Diabetologia

, Volume 10, Issue 1, pp 27–35

An inhibitory effect of tolbutamide and glibenclamide (glyburide) on the pancreatic islets of normal animals

  • J. C. Dunbar
  • P. P. Foà
Originals

Summary

Tolbutamide and glibenclamide (glyburide) were administered to normal hamsters, mice or rats in daily doses proportional to their body weight and equivalent to those used in human therapy. The animals were sacrificed after 6 to 8 weeks of treatment. Pieces of pancreas or isolated pancreatic islets were incubated or perifused in a medium containing glucose or tolbutamide, with or without Ieucine-114C or glucose-U-14C. The results indicate that the B cells of sulfonylurea treated animals synthesized and released less insulin and oxidized less glucose than those of insulin or saline treated controls. Accordingly, at least in the glibenclamide treated animals, the tolerance for glucose and the insulinogenic response to a glucose load in vivo were suppressed. Although insular function tended to return, to normal after treatment was discontinued, the results reported in this paper do not support the generally accepted view that the lasting therapeutic effectiveness of the sulfonylureas is due to a beta-cytotrophic action.

Key words

Insulin secretion perifusion isolated islets sulfonylureas intravenous glucose tolerance intravenous tolbutamide response glucose utilization tolbutamide glibenclamide 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Loubatières, A.: Etude physiologique et pharmaco-dynamique de certains dérivés sulfamides hypoglycémiants. Arch. Int. Physiol. 54, 174–177 (1946)Google Scholar
  2. 2.
    Pozza, G., Galansino, G., Foà, P.P.: Insulin secretion following carbutamide injections in normal dogs. Proc. Soc. exp. Biol. 93, 539–542 (1956)Google Scholar
  3. 3.
    Creutzfeldt, W., Soling, H.D.: Orale Diabetestherapie und ihre experimentellen Grundlagen. Erg. inn. Med. Kinderheilk. 15, 1–213 (1960)Google Scholar
  4. 4.
    Sussman, K.E., Stjernholm, M., Vaughan, G.D.: Tolbutamide and its effect upon insulin secretion in the isolated perfused rat pancreas. In: Tolbutamide... after ten years, p. 22–33 (ed. by Butterfield, W.J.H, and Van Westering, W.) Amsterdam: Excerpta Med. Found. I.C.S. 149, 1967Google Scholar
  5. 5.
    Loubatières, A., Mariani, M.M., Ribes, G., De Malbose, H., Alric, R., Chapal, J.: Pharmacological study of a new particularly active hypoglycemic sulfonamide. Glibenclamide (HB 419). HB 419 — new oral anti-diabetic drug, Pub. Symp. 1969, 18–24, 1969Google Scholar
  6. 6.
    Loubatières, A., Mariani, M.M., Chapal, J.: Insulino-sécrétion étudiée sur le pancréas isolé et perfuse du rat. I. Synergie entre glucose et sulfamides hypoglycémiants. Diabetologia 6, 457–466 (1970)Google Scholar
  7. 7.
    Lee, J.C., Grodsky, G.M., Bennett, L.L., Smith-Kyle, D.F., Craw, L.: Ultrastrueture of β-cells during the dynamic response to glucose and tolbutamide in vitro. Diabetologia 6, 542–549 (1970)Google Scholar
  8. 8.
    Grodsky, G.M., Bennett, L.L., Smith, D., Nemechek, K.: The effect of tolbutamide and glucose on the timed release of insulin from the isolated perfused pancreas. In: Tolbutamide ... after ten years, p. 11–21 (ed. by Butterfleld, W. J.H. and Van Westering, W.) Amsterdam: Excerpta Med. Found. I.C.S. 149, 1967Google Scholar
  9. 9.
    Kaupt, E., Köberich, W., Beyer, J., Schöffling, K.: Pharmacodynamic aspects of tolbutamide, glibenclamide, glibornuride and glisoxepide. I. Dose response relations and repeated administration in diabetic subjects. Diabetologia 7, 449–454 (1971)Google Scholar
  10. 10.
    Volk, B.W., Goldner, M.G., Weisenfeld, S., Lazarus, S.S.: Functional and histological studies concerning the action of sulfonylureas. Ann. N.Y. Acad. Sci. 71, 141–151 (1957)Google Scholar
  11. 11.
    Williamson, J.R., Lacy, P.E., Grishaw, J.W.: Ultrastructural changes in islets of the rat produced by tolbutamide. Diabetes 10, 460–469 (1961)Google Scholar
  12. 12.
    Weber, J.W., Colombo, J.P., Goldberg, R.L, Saperstein, S., Shulkind, M.L., Kanameishi, D., Foà, P.P.: Pancreatic function in alloxan “subdiabetic” rats long-term treated with tolbutamide. Diabetes 10, 122–129 (1961)Google Scholar
  13. 13.
    Loubatières, A., Mariani, M.M., Alric, R., Houareau, M.M.: Etude chez le rat du développement des îlots de Langerhans sous l'effet de l'administration chronique, séparée ou combinée, de tolbutamide et de diazoxide. C. R. Soc. Biol. (Paris) 162, 191–196 (1968)Google Scholar
  14. 14.
    Seltzer, H.S., Allen, E.W., Brennan, M.T.: Failure of prolonged sulfonylurea administration to enhance insulinogenic response to glycemic stimulus. Diabetes 14, 392–396 (1965)Google Scholar
  15. 15.
    Creutzfeldt, W., Frerichs, H., Creutzfeldt, C.: Studies with tolbutamide on islet tissue in vitro and islet homografts. In: Tolbutamide ... after ten years, p. 34–48, (ed. by Butterfleld, W.J.H. and Van Westering, W.) Amsterdam: Excerpta Med. Found. I.C.S. 149, 1967Google Scholar
  16. 16.
    Sodoyez, J.-C., Sodoyez-Goffaux, F., Dunbar, J.C., Foà, P.P.: Reduction in the activity of the pancreatic islets induced in normal rodents by prolonged treatment with derivatives of sulfonylurea. Diabetes 19, 603–609 (1970)Google Scholar
  17. 17.
    Lacy, P.E., Kostianovsky, M.: Method for the isolation of intact islets of Langerhans from the rat pancreas. Diabetes 16, 35–39 (1967)Google Scholar
  18. 18.
    Malaisse, W.J., Malaisse-Lagae, F., Wright, P.H.: A new method for the measurement in vitro of pancreatic insulin secretion. Endocrinology 80, 99–108 (1967)Google Scholar
  19. 19.
    Grodsky, G., Tarver, H., Light, A., Simpson, M.V.: Paper chromatography of insulin. Nature 177, 223–225 (1956)Google Scholar
  20. 20.
    Taylor, K.W., Gardner, G., Perry, D.G., Jones, V.E.: The purification of tritium-labelled insulin by precipitation with insulin antibodies. Biochim. biophys. Acta (Amst.) 100, 521–529 (1965)Google Scholar
  21. 21.
    Howell, S.L., Taylor, K.W.: The secretion of newly synthesized insulin in vitro. Biochem. J. 102, 922–927 (1967)Google Scholar
  22. 22.
    Hill, J.B., Kessler, G.: An automated determination of glucose utilizing a glucose oxidase-peroxidase system. J. Lab. clin. Med. 57, 970–980 (1961)Google Scholar
  23. 23.
    Ariëns, E.J.: Oral antidiabetics. Dose, plasma concentration and effect. In: Pharmacokinetics and mode of action of oral hypoglycemic agents, p. 143–197 (ed. by Loubatiéres, A. and Renold, A.E. Milano: Casa Ed. Il Ponte 1969Google Scholar
  24. 24.
    Hershman, J.M., Konerding, K.: Effects of sulfonylurea drugs on the thyroid and serum protein binding of thyroxine in the rat. Endocrinology 83, 74–78 (1968)Google Scholar
  25. 25.
    Idahl, L.-Å.: A micro perifusion device for pancreatic islets allowing concomitant recordings of intermediate metabolites and insulin release. Analyt. Biochem. 50, 386–398 (1972)Google Scholar
  26. 26.
    Lernmark, A.: Isolated mouse islets as a model for studying insulin release. Acta diabet. lat. 8, 649–679 (1971)Google Scholar
  27. 27.
    Volk, B.W., Lazarus, S.S.: B cell hyperfunction after longterm sulfonylurea treatment. Arch. Path. 78, 114–126 (1964)Google Scholar
  28. 28.
    Permutt, M.A., Kipnis, D.M.: Insulin biosynthesis. I. On the mechanism of glucose stimulation. J. biol. Chem. 247, 1194–1199 (1972)Google Scholar
  29. 29.
    Taylor, K.W., Perry, D.G.: Tolbutamide and the incorporation of (3H) leucine in vitro. J. Endocr. 39, 457–458 (1967)Google Scholar
  30. 30.
    Morris, G.E., Korner, A.: The effect of glucose on insulin biosynthesis by isolated islets of Langerhans of the rat. Biochim. Biophys. Acta (Amst.) 208, 404–413 (1970)Google Scholar
  31. 31.
    Tanese, T., Lazarus, N.R., Devrim, S., Recant, L.: Synthesis and release of proinsulin and insulin by isolated rat islets of Langerhans. J. clin. Invest. 49, 1394–1404 (1970)Google Scholar
  32. 32.
    Snyder, P.J., Kashket, S., O'Sullivan, J.B.: Pentose cycle in isolated islets during glucose stimulated insulin release. Amer. J. Physiol. 219, 876–880 (1970)Google Scholar
  33. 33.
    Stork, H., Schmidt, F.H., Hellerström, C., Westman, S.: Respiration of the β-cells in the presence of sulfonylureas. In: The structure and metabolism of the pancreatic islets, p. 331–336 (ed. by Falkmer, S., Hellman, B. and Täljedal, I.-B.) Oxford and New York: Pergamon Press 1970Google Scholar
  34. 34.
    Ashcroft, S.J.H., Bassett, J.M., Randle, P.J.: Isolation of human pancreatic islets capable of releasing insulin and metabolizing glucose in vitro. Lancet 1971 I, 888–889Google Scholar
  35. 35.
    Ammon, H.P.T., Steinke, J.: Effect of 6-aminonicotinamide on insulin release and C-14 glucose oxidation by isolated pancreatic rat islets: difference between glucose, tolbutamide and aminophylline. Endocrinology 91, 33–38 (1972)Google Scholar
  36. 36.
    Hellerström, C.: Effects of glucosamine on the respiration of pancreatic islet B-cells. Acta endocr. (Kbh) 58, 558–564 (1968)Google Scholar
  37. 37.
    Georg, R.H., Sussman, K.E., Leitner, J.W., Kirsch, W.M.: Inhibition of glucose and tolbutamide-induced insulin release by iodoacetate and antimycin A. Endocrinology 89, 169–176 (1971)Google Scholar
  38. 38.
    Gepts, W.: Contribution à l'étude morphologique des îlots de Langerhans au cours du diabète. Bruxelles: Acta Medica Belgica (1967)Google Scholar
  39. 39.
    Kracht, J., v. Holt, C., v. Holt, L.: Morphologische Befunde zur Wirkungsweise oraler Antidiabetika. Endokrinologie 34, 129–146 (1957)Google Scholar
  40. 40.
    Sodoyez, J.-C., Sodoyez-Goffaux, F., Rossen, R.M., Foà, P.P.: Function of the pancreatic B-cells in hamsters bearing a transplantable islet cell tumor. Metabolism 18, 433–438 (1969)Google Scholar
  41. 41.
    Frerichs, H., Creutzfeldt, C., Creutzfeldt, W.: Inhibitors of insulin secretion. In: Mechanism and regulation of insulin secretion, p. 105–123 (ed. by Levine, R. and Pfeiffer, E.F.) Milano: Casa Ed. Il Ponte 1968Google Scholar
  42. 42.
    Sodoyez, J.-C., Sodoyez-Goffaux, F., Foà, P.P.: Feedback regulation of insulin secretion by insulin: role of 3′, 5′-cyclic AMP. In: The structure and metabolism of the pancreatic islets, p. 445–451 (ed. by Falkmer, S., Hellman, B. and Täljedal, I.-B.). Oxford and New York: Pergamon Press 1970Google Scholar
  43. 43.
    Sodoyez, J.-C., Sodoyez-Goffaux, F., Foà, P.P.: Evidence for an insulin-induced inhibition of insulin release by isolated islets of Langerhans. Proc. Soc. exp. Biol. (N.Y.) 130, 568–571 (1969)Google Scholar
  44. 44.
    Hahn, H.J., Michael, R.: Untersuchungen an Langer — hansschen Inseln in vitro. V. Die Hemmung der glukoseinduzierten Insulinsekretion durch endogenes Insulin in vitro. Endokrinologie 57, 98–107 (1970)Google Scholar
  45. 45.
    Loreti, L., Chen, S., Dunbar, J.C., Foà, P.P.: Effect of exogenous insulin on insulin secretion by isolated pancreatic islets of normal and obese-hyperglycemic (ob/ob) mice. Diabetes 21 (Suppl. 1), 344 (1972)Google Scholar
  46. 46.
    Hellman, B., Idahl, L.-Å., Danielsson, A.: Adenosine triphosphate levels of mammalian pancreatic B cells after stimulation with glucose and hypoglycemic sulfonylurea. Diabetes 18, 509–516 (1969)Google Scholar
  47. 47.
    Idahl, L.-Å.: Glucose-6-phosphate content in mammalian pancreatic β-cells. Effects of various stimulators and inhibitors of insulin release. Hormones (Basel) 2, 371–377 (1971)Google Scholar
  48. 48.
    Westman, S., Hellerström, C.: Metabolism of the pancreatic beta-cells of mice in the presence of hypoclycemic sulfonylureas. Postgrad, med. J., Suppl. 46, 28–31 (1970)Google Scholar
  49. 49.
    Krzanowski, J.J., Jr., Fertel, R., Matschinsky, F.M.: Energy metabolism in pancreatic islets of rats. Studies with tolbutamide and hypoxia. Diabetes 20, 598–606 (1971)Google Scholar
  50. 50.
    DeSchepper, P.J.: Metabolic effects of hypoglycemic sulfonylureas. I. In vitro effect of sulfonylureas on leucine incorporation and metabolism and on respiration of rat tissues. Biochem. Pharmacol. 16, 2337–2353 (1967)Google Scholar
  51. 51.
    Chan, S.S., Fain, J.N.: Uncoupling action of sulfonylureas on brown fat cells. Molec. Pharmacol. 6, 513–523 (1970)Google Scholar
  52. 52.
    Madsen, J.: Extrapancreatic and intrapancreatic action of antidiabetic sulfonylureas. A Review. Acta med. scand. Suppl. 476, 109–122 (1967)Google Scholar
  53. 53.
    Feldman, J.M., Lebovitz, H.E.: Endocrine and metabolic effects of glybenclamide. Evidence for an extrapancreatic mechanism of action. Diabetes 20 745–755 (1971)Google Scholar

Copyright information

© Springer-Verlag 1974

Authors and Affiliations

  • J. C. Dunbar
    • 1
  • P. P. Foà
    • 1
  1. 1.Department of ResearchSinai Hospital of DetroitDetroit

Personalised recommendations