Springer Nature is making Coronavirus research free. View research | View latest news | Sign up for updates

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

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.

References

  1. 1.

    Loubatières, A.: Etude physiologique et pharmaco-dynamique de certains dérivés sulfamides hypoglycémiants. Arch. Int. Physiol. 54, 174–177 (1946)

  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)

  3. 3.

    Creutzfeldt, W., Soling, H.D.: Orale Diabetestherapie und ihre experimentellen Grundlagen. Erg. inn. Med. Kinderheilk. 15, 1–213 (1960)

  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, 1967

  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, 1969

  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)

  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)

  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, 1967

  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)

  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)

  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)

  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)

  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)

  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)

  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, 1967

  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)

  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)

  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)

  19. 19.

    Grodsky, G., Tarver, H., Light, A., Simpson, M.V.: Paper chromatography of insulin. Nature 177, 223–225 (1956)

  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)

  21. 21.

    Howell, S.L., Taylor, K.W.: The secretion of newly synthesized insulin in vitro. Biochem. J. 102, 922–927 (1967)

  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)

  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 1969

  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)

  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)

  26. 26.

    Lernmark, A.: Isolated mouse islets as a model for studying insulin release. Acta diabet. lat. 8, 649–679 (1971)

  27. 27.

    Volk, B.W., Lazarus, S.S.: B cell hyperfunction after longterm sulfonylurea treatment. Arch. Path. 78, 114–126 (1964)

  28. 28.

    Permutt, M.A., Kipnis, D.M.: Insulin biosynthesis. I. On the mechanism of glucose stimulation. J. biol. Chem. 247, 1194–1199 (1972)

  29. 29.

    Taylor, K.W., Perry, D.G.: Tolbutamide and the incorporation of (3H) leucine in vitro. J. Endocr. 39, 457–458 (1967)

  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)

  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)

  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)

  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 1970

  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, 888–889

  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)

  36. 36.

    Hellerström, C.: Effects of glucosamine on the respiration of pancreatic islet B-cells. Acta endocr. (Kbh) 58, 558–564 (1968)

  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)

  38. 38.

    Gepts, W.: Contribution à l'étude morphologique des îlots de Langerhans au cours du diabète. Bruxelles: Acta Medica Belgica (1967)

  39. 39.

    Kracht, J., v. Holt, C., v. Holt, L.: Morphologische Befunde zur Wirkungsweise oraler Antidiabetika. Endokrinologie 34, 129–146 (1957)

  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)

  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 1968

  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 1970

  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)

  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)

  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)

  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)

  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)

  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)

  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)

  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)

  51. 51.

    Chan, S.S., Fain, J.N.: Uncoupling action of sulfonylureas on brown fat cells. Molec. Pharmacol. 6, 513–523 (1970)

  52. 52.

    Madsen, J.: Extrapancreatic and intrapancreatic action of antidiabetic sulfonylureas. A Review. Acta med. scand. Suppl. 476, 109–122 (1967)

  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)

Download references

Author information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Dunbar, J.C., Foà, P.P. An inhibitory effect of tolbutamide and glibenclamide (glyburide) on the pancreatic islets of normal animals. Diabetologia 10, 27–35 (1974). https://doi.org/10.1007/BF00421411

Download citation

Key words

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