Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1984 Nov;74(5):1679–1685. doi: 10.1172/JCI111584

Furosemide inhibits glucose transport in isolated rat adipocytes via direct inactivation of carrier proteins.

D B Jacobs, B K Mookerjee, C Y Jung
PMCID: PMC425345  PMID: 6542109

Abstract

Furosemide inhibits 3-O-methyl-D-glucose equilibrium flux in isolated adipocytes. The inhibition is saturable with an increasing concentration of furosemide and shows a noncompetitive type of kinetics. Both basal and insulin-stimulated fluxes are equally affected by the inhibition. Hydrochlorothiazide and piretanide also inhibit the flux with a similar potency, whereas bumetanide, a more potent diuretic, is much less potent. To understand the molecular basis of this inhibition, effects of furosemide on the glucose-sensitive cytochaslasin B binding activities of adipocytes were studied. Furosemide inhibits the glucose-sensitive cytochalasin B binding of both microsomal and plasma membrane preparations. For both preparations, the inhibition is time dependent and only slowly reversible, is saturable with an increasing concentration of furosemide, shows a noncompetitive type of kinetics with apparent Ki (the inhibitor concentration that gives the half-maximum effect) of 3.5 and 0.7 mM after 2 and 18 h incubation, respectively, and is essentially identical between the basal and insulin-stimulated adipocytes. The inhibition develops with a first-order rate constant of approximately 0.12/h at 4 degrees C. These results indicate that furosemide inhibits glucose transport in adipocytes by directly inactivating transport carriers of both plasma membranes and microsomal reserve pool. This inactivation of glucose carrier may play a part in the diuretic-induced glucose intolerance frequently observed during diuretic therapy.

Full text

PDF
1679

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. BEARDWOOD D. M., ALDEN J. S., GRAHAM C. A., BEARDWOOD J. T., Jr, MARBLE A. EVIDENCE FOR A PERIPHERAL ACTION OF CHLOROTHIAZIDE IN NORMAL MAN. Metabolism. 1965 May;14:561–567. doi: 10.1016/s0026-0495(65)80016-6. [DOI] [PubMed] [Google Scholar]
  2. Barnett C. A., Whitney J. E. The effect of diazoxide and chlorothiazide on glucose uptake in vitro. Metabolism. 1966 Jan;15(1):88–93. doi: 10.1016/0026-0495(66)90013-8. [DOI] [PubMed] [Google Scholar]
  3. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1016/0003-2697(76)90527-3. [DOI] [PubMed] [Google Scholar]
  4. Charnock J. S., Potter H. A., McKee D. Ethacrynic acid inhibition of (Na + +K + )-activated adenosine triphosphatase. Biochem Pharmacol. 1970 May;19(5):1637–1641. doi: 10.1016/0006-2952(70)90152-8. [DOI] [PubMed] [Google Scholar]
  5. Ciaraldi T. P., Olefsky J. M. Kinetic relationships between insulin receptor binding and effects on glucose transport in isolated rat adipocytes. Biochemistry. 1982 Jul 6;21(14):3475–3480. doi: 10.1021/bi00257a034. [DOI] [PubMed] [Google Scholar]
  6. Cohen M. R., Hinsch E., Vergona R., Ryan J., Kolis S. J., Schwartz M. A. A comparative diuretic and tissue distribution study of bumetanide and furosemide in the dog. J Pharmacol Exp Ther. 1976 Jun;197(3):697–702. [PubMed] [Google Scholar]
  7. Cushman S. W., Wardzala L. J. Potential mechanism of insulin action on glucose transport in the isolated rat adipose cell. Apparent translocation of intracellular transport systems to the plasma membrane. J Biol Chem. 1980 May 25;255(10):4758–4762. [PubMed] [Google Scholar]
  8. Fajans S. S., Floyd J. C., Jr, Knopf R. F., Rull J., Guntsche E. M., Conn J. W. Benzothiadiazine suppression of insulin release from normal and abnormal islet tissue in man. J Clin Invest. 1966 Apr;45(4):481–492. doi: 10.1172/JCI105362. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. GOLDNER M. G., ZAROWITZ H., AKGUN S. Hyperglycemia and glycosuria due to thiazide derivatives administered in diabetes mellitus. N Engl J Med. 1960 Feb 25;262:403–405. doi: 10.1056/NEJM196002252620807. [DOI] [PubMed] [Google Scholar]
  10. Geck P., Pietrzyk C., Burckhardt B. C., Pfeiffer B., Heinz E. Electrically silent cotransport on Na+, K+ and Cl- in Ehrlich cells. Biochim Biophys Acta. 1980 Aug 4;600(2):432–447. doi: 10.1016/0005-2736(80)90446-0. [DOI] [PubMed] [Google Scholar]
  11. Gorden P. Glucose intolerance with hypokalemia. Failure of short-term potassium depletion in normal subjects to reproduce the glucose and insulin abnormalities of clinical hypokalemia. Diabetes. 1973 Jul;22(7):544–551. doi: 10.2337/diab.22.7.544. [DOI] [PubMed] [Google Scholar]
  12. Gutsche H. U., Müller-Ott K., Brunkhorst R., Niedermayer W. Dose-related effects of furosemide, bumetanide, and piretanide on the thick ascending limb function in the rat. Can J Physiol Pharmacol. 1983 Feb;61(2):159–165. doi: 10.1139/y83-024. [DOI] [PubMed] [Google Scholar]
  13. Helderman J. H., Elahi D., Andersen D. K., Raizes G. S., Tobin J. D., Shocken D., Andres R. Prevention of the glucose intolerance of thiazide diuretics by maintenance of body potassium. Diabetes. 1983 Feb;32(2):106–111. doi: 10.2337/diab.32.2.106. [DOI] [PubMed] [Google Scholar]
  14. Hirsch G. H., Pakuts A. P., Bayne A. J. Furosemide accumulation by renal tissue. Biochem Pharmacol. 1975 Nov 1;24(21):1943–1946. doi: 10.1016/0006-2952(75)90379-2. [DOI] [PubMed] [Google Scholar]
  15. Jung C. Y., Carlson L. M., Whaley D. A. Glucose transport carrier activities in extensively washed human red cell ghosts. Biochim Biophys Acta. 1971 Aug 13;241(2):613–627. doi: 10.1016/0005-2736(71)90059-9. [DOI] [PubMed] [Google Scholar]
  16. Jung C. Y., Mookerjee B. K. Inhibitory effect of furosemide on glucose transport. J Lab Clin Med. 1976 Jun;87(6):960–966. [PubMed] [Google Scholar]
  17. Jung C. Y., Rampal A. L. Cytochalasin B binding sites and glucose transport carrier in human erythrocyte ghosts. J Biol Chem. 1977 Aug 10;252(15):5456–5463. [PubMed] [Google Scholar]
  18. Karnieli E., Zarnowski M. J., Hissin P. J., Simpson I. A., Salans L. B., Cushman S. W. Insulin-stimulated translocation of glucose transport systems in the isolated rat adipose cell. Time course, reversal, insulin concentration dependency, and relationship to glucose transport activity. J Biol Chem. 1981 May 25;256(10):4772–4777. [PubMed] [Google Scholar]
  19. Kubik M. M., Bowers E., Underwood P. N. Longterm experience of the routine use of bumetanide. Br J Clin Pract. 1976 Jan;30(1):11–14. [PubMed] [Google Scholar]
  20. Lucci M. S., Warnock D. G. Effects of anion-transport inhibitors on NaCl reabsorption in the rat superficial proximal convoluted tubule. J Clin Invest. 1979 Aug;64(2):570–579. doi: 10.1172/JCI109495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Maloff B. L., Lockwood D. H. In vitro effects of a sulfonylurea on insulin action in adipocytes. Potentiation of insulin-stimulated hexose transport. J Clin Invest. 1981 Jul;68(1):85–90. doi: 10.1172/JCI110257. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. McKeel D. W., Jarett L. Preparation and characterization of a plasma membrane fraction from isolated fat cells. J Cell Biol. 1970 Feb;44(2):417–432. doi: 10.1083/jcb.44.2.417. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Mookerjee B. K., Cuppoletti J., Rampal A. L., Jung C. Y. The effects of cytochalasins on lymphocytes. Identification of distinct cytochalasin-binding sites in relation to mitogenic response and hexose transport. J Biol Chem. 1981 Feb 10;256(3):1290–1300. [PubMed] [Google Scholar]
  24. RODBELL M. METABOLISM OF ISOLATED FAT CELLS. I. EFFECTS OF HORMONES ON GLUCOSE METABOLISM AND LIPOLYSIS. J Biol Chem. 1964 Feb;239:375–380. [PubMed] [Google Scholar]
  25. Rowe J. W., Tobin J. D., Rosa R. M., Andres R. Effect of experimental potassium deficiency on glucose and insulin metabolism. Metabolism. 1980 Jun;29(6):498–502. doi: 10.1016/0026-0495(80)90074-8. [DOI] [PubMed] [Google Scholar]
  26. SAGILD U., ANDERSEN V., ANDREASEN P. B. Glucose tolerance and insulin responsiveness in experimental potassium depletion. Acta Med Scand. 1961 Mar;169:243–251. doi: 10.1111/j.0954-6820.1961.tb07829.x. [DOI] [PubMed] [Google Scholar]
  27. Sullivan L. P., Tucker J. M., Scherbenske M. J. Effect of furosemide on sodium transport and metabolism in toad bladder. Am J Physiol. 1971 May;220(5):1316–1324. doi: 10.1152/ajplegacy.1971.220.5.1316. [DOI] [PubMed] [Google Scholar]
  28. WELLER J. M., BORONDY P. E. EFFECTS OF BENZOTHIADIAZINE DRUGS ON CARBOHYDRATE METABOLISM. Metabolism. 1965 Jun;14:708–714. doi: 10.1016/0026-0495(65)90054-5. [DOI] [PubMed] [Google Scholar]
  29. WILKINS R. W. New drugs for the treatment of hypertension. Ann Intern Med. 1959 Jan;50(1):1–10. doi: 10.7326/0003-4819-50-1-1. [DOI] [PubMed] [Google Scholar]
  30. Whitesell R. R., Gliemann J. Kinetic parameters of transport of 3-O-methylglucose and glucose in adipocytes. J Biol Chem. 1979 Jun 25;254(12):5276–5283. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES