Metabolic, cationic and secretory effects of hypoglycemic sulfonylureas in pancreatic islets

  • Shoji Kawazu
  • Abdullan Sener
  • Etienne Couturier
  • Willy J. Malaisse
Article

Summary

Tolbutamide, gliclazide and glibenclamide failed to stimulate glucose oxidation in rat pancreatic islets. Tolbutamide also failed to stimulate pyruvate and palmitate oxidation and decreased the islet content of NAD(P)H and ATP. Tolbutamide stimulated 45Ca net uptake, inhibited 86Rb net uptake and tended to increase 22Na net uptake by the islets. The effect of theophylline upon islet function differed from that of tolbutamide by the magnitude of its insulinotropic action as a function of the glucose concentration, by its stimulant action upon the utilization of endogenous nutrients in islets deprived of glucose and by the lack of gross alteration in 45Ca and 86Rb net uptake. It is concluded that the insulinotropic effect of hypoglycemic sulfonylureas cannot be merely equated to a facilitation of nutrient metabolism or inactivation of phosphodiesterase in the islet cells. The primary action of these drugs could be to affect cations transport across the B-cell membrane.

Key words

Hypoglycemic sulfonylureas Theophylline Pancreatic islets Insulin release Cations 

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References

  1. Ammon, H. P. T.: Effect of tolbutamide on aminophylline-, 3,5-AMP-dibutyrate-or glucagon-induced insulin release from pancreatic islets after impairment of pyridine nucleotide metabolism caused by 6-aminonicotinamide (6-AN). Naunyn-Schmiedeberg's Arch. Pharmacol. 290, 251–264 (1975)Google Scholar
  2. Anjanevulu, R., Anjaneyulu, K., Couturier, E., Malaisse, W. J.: Opposite effects of hypoglycemic and hyperglycemic sulfonamides upon ionophore-mediated calcium transport. Biochem. Pharmacol. (in press, 1980)Google Scholar
  3. Ashcroft, S. J. H., Randle, P. J., Täljedal, I.-B.: Cyclic nucleotide phosphodiesterase activity in normal mouse pancreatic islets. FEBS Lett. 20, 263–266 (1972)Google Scholar
  4. Ashcroft, S. J. H., Weerasinghe, L. C. C., Randle, P. J.: Interrelationship of islet metabolism, adenosine triphosphate content and insulin release. Biochem. J. 132, 223–231 (1973)Google Scholar
  5. Boschero, A. C., Malaisse, W. J.: Stimulus-secretion coupling of glucose-induced insulin release. XXIX. Regulation of 86Rb+ efflux from perifused islets. Am. J. Physiol. 236, E139-E146 (1979)Google Scholar
  6. Boschero, A. C., Kawazu, S., Duncan, G., Malaisse, W. J.: Effect of glucose on K+ handling by pancreatic islets. FEBS Lett. 83, 151–154 (1977)Google Scholar
  7. Brisson, G. R., Malaisse, W. J.: The stimulus-secretion coupling of glucose-induced insulin release. XI. Effects of theophylline and epinephrine on 45Ca efflux from perifused islets. Metabolism 22, 455–465 (2973)Google Scholar
  8. Goldfine, I. D., Perlman, R., Roth, J.: Inhibition of cyclic 3′,5′-AMP phosphodiesterase in islet cells and other tissues by tolbutamide. Nature 234, 295–297 (1971)Google Scholar
  9. Grill, V., Cerasi, E.: Interacting effects of sulfonylureas and glucose on cyclic AMP metabolism and insulin release in pancreatic islets of the rat. J. Clin. Invest. 62, 1346–1354 (1978)Google Scholar
  10. Grodsky, G. M., Epstein, G. H., Fanska, R., Karam, J. H.: Pancreatic action of the sulfonylureas. Fed. Proc. 36, 2714–2719 (1977)Google Scholar
  11. Hellman, B.: Methodological approaches to studies on the pancreatic islets. Diabetologia 6, 110–120 (1970)Google Scholar
  12. Hellman, B.: On the mechanism of glibenclamide-induced insulin release. Medikon 4, 17–23 (1975)Google Scholar
  13. Hellman, B., Täljedal, I.-B.: Effects of sulfonylureas derivatives on pancreatic β-cells. In: Insulin II (A. Hasselblatt, F. v. Bruchhausen, eds.), pp. 175–194. Berlin, Heidelberg, New York: Springer 1975Google Scholar
  14. Henquin, J. C.: Tolbutamide stimulation and inhibition of insulin release: Studies of the underlying ionic mechanisms in isolated rat islets. Diabetologia 18, 151–160 (1980)Google Scholar
  15. Hutton, J. C., Sener, A., Malaisse, W. J.: The metabolism of 4-methyl-2-oxopentanoate in rat pancreatic islets. Biochem. J. 184, 291–301 (1979a)Google Scholar
  16. Hutton, J. C., Sener, A., Malaisse, W. J.: The stimulus-secretion coupling of 4-methyl-2-oxopentanoate induced insulin release. Biochem. J. 184, 303–311 (1979b)Google Scholar
  17. Kawazu, S., Boschero, A. C., Delcroix, C., Malaisse, W. J.: The stimulus-secretion coupling of glucose-induced insulin release. XXVIII. Effect of glucose on Na+ fluxes in isolated islets. Pflügers Arch 375, 197–206 (1978)Google Scholar
  18. Levy, J., Malaisse, W. J.: The stimulus-secretion coupling of glucose-induced insulin release. XVII. Effect of sulfonylureas and diazoxide on insular biosynthetic activity. Biochem. Pharmacol. 24, 235–239 (1975)Google Scholar
  19. Levy, J., Herchuelz, A., Sener, A., Malaisse-Lagae, F., Malaisse, W. J.: Cytochalasin B-induced impairment of glucose metabolism in islets of Langerhans. Endocrinology 98, 429–437 (1976)Google Scholar
  20. Malaisse, W. J.: Insulinotropic action of different sulfonylureas in vitro: A comparative study. In: New antidiabetic drugs. Proc. XIIth International Therapeutic Union Congress, pp. 67–69. Geneva, Medecine et Hygiène 1974Google Scholar
  21. Malaisse, W. J., Malaisse-Lagae, F.: Effects of glucodiazin and glibenclamide upon insulin secretion in vitro. Eur. J. Pharmacol. 9, 93–98 (1970)Google Scholar
  22. Malaisse, W. J., Brisson, G., Malaisse-Lagae, F.: The stimulus-secretion coupling of glucose-induced insulin release. I. Interaction of epinephrine and alkaline earth cations. J. Lab. Clin. Med. 76, 895–902 (1970)Google Scholar
  23. Malaisse, W. J., Mahy, M., Brisson, G. R., Malaisse-Lagae, F.: The stimulus-secretion coupling of glucose-induced insulin release, VIII. Combined effects of glucose and sulfonylureas. Eur. J. Clin. Invest. 2, 85–90 (1972)Google Scholar
  24. Malaisse, W. J., Pipeleers, D. G., Mahy, M.: The stimulus-secretion coupling of glucose-induced insulin release. XII. Effects of diazoxide and gliclazide upon 45calcium efflux from perifused islets. Diabetologia 9, 1–5 (1973)Google Scholar
  25. Malaisse, W. J., Sener, A., Mahy, M.: The stimulus-secretion coupling of glucose-induced insulin release. XVIII. Sorbitol metabolism in isolated islets. Eur. J. Biochem. 47, 365–370 (1974)Google Scholar
  26. Malaisse, W. J., Hutton, J. C., Kawazu, S., Sener, A.: The stimulus-secretion coupling of glucose-induced insulin release. XXXI. Metabolie effects of menadione in isolated islets. Eur. J. Biochem. 87, 121–130 (1978a)Google Scholar
  27. Malaisse, W. J., Boschero, A. C., Kawazu, S., Hutton, J. C.: The stimulus-secretion coupling of glucose-induced insulin release. XXVII. Effect of glucose on K+ fluxes in isolated islets. Pflügers Arch. 373, 237–242 (1978b)Google Scholar
  28. Malaisse, W. J., Hutton, J. C., Kawazu, S., Herchuelz, A., Valverde, I., Sener, A.: The stimulus-secretion coupling of glucose-induced insulin release. XXXV. The links between metabolic and cationic events. Diabetologia 16, 331–341 (1979a)Google Scholar
  29. Malaisse, W. J., Kawazu, S., Herchuelz, A., Hutton, J. C., Somers, G., Devis, G., Sener, A.: The stimulus-secretion coupling of glucose-induced insulin release. XXXIV. Effect of lactate upon islet function. Arch. Biochem. Biophys. 194, 49–62 (1979b)Google Scholar
  30. Malaisse, W. J., Hutton, J. C., Carpinelli, A. R., Herchuelz, A., Sener, A.: The stimulus-secretion coupling of amino acid-induced insulin release. I. Metabolism and cationic effects of leucine. Diabetes (in press, 1980)Google Scholar
  31. Matthews, E. K., Dean, P. M.: The biophysical effects of insulin-releasing agents on islet cells. Postgrad. Med. J. 46, (Suppl.), 21–23 (1970)Google Scholar
  32. Meissner, H. P., Atwater, I. J.: The kinetics of electrical activity of beta cells in response to a “square wave” stimulation by glucose or glibenclamide. Horm. Metab. Res. 8, 11–16 (1976)Google Scholar
  33. Morris, G. E., Korner, A.: The effect of glucose on insulin biosynthesis by isolated islets of Langerhans of the rat. Biochim. Biophys. Acta 208, 404–413 (1970)Google Scholar
  34. Obberghen, E. van, Somers, G., Devis, G., Vaughan, G. D., Malaisse-Lagae, F., Orci, L., Malaisse, W. J.: Dynamics of insulin release and microtubular-microfilamentous system. I. Effect of cytochalasin B. J. Clin. Invest. 52, 1041–1051 (1973)Google Scholar
  35. Orci, L., Ravazzola, M., Amherdt, M., Malaisse-Lagae, F.: The B-cell boundary. Excerpta Medica I.C.S. 312, 104–118 (1974)Google Scholar
  36. Panten, U., Christians, J., Kriegstein, E. V., Poser, W., Hasselblatt, A.: Effect of carbohydrate upon fluorescence of reduced pyridine nucleotides from perifused isolated pancreatic islets. Diabetologia 9, 447–482 (1973)Google Scholar
  37. Sams, D. J., Montague, W.: The role of adenosine 3′,5′-cyclic monophosphate in the regulation of insulin release. Properties of islet-cell adenosine 3′,5′-cyclic monophosphate phosphodiesterase. Biochem. J. 129, 945–952 (1972)Google Scholar
  38. Schatz, H., Maier, V., Hinz, M., Nierde, C., Pfeiffer, E. F.: The effect of tolbutamide and glibenclamide on the incorporation of (3H)-leucine and on the conversion of proinsulin to insulin in isolated pancreatic islets. FEBS Lett 26, 237–240 (1972)Google Scholar
  39. Sehlin, J.: Evidence for specific binding of tolbutamide to the plasma membrane of the plasma membrane of the pancreatic B-cells. Acta Diabetol. Lat. 10, 1052–1060 (1973)Google Scholar
  40. Sener, J., Malaisse, W. J.: The stimulus-secretion coupling of glucose-induced insulin release. Metabolic events in islets stimulated by non-metabolizable secretagogues. Eur. J. Biochem. 98, 141–147 (1979)Google Scholar
  41. Sener, A., Kawazu, S., Hutton, J. C., Boschero, A. C., Devis, G., Somers, G., Herchuelz, A., Malaisse, W. J.: The stimulus-secretion coupling of glucose-induced insulin release. XXXIII. Effect of exogenous pyruvate on islet function. Biochem. J. 176, 217–232 (1978a)Google Scholar
  42. Sener, A., Hutton, J. C., Kawazu, S., Boschero, A. C., Somers, G., Devis, G., Herchuelz, A., Malaisse, W. J.: The stimulus-secretion coupling of glucose-induced insulin release. XXXII. Metabolic and functional effects of NH4+ in rat islets. J. Clin. Invest. 62, 868–878 (1978b)Google Scholar
  43. Sener, A., Kawazu, S., Malaisse, W. J.: The stimulus-secretion coupling of glucose-induced insulin release. XXXVII. Metabolism of glucose in K+-deprived islets. Biochem. J. 186, 183–190 (1980)Google Scholar
  44. Stork, H., Schmidt, F. H., Westman, S., Hellerström, C.: Action of some hypoglycemic sulfonylureas on the oxygen consumption of isolated pancreatic islets of mice. Diabetologia 5, 279–283 (1969)Google Scholar
  45. Valverde, I., Vandermeers, A., Anjaneyulu, R., Malaisse, W. J.: Calmodulin activation of adenylate cyclase in pancreatic islets. Science 206, 225–227 (1979)Google Scholar

Copyright information

© Springer-Verlag 1980

Authors and Affiliations

  • Shoji Kawazu
    • 1
  • Abdullan Sener
    • 1
  • Etienne Couturier
    • 1
  • Willy J. Malaisse
    • 1
  1. 1.Laboratory of Experimental MedicineBrussels UniversityBrusselsBelgium

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