Probing SGLT2 as a therapeutic target for diabetes: basic physiology and consequences.

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  • Author(s): Gallo LA;Gallo LA; Wright EM; Wright EM; Vallon V; Vallon V
  • Source:
    Diabetes & vascular disease research [Diab Vasc Dis Res] 2015 Mar; Vol. 12 (2), pp. 78-89. Date of Electronic Publication: 2015 Jan 23.
  • Publication Type:
    Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Review
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Sage Publications Country of Publication: England NLM ID: 101234011 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1752-8984 (Electronic) Linking ISSN: 14791641 NLM ISO Abbreviation: Diab Vasc Dis Res Subsets: MEDLINE
    • Publication Information:
      Publication: 2009- : London : Sage Publications
      Original Publication: Edgbaston, Birmingham, UK : Sherborne Gibbs, c2005-
    • Subject Terms:
      Sodium-Glucose Transporter 2 Inhibitors*; Blood Glucose/*drug effects ; Diabetes Mellitus, Type 1/*drug therapy ; Diabetes Mellitus, Type 2/*drug therapy ; Hypoglycemic Agents/*therapeutic use ; Kidney Tubules, Proximal/*drug effects; Animals ; Blood Glucose/metabolism ; Diabetes Mellitus, Type 1/blood ; Diabetes Mellitus, Type 1/diagnosis ; Diabetes Mellitus, Type 1/physiopathology ; Diabetes Mellitus, Type 2/blood ; Diabetes Mellitus, Type 2/diagnosis ; Diabetes Mellitus, Type 2/physiopathology ; Humans ; Hypoglycemic Agents/adverse effects ; Kidney Tubules, Proximal/metabolism ; Kidney Tubules, Proximal/physiopathology ; Molecular Targeted Therapy ; Renal Elimination/drug effects ; Renal Reabsorption/drug effects ; Sodium-Glucose Transporter 1/antagonists & inhibitors ; Sodium-Glucose Transporter 1/metabolism ; Sodium-Glucose Transporter 2/metabolism ; Treatment Outcome
    • Abstract:
      Traditional treatments for type 1 and type 2 diabetes are often associated with side effects, including weight gain and hypoglycaemia that may offset the benefits of blood glucose lowering. The kidneys filter and reabsorb large amounts of glucose, and urine is almost free of glucose in normoglycaemia. The sodium-dependent glucose transporter (SGLT)-2 in the early proximal tubule reabsorbs the majority of filtered glucose. Remaining glucose is reabsorbed by SGLT1 in the late proximal tubule. Diabetes enhances renal glucose reabsorption by increasing the tubular glucose load and the expression of SGLT2 (as shown in mice), which maintains hyperglycaemia. Inhibitors of SGLT2 enhance urinary glucose excretion and thereby lower blood glucose levels in type 1 and type 2 diabetes. The load-dependent increase in SGLT1-mediated glucose reabsorption explains why SGLT2 inhibitors in normoglycaemic conditions enhance urinary glucose excretion to only ~50% of the filtered glucose. The role of SGLT1 in both renal and intestinal glucose reabsorption provides a rationale for the development of dual SGLT1/2 inhibitors. SGLT2 inhibitors lower blood glucose levels independent of insulin and induce pleiotropic actions that may be relevant in the context of lowering cardiovascular risk. Ongoing long-term clinical studies will determine whether SGLT2 inhibitors have a safety profile and exert cardiovascular benefits that are superior to traditional agents.
      (© The Author(s) 2015.)
    • References:
      Kidney Int. 1999 Jun;55(6):2548-72. (PMID: 10354307)
      Diabetes. 2011 Mar;60(3):890-8. (PMID: 21357472)
      Clin Pharmacol Ther. 2009 May;85(5):520-6. (PMID: 19129748)
      Am J Physiol Renal Physiol. 2014 Jan;306(2):F194-204. (PMID: 24226524)
      Nephrol Dial Transplant. 2004 Sep;19(9):2394-6. (PMID: 15299100)
      Physiol Rev. 2013 Jan;93(1):137-88. (PMID: 23303908)
      Am J Physiol Cell Physiol. 2012 May 1;302(9):C1293-305. (PMID: 22159082)
      Am J Physiol Renal Physiol. 2007 Oct;293(4):F974-84. (PMID: 17686957)
      PLoS One. 2013;8(2):e54442. (PMID: 23390498)
      FEBS Lett. 1983 Sep 19;161(2):279-83. (PMID: 6684594)
      Diabet Med. 2010 Feb;27(2):136-42. (PMID: 20546255)
      J Am Soc Nephrol. 2014 Sep;25(9):2028-39. (PMID: 24652792)
      Nat Rev Drug Discov. 2010 Jul;9(7):551-9. (PMID: 20508640)
      Diabetes Care. 2014 May;37(5):1480-3. (PMID: 24595630)
      J Am Soc Nephrol. 2011 Jan;22(1):104-12. (PMID: 20616166)
      J Am Geriatr Soc. 2014 Jul;62(7):1252-62. (PMID: 24890683)
      Cardiovasc Diabetol. 2014 Jan 29;13:28. (PMID: 24475922)
      Drugs. 2014 Jun;74(8):945-50. (PMID: 24848756)
      Braz J Med Biol Res. 2014 Oct;47(10):917-23. (PMID: 25250631)
      Diabetes Care. 2014 Jan;37 Suppl 1:S14-80. (PMID: 24357209)
      Diabetes. 2012 Jan;61(1):187-96. (PMID: 22124465)
      Am J Physiol Regul Integr Comp Physiol. 2012 Jan 1;302(1):R75-83. (PMID: 21940401)
      Am J Physiol Cell Physiol. 2012 Aug 1;303(3):C348-54. (PMID: 22673616)
      CMAJ. 2006 Jan 17;174(2):185-6. (PMID: 16415463)
      J Histochem Cytochem. 1991 Mar;39(3):287-98. (PMID: 1993828)
      Circulation. 2014 Feb 4;129(5):587-97. (PMID: 24334175)
      J Biol Chem. 2004 Apr 16;279(16):16229-36. (PMID: 14739288)
      Proc Natl Acad Sci U S A. 2005 Dec 6;102(49):17864-9. (PMID: 16314573)
      Am J Physiol Cell Physiol. 2011 Jan;300(1):C14-21. (PMID: 20980548)
      N Engl J Med. 2005 Dec 22;353(25):2643-53. (PMID: 16371630)
      Lancet. 1998 Sep 12;352(9131):837-53. (PMID: 9742976)
      Clin J Am Soc Nephrol. 2010 Jan;5(1):133-41. (PMID: 19965550)
      Physiol Rev. 2011 Apr;91(2):733-94. (PMID: 21527736)
      J Clin Invest. 1933 Nov;12(6):1083-90. (PMID: 16694183)
      N Engl J Med. 2009 Jan 8;360(2):129-39. (PMID: 19092145)
      J Am Soc Nephrol. 2011 Jan;22(1):113-23. (PMID: 21209254)
      N Engl J Med. 2008 Jun 12;358(24):2545-59. (PMID: 18539917)
      JAMA. 2002 Jan 16;287(3):360-72. (PMID: 11790216)
      N Engl J Med. 2011 Mar 03;364(9):829-841. (PMID: 21366474)
      J Am Soc Nephrol. 1999 Dec;10(12):2569-76. (PMID: 10589696)
      Nature. 2010 Dec 16;468(7326):988-91. (PMID: 21131949)
      Science. 2008 Aug 8;321(5890):810-4. (PMID: 18599740)
      Diabetes Res Clin Pract. 2009 Jan;83(1):e27-30. (PMID: 19095325)
      Proc Natl Acad Sci U S A. 1984 Apr;81(7):2223-6. (PMID: 6425830)
      Clin Pharmacol Ther. 2012 Aug;92(2):158-69. (PMID: 22739142)
      Pflugers Arch. 2004 Feb;447(5):510-8. (PMID: 12748858)
      Biochem Biophys Res Commun. 1991 Dec 31;181(3):1208-17. (PMID: 1764071)
      Am J Physiol. 1992 Sep;263(3 Pt 2):F459-65. (PMID: 1415574)
      J Clin Endocrinol Metab. 2012 Mar;97(3):1020-31. (PMID: 22238392)
      Diabetes. 1992 Jun;41(6):766-70. (PMID: 1350259)
      PLoS Med. 2008 Oct 7;5(10):e197. (PMID: 18842065)
      Am J Physiol. 1982 Apr;242(4):F406-14. (PMID: 6278960)
      Diabetes Res Clin Pract. 2014 Jun;104(3):297-322. (PMID: 24735709)
      Ann Med. 2012 Jun;44(4):375-93. (PMID: 21495788)
      Nature. 1987 Nov 26-Dec 2;330(6146):379-81. (PMID: 2446136)
      N Engl J Med. 2008 Jun 12;358(24):2560-72. (PMID: 18539916)
      Am J Physiol. 1981 Sep;241(3):F322-32. (PMID: 7282931)
      Diabetes. 2014 May;63(5):1738-47. (PMID: 24757202)
      Cell Tissue Res. 1992 Jan;267(1):3-9. (PMID: 1735116)
      Proc Natl Acad Sci U S A. 1989 Aug;86(15):5748-52. (PMID: 2490366)
      Annu Rev Physiol. 2012;74:351-75. (PMID: 22335797)
      Am J Physiol Endocrinol Metab. 2004 Dec;287(6):E1049-56. (PMID: 15304374)
      Diabetes Care. 2013 Aug;36(8):2154-61. (PMID: 23412078)
      N Engl J Med. 2008 Oct 9;359(15):1577-89. (PMID: 18784090)
      Am J Physiol Cell Physiol. 2012 Jan 15;302(2):C373-82. (PMID: 21940664)
      Annu Rev Med. 2015;66:255-70. (PMID: 25341005)
      J Clin Invest. 2014 Feb;124(2):509-14. (PMID: 24463448)
      J Am Soc Nephrol. 2001 Oct;12(10):2003-11. (PMID: 11562398)
      J Pharmacol Exp Ther. 2013 Jun;345(3):464-72. (PMID: 23492941)
      Am J Physiol Endocrinol Metab. 2013 Jan 15;304(2):E117-30. (PMID: 23149623)
      Lancet. 2010 Jun 26;375(9733):2223-33. (PMID: 20609968)
      J Clin Invest. 1987 May;79(5):1510-5. (PMID: 3571496)
      Diabetes Care. 2013 Oct;36(10):3169-76. (PMID: 23735727)
      J Membr Biol. 2011 Feb;239(3):157-65. (PMID: 21140140)
      Am J Physiol Regul Integr Comp Physiol. 2011 May;300(5):R1009-22. (PMID: 21228342)
      Postgrad Med. 2013 May;125(3):21-32. (PMID: 23748504)
      Am J Physiol Renal Physiol. 2013 Jan 15;304(2):F156-67. (PMID: 23152292)
      Nature. 1991 Mar 28;350(6316):354-6. (PMID: 2008213)
      Drugs. 2014 Apr;74(5):611-7. (PMID: 24668021)
      Nat Genet. 1996 Feb;12 (2):216-20. (PMID: 8563765)
      Br J Pharmacol. 2013 Oct;170(3):519-31. (PMID: 23751087)
      Am J Physiol. 1991 Aug;261(2 Pt 1):C296-304. (PMID: 1714681)
      Physiol Rep. 2014 Jun 27;2(6):null. (PMID: 24973332)
      J Clin Invest. 1951 Feb;30(2):125-9. (PMID: 14814204)
      Am J Physiol Renal Physiol. 2014 Jan;306(2):F188-93. (PMID: 24226519)
    • Grant Information:
      R01 DK019567 United States DK NIDDK NIH HHS; P30DK079337 United States DK NIDDK NIH HHS; R01 DK056248 United States DK NIDDK NIH HHS; R01DK56248 United States DK NIDDK NIH HHS; R01DK19567 United States DK NIDDK NIH HHS; P30 DK079337 United States DK NIDDK NIH HHS; R01 HL094728 United States HL NHLBI NIH HHS; R01HL094728 United States HL NHLBI NIH HHS
    • Contributed Indexing:
      Keywords: Renal glucose reabsorption; anti-diabetic therapy; cardiovascular outcomes; kidney physiology
    • Accession Number:
      0 (Blood Glucose)
      0 (Hypoglycemic Agents)
      0 (SLC5A1 protein, human)
      0 (SLC5A2 protein, human)
      0 (Sodium-Glucose Transporter 1)
      0 (Sodium-Glucose Transporter 2)
      0 (Sodium-Glucose Transporter 2 Inhibitors)
    • Publication Date:
      Date Created: 20150125 Date Completed: 20151201 Latest Revision: 20221109
    • Publication Date:
      20221213
    • Accession Number:
      PMC5886707
    • Accession Number:
      10.1177/1479164114561992
    • Accession Number:
      25616707