SGLT2: from a Mendelian trait to a therapeutic target. Clin. J. Am. Soc. Nephrol. 5:133–41 [Google Scholar]
  10. Wright EM, Loo DD, Hirayama BA. 10.  2011. Biology of human sodium glucose transporters. Physiol. Rev. 91:733–94 [Google Scholar]
  11. Wood IS, Trayhurn P. 11.  2003. Glucose transporters (GLUT and SGLT): expanded families of sugar transport proteins. Br. J. Nutr. 89:3–9 [Google Scholar]
  12. Balen D, Ljubojevic M, Breljak D. 12.  et al. 2008. Revised immunolocalization of the Na+-D-glucose cotransporter SGLT1 in rat organs with an improved antibody. Am. J. Physiol. Cell Physiol. 295:C475–89 [Google Scholar]
  13. Vallon V, Platt KA, Cunard R. 13.  et al. 2011. SGLT2 mediates glucose reabsorption in the early proximal tubule. J. Am. Soc. Nephrol. 22:104–12 [Google Scholar]
  14. Sabolic I, Vrhovac I, Eror DB. 14.  et al. 2012. Expression of Na+-D-glucose cotransporter SGLT2 in rodents is kidney-specific and exhibits sex and species differences. Am. J. Physiol. Cell Physiol. 302:C1174–88 [Google Scholar]
  15. Rieg T, Masuda T, Gerasimova M. 15.  et al. 2014. Increase in SGLT1-mediated transport explains renal glucose reabsorption during genetic and pharmacological SGLT2 inhibition in euglycemia. Am. J. Physiol. Ren. Physiol. 306:F188–93 [Google Scholar]
  16. Gorboulev V, Schurmann A, Vallon V. 16.  et al. 2012. Na+-D-glucose cotransporter SGLT1 is pivotal for intestinal glucose absorption and glucose-dependent incretin secretion. Diabetes 61:187–96 [Google Scholar]
  17. Hummel CS, Lu C, Loo DD. 17.  et al. 2011. Glucose transport by human renal Na+/D-glucose cotransporters SGLT1 and SGLT2. Am. J. Physiol. Cell Physiol. 300:C14–21 [Google Scholar]
  18. von Mering J. 18.  1886. Ueber kuenstlichen Diabetes. Centralbl. Med. Wiss. xxii:531 [Google Scholar]
  19. Ehrenkranz JR, Lewis NG, Kahn CR. 19.  et al. 2005. Phlorizin: a review. Diabetes Metab. Res. Rev. 21:31–38 [Google Scholar]
  20. Washburn WN, Poucher SM. 20.  2013. Differentiating sodium-glucose co-transporter-2 inhibitors in development for the treatment of type 2 diabetes mellitus. Expert Opin. Investig. Drugs 22:463–86 [Google Scholar]
  21. Abdul-Ghani MA, DeFronzo RA. 21.  2014. Lowering plasma glucose concentration by inhibiting renal sodium-glucose co-transport. J. Intern. Med. 276352–63
  22. Hasan FM, Alsahli M, Gerich JE. 22.  2014. SGLT2 inhibitors in the treatment of type 2 diabetes. Diabetes Res. Clin. Pract. 104:3297–322 [Google Scholar]
  23. Komoroski B, Vachharajani N, Boulton D. 23.  et al. 2009. Dapagliflozin, a novel SGLT2 inhibitor, induces dose-dependent glucosuria in healthy subjects. Clin. Pharmacol. Ther. 85:520–26 [Google Scholar]
  24. Heise T, Seewaldt-Becker E, Macha S. 24.  et al. 2013. Safety, tolerability, pharmacokinetics and pharmacodynamics following 4 weeks' treatment with empagliflozin once daily in patients with type 2 diabetes. Diabetes Obes. Metab. 15:613–21 [Google Scholar]
  25. Sha S, Devineni D, Ghosh A. 25.  et al. 2011. Canagliflozin, a novel inhibitor of sodium glucose co-transporter 2, dose dependently reduces calculated renal threshold for glucose excretion and increases urinary glucose excretion in healthy subjects. Diabetes Obes. Metab. 13:669–72 [Google Scholar]
  26. Ghezzi C, Hirayama BA, Gorraitz E. 25a.  et al. 2014. SGLT2 inhibitors act from the extracellular surface of the cell membrane. Physiol. Rep. 2:e12058 [Google Scholar]
  27. Ferrannini E, Muscelli E, Frascerra S. 26.  et al. 2014. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J. Clin. Invest. 124:499–508 [Google Scholar]
  28. Cherney DZ, Perkins BA, Soleymanlou N. 27.  et al. 2014. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation 129:587–97 [Google Scholar]
  29. Jurczak MJ, Lee HY, Birkenfeld AL. 28.  et al. 2011. SGLT2 deletion improves glucose homeostasis and preserves pancreatic beta-cell function. Diabetes 60:890–98 [Google Scholar]
  30. Macdonald FR, Peel JE, Jones HB. 29.  et al. 2010. The novel sodium glucose transporter 2 inhibitor dapagliflozin sustains pancreatic function and preserves islet morphology in obese, diabetic rats. Diabetes Obes. Metab. 12:1004–12 [Google Scholar]
  31. Merovci A, Solis-Herrera C, Daniele G. 30.  et al. 2014. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J. Clin. Invest. 124:2509–14 [Google Scholar]
  32. Rahmoune H, Thompson PW, Ward JM. 31.  et al. 2005. Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes. Diabetes 54:3427–34 [Google Scholar]
  33. Vallon V, Thomson SC. 32.  2012. Renal function in diabetic disease models: the tubular system in the pathophysiology of the diabetic kidney. Annu. Rev. Physiol. 74:351–75 [Google Scholar]
  34. Vallon V, Rose M, Gerasimova M. 33.  et al. 2013. Knockout of Na-glucose transporter SGLT2 attenuates hyperglycemia and glomerular hyperfiltration but not kidney growth or injury in diabetes mellitus. Am. J. Physiol. Ren. Physiol. 304:F156–67 [Google Scholar]
  35. Vallon V, Gerasimova M, Rose MA. 34.  et al. 2014. SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice. Am. J. Physiol. Ren. Physiol. 306:F194–F204 [Google Scholar]
  36. Ghezzi C, Wright EM. 35.  2012. Regulation of the human Na+ dependent glucose cotransporter hSGLT2. Am. J. Physiol. Cell Physiol. 303:C348–54 [Google Scholar]
  37. Osorio H, Bautista R, Rios A. 36.  et al. 2009. Effect of treatment with losartan on salt sensitivity and SGLT2 expression in hypertensive diabetic rats. Diabetes Res. Clin. Pract. 86:e46–49 [Google Scholar]
  38. Freitas HS, Anhe GF, Melo KF. 37.  et al. 2008. Na+-glucose transporter-2 messenger ribonucleic acid expression in kidney of diabetic rats correlates with glycemic levels: involvement of hepatocyte nuclear factor-1α expression and activity. Endocrinology 149:717–24 [Google Scholar]
  39. Vallon V.38.  2011. The proximal tubule in the pathophysiology of the diabetic kidney. Am. J. Physiol. Regul. Integr. Comp. Physiol. 300:R1009–R1022 [Google Scholar]
  40. Seyer-Hansen K.39.  1987. Renal hypertrophy in experimental diabetes: some functional aspects. J. Diabetes Complications 1:7–10 [Google Scholar]
  41. Powell DR, DaCosta CM, Gay J. 40.  et al. 2013. Improved glycemic control in mice lacking Sglt1 and Sglt2. Am. J. Physiol. Endocrinol. Metab. 304:E117–30 [Google Scholar]
  42. Marks J, Carvou NJ, Debnam ES. 41.  et al. 2003. Diabetes increases facilitative glucose uptake and GLUT2 expression at the rat proximal tubule brush border membrane. J. Physiol. 553:137–45 [Google Scholar]
  43. Goestemeyer AK, Marks J, Srai SK. 42.  et al. 2007. GLUT2 protein at the rat proximal tubule brush border membrane correlates with protein kinase C (PKC)-βl and plasma glucose concentration. Diabetologia 50:2209–17 [Google Scholar]
  44. Kellett GL, Brot-Laroche E, Mace OJ. 43.  et al. 2008. Sugar absorption in the intestine: the role of GLUT2. Annu. Rev. Nutr. 28:35–54 [Google Scholar]
  45. Gerich JE.44.  2010. Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: therapeutic implications. Diabetes Med. 27:136–42 [Google Scholar]
  46. Gerich JE, Meyer C, Woerle HJ. 45.  et al. 2001. Renal gluconeogenesis: its importance in human glucose homeostasis. Diabetes Care 24:382–91 [Google Scholar]
  47. Quinn PG, Yeagley D. 46.  2005. Insulin regulation of PEPCK gene expression: a model for rapid and reversible modulation. Curr. Drug Targets Immune Endocr. Metabol. Disord. 5:423–37 [Google Scholar]
  48. Gatica R, Bertinat R, Silva P. 47.  et al. 2013. Altered expression and localization of insulin receptor in proximal tubule cells from human and rat diabetic kidney. J. Cell Biochem. 114:639–49 [Google Scholar]
  49. Bolinder J, Ljunggren O, Kullberg J. 48.  et al. 2012. Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin. J. Clin. Endocrinol. Metab. 97:1020–31 [Google Scholar]
  50. Bonner C, Popescu I, Queniat G. 49.  et al. 2014. The glucose transporter SGLT 2 is expressed in human pancreatic alpha cells and is required for proper control of glucagon secretion in type 2 diabetes. Diabetes 63:Suppl. 1A101 (Abstr.) [Google Scholar]
  51. Barnett AH, Mithal A, Manassie J. 50.  et al. 2014. Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2:369–84 [Google Scholar]
  52. Geerlings S, Fonseca V, Castro-Diaz D. 51.  et al. 2014. Genital and urinary tract infections in diabetes: impact of pharmacologically-induced glucosuria. Diabetes Res. Clin. Pract. 103:373–81 [Google Scholar]
  53. Chen J, Williams S, Ho S. 52.  et al. 2010. Quantitative PCR tissue expression profiling of the human SGLT2 gene and related family members. Diabetes Ther. 1:57–92 [Google Scholar]
  54. Wright EM, Hirayama BA, Loo DF. 53.  2007. Active sugar transport in health and disease. J. Intern. Med. 261:32–43 [Google Scholar]
  55. Zhou L, Cryan EV, D'Andrea MR. 54.  et al. 2003. Human cardiomyocytes express high level of Na+/glucose cotransporter 1 (SGLT1). J. Cell Biochem. 90:339–46 [Google Scholar]
  56. Ly JP, Onay T, Sison K. 55.  et al. 2011. The sweet pee model for Sglt2 mutation. J. Am. Soc. Nephrol. 22:113–23 [Google Scholar]
  57. Wright EM.56.  2008. Diseases of renal glucose handling. Genetic Diseases of the Kidney R Lifton 1130–40 New York: Elsevier [Google Scholar]
  58. Polidori D, Sha S, Mudaliar S. 57.  et al. 2013. Canagliflozin lowers postprandial glucose and insulin by delaying intestinal glucose absorption in addition to increasing urinary glucose excretion: results of a randomized, placebo-controlled study. Diabetes Care 36:2154–61 [Google Scholar]
  59. Moriya R, Shirakura T, Ito J. 58.  et al. 2009. Activation of sodium-glucose cotransporter 1 ameliorates hyperglycemia by mediating incretin secretion in mice. Am. J. Physiol. Endocrinol. Metab. 297:E1358–65 [Google Scholar]
  60. Drucker DJ.59.  2013. Incretin action in the pancreas: potential promise, possible perils, and pathological pitfalls. Diabetes 62:3316–23 [Google Scholar]
  61. Powell DR, Smith M, Greer J. 60.  et al. 2013. LX4211 increases serum glucagon-like peptide 1 and peptide YY levels by reducing sodium/glucose cotransporter 1 (SGLT1)-mediated absorption of intestinal glucose. J. Pharmacol. Exp. Ther. 345:250–59 [Google Scholar]
  62. Shibazaki T, Tomae M, Ishikawa-Takemura Y. 61.  et al. 2012. KGA-2727, a novel selective inhibitor of a high-affinity sodium glucose cotransporter (SGLT1), exhibits antidiabetic efficacy in rodent models. J. Pharmacol. Exp. Ther. 342:288–96 [Google Scholar]
  63. Zambrowicz B, Freiman J, Brown PM. 62.  et al. 2012. LX4211, a dual SGLT1/SGLT2 inhibitor, improved glycemic control in patients with type 2 diabetes in a randomized, placebo-controlled trial. Clin. Pharmacol. Ther. 92:158–69 [Google Scholar]
  64. Tolhurst G, Heffron H, Lam YS. 63.  et al. 2012. Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2. Diabetes 61:364–71 [Google Scholar]
  65. Guthrie RM.64.  2013. Sodium-glucose co-transporter 2 inhibitors and the potential for cardiovascular risk reduction in patients with type 2 diabetes mellitus. Postgrad. Med. 125:21–32 [Google Scholar]
  66. Basile JN.65.  2013. The potential of sodium glucose cotransporter 2 (SGLT2) inhibitors to reduce cardiovascular risk in patients with type 2 diabetes (T2DM). J. Diabetes Complications 27:280–86 [Google Scholar]
  67. Kojima N, Williams JM, Takahashi T. 66.  et al. 2013. Effects of a new SGLT2 inhibitor, luseogliflozin, on diabetic nephropathy in T2DN rats. J. Pharmacol. Exp. Ther. 345:464–72 [Google Scholar]
  68. Gross JL, de Azevedo MJ, Silveiro SP. 67.  et al. 2005. Diabetic nephropathy: diagnosis, prevention, and treatment. Diabetes Care 28:164–76 [Google Scholar]
  69. Baker WL, Smyth LR, Riche DM. 68.  et al. 2014. Effects of sodium-glucose co-transporter 2 inhibitors on blood pressure: a systematic review and meta-analysis. J. Am. Soc. Hypertens. 8:262–75 [Google Scholar]
  70. Oliva RV, Bakris GL. 69.  2014. Blood pressure effects of sodium-glucose co-transport 2 (SGLT2) inhibitors. J. Am. Soc. Hypertens. 8:330–39 [Google Scholar]
  71. Foote C, Perkovic V, Neal B. 70.  2012. Effects of SGLT2 inhibitors on cardiovascular outcomes. Diab. Vasc. Dis. Res. 9:117–23 [Google Scholar]
  72. Beloto-Silva O, Machado UF, Oliveira-Souza M. 71.  2011. Glucose-induced regulation of NHEs activity and SGLTs expression involves the PKA signaling pathway. J. Membr. Biol. 239:157–65 [Google Scholar]
  73. Pessoa TD, Campos LC, Carraro-Lacroix L. 72.  et al. 2014. Functional role of glucose metabolism, osmotic stress, and sodium-glucose cotransporter isoform-mediated transport on Na+/H+ exchanger isoform 3 activity in the renal proximal tubule. J. Am. Soc. Nephrol. 25:2028–39 [Google Scholar]
  74. Fu Y, Gerasimova M, Mayoux E. 73.  et al. 2014. SGLT2 inhibitor empagliflozin increases renal NHE3 phosphorylation in diabetic Akita mice: possible implications for the prevention of glomerular hyperfiltration. Diabetes 63:Suppl. 1A132 (Abstr.) [Google Scholar]
  75. Magee GM, Bilous RW, Cardwell CR. 74.  et al. 2009. Is hyperfiltration associated with the future risk of developing diabetic nephropathy? A meta-analysis. Diabetologia 52:691–97 [Google Scholar]
  76. Vallon V, Richter K, Blantz RC. 75.  et al. 1999. Glomerular hyperfiltration in experimental diabetes mellitus: potential role of tubular reabsorption. J. Am. Soc. Nephrol. 10:2569–76 [Google Scholar]
  77. Thomson SC, Rieg T, Miracle C. 76.  et al. 2012. Acute and chronic effects of SGLT2 blockade on glomerular and tubular function in the early diabetic rat. Am. J. Physiol. Regul. Integr. Comp. Physiol. 302:R75–R83 [Google Scholar]
  78. Yale JF, Bakris G, Cariou B. 77.  et al. 2013. Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes. Metab. 15:463–73 [Google Scholar]
  79. Holtkamp FA, de Zeeuw D, Thomas MC. 78.  et al. 2011. An acute fall in estimated glomerular filtration rate during treatment with losartan predicts a slower decrease in long-term renal function. Kidney Int. 80:282–87 [Google Scholar]
/content/journals/10.1146/annurev-med-051013-110046
Loading
/content/journals/10.1146/annurev-med-051013-110046
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error