, Volume 29, Issue 9, pp 648–654 | Cite as

Regulation of energy metabolism in pancreatic islets by glucose and tolbutamide

  • U. Panten
  • B. J. Zünkler
  • S. Scheit
  • K. Kirchhoff
  • S. Lenzen


The kinetics of insulin secretion and oxygen uptake in response to D-glucose and tolbutamide were compared in mouse pancreatic islets. In addition, the role of decreased ATP as a driving force for secretagogue-induced oxygen consumption was examined. D-glucose (10–30 mmol/1) triggered a biphasic insulin release which always coincided with a monophasic increase in islet oxygen uptake. In the presence of D-glucose (5–30 mmol/1), tolbutamide (3–500 g,mol/1) consistently elicited an initial peak of insulin secretion which was followed by a continued decline. Tolbutamide-induced secretory profiles were accompanied by similar respiratory profiles. Oxygen consumption per ng of insulin released during the test phase was higher after elevation of the glucose concentration than after addition of tolbutamide. In conjunction with 5 or 10 mmol/l D-glucose, but not with 15 or 30 mmol/1 D-glucose, tolbutamide (30–100 μmol/1) lowered islet ATP content significantly (p < 0.02). Phosphocreatine was not found in isolated islets, although they contained substantial creatine kinase activity. It is concluded that the driving force for Tobutamide-induced oxygen uptake is a decrease in the phosphorylation potential caused by the work load imposed by stimulation of the secretion process. However, a major proportion of the respiratory response to glucose also results from enhancement of biosynthesis.

Key words

Islets of Langerhans insulin secretion O2 uptake ATP creatine kinase D-glucose tolbutamide 


  1. 1.
    Ashcroft SJH (1980) Glucoreceptor mechanisms and the control of insulin release and biosynthesis. Diabetologia 18: 5–15PubMedGoogle Scholar
  2. 2.
    Panten U, Zielmann S, Langer J, Zünkler B-J, Lenzen S (1984) Regulation of insulin secretion by energy metabolism in pancreatic B-cell mitochondria. Studies with a non-metabolizable leucine analogue. Biochem J 219: 189–196PubMedGoogle Scholar
  3. 3.
    Panten U, Zielmann S, Joost H-G, Lenzen S (1984) Branched chain amino and keto acids - tools for the investigation of fuel recognition mechanism in pancreatic B-cells. In: Adibi SA, Fekl W, Langenbeck U, Schauder P (eds) Branched chain amino and keto acids in health and disease. Karger, Basle, pp 134–146Google Scholar
  4. 4.
    Lenzen S, Schmidt W, Panten U (1985) Transamination of neutral amino acids and 2-keto acids in pancreatic B-cell mitochondria. J Biol Chem 260: 12629–12634PubMedGoogle Scholar
  5. 5.
    Cook DL, Hales CN (1984) Intracellular ATP directly blocks K+ channels in pancreatic B-cells. Nature 311: 271–273PubMedGoogle Scholar
  6. 6.
    Ashcroft FM, Harrison DE, Ashcroft SJH (1984) Glucose induces closure of single potassium channels in isolated rat pancreaticβ-cells. Nature 312: 446–448PubMedGoogle Scholar
  7. 7.
    Rorsman P, Trube G (1985) Glucose dependent K+-channels in pancreaticβ-cells are regulated by intracellular ATP. Pflügers Arch 405: 305–309Google Scholar
  8. 8.
    Ashcroft SJH, Weerasinghe LCC, Randle PJ (1973) Interrelationship of islet metabolism, adenosine triphosphate content and insulin release. Biochem J 132: 223–231PubMedGoogle Scholar
  9. 9.
    Malaisse WJ, Hutton JC, Kawazu S, Sener A (1978) The stimulussecretion coupling of glucose-induced insulin release. Metabolic effects of menadione in isolated islets. Eur J Biochem 87: 121–130PubMedGoogle Scholar
  10. 10.
    Hellman B, Täljedal I-B (1975) Effects of sulfonylurea derivatives on pancreaticβ-cells. In: Hasselblatt A, von Bruchhausen F (eds) Handbook of experimental pharmacology, Vol 32, part 2. Springer, Berlin Heidelberg New York, pp 175–194Google Scholar
  11. 11.
    Sturgess NC, Ashford MLJ, Cook DL, Hales CN (1985) The sulphonylurea receptor may be an ATP-sensitive potassium channel. Lancet 2: 474–475PubMedGoogle Scholar
  12. 12.
    Kawazu S, Sener A, Couturier E, Malaisse WJ (1980) Metabolic, cationic and secretory effects of hypoglycemic sulfonylureas in pancreatic islets. Naunyn-Schmiedeberg's Arch Pharmacol 312: 277–283Google Scholar
  13. 13.
    Panten U, Christians J, von Kriegstein E, Poser W, Hasselblatt A (1973) Effects of carbohydrates upon fluorescence of reduced pyridine nucleotides from perifused isolated pancreatic islets. Diabetologia 9: 477–482PubMedGoogle Scholar
  14. 14.
    Ammon HPT (1975) 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: 251–264Google Scholar
  15. 15.
    Curry DL, Bennett LL, Grodsky GM (1968) Dynamics of insulin secretion by the perfused rat pancreas. Endocrinology (Baltimore) 83: 572–584Google Scholar
  16. 16.
    Henquin J-C (1980) Tolbutamide stimulation and inhibition of insulin release: studies of the underlying ionic mechanisms in isolated rat islets. Diabetologia 18: 151–160PubMedGoogle Scholar
  17. 17.
    Stork H, Schmidt FH, Westman S, Hellerström C (1969) Action of some hypoglycaemic sulphonylureas on the oxygen consumption of isolated pancreatic islets of mice. Diabetologia 5: 279–283PubMedGoogle Scholar
  18. 18.
    Welsh M (1983) The effects of glibenclamide on rat islet radioactive nucleotide efflux, ATP contents and respiratory rates. Biochem Pharmacol 32: 2903–2908PubMedGoogle Scholar
  19. 19.
    Hellman B, Idahl L-Å, Danielsson Å (1969) Adenosine triphosphate levels of mammalian pancreatic B cells after stimulation with glucose and hypoglycemic sulfonylureas. Diabetes 18: 509–516PubMedGoogle Scholar
  20. 20.
    Krzanowski JJ, Fertel R, Matschinsky FM (1971) Energy metabolism in pancreatic islets of rats. Studies with tolbutamide and hypoxia. Diabetes 20: 598–606PubMedGoogle Scholar
  21. 21.
    Gylfe E, Hellman B, Sehlin J, Täljedal I-B (1984) Interaction of sulfonylurea with the pancreatic B-cell. Experientia 40: 1126–1134PubMedGoogle Scholar
  22. 22.
    Panten U, Biermann J, Graen W (1981) Recognition of insulin-releasing fuels by pancreatic B-cells. α-Ketoisocaproic acid is an appropriate model compound to study the role of B-cell metabolism. Mol Pharmacol 20: 76–82PubMedGoogle Scholar
  23. 23.
    Lernmark Å (1974) The preparation of, and studies on, free cell suspensions from mouse pancreatic islets. Diabetologia 10: 431–438PubMedGoogle Scholar
  24. 24.
    Panten U, Ishida H, Schauder P, Frerichs H, Hasselblatt A (1977) A versatile microperifusion system. Anal Biochem 82: 317–326PubMedGoogle Scholar
  25. 25.
    Joost H-G (1979) Effects of a possible beta-cell membrane label, metahexamide-isothiocyanate, on insulin release. Horm Metab Res 11: 104–106PubMedGoogle Scholar
  26. 26.
    Panten U, Klein H (1982) O2 consumption by isolated pancreatic islets, as measured in a microincubation system with a Clark-type electrode. Endocrinology (Baltimore) 111: 1595–1600Google Scholar
  27. 27.
    Lust WD, Feussner GK, Barbehenn EK, Passonneau JA (1981) The enzymatic measurement of adenine nucleotides and P-creatine in picomole amounts. Anal Biochem 110: 258–266PubMedGoogle Scholar
  28. 28.
    Peterson GL (1977) A simplification of the protein assay method of Lowry et al. which is more generally applicable. Anal Biochem 83: 346–356PubMedGoogle Scholar
  29. 29.
    Hellerström C (1966) Oxygen consumption of isolated pancreatic islets of mice studied with the cartesian-diver micro-gasometer. Biochem J 98: 7c-9cPubMedGoogle Scholar
  30. 30.
    Hutton JC, Malaisse WJ (1980) Dynamics of O2 consumption in rat pancreatic islets. Diabetologia 18: 395–405PubMedGoogle Scholar
  31. 31.
    Herchuelz A, Couturier E, Malaisse WJ (1980) Regulation of calcium fluxes in pancreatic islets: glucose-induced calcium-calcium exchange. Am J Physiol 238: E96-E103PubMedGoogle Scholar
  32. 32.
    Permutt MA (1981) Biosynthesis of insulin. In: Cooperstein SJ, Watkins D (eds) The islets of Langerhans. Biochemistry, physiology and pathology. Academic Press, New York London Toronto, pp 75–95Google Scholar
  33. 33.
    Perez-Armendariz E, Atwater I, Rojas E (1985) Glucose induced oscillatory changes in extracellular ionized potassium concentration in mouse islets of Langerhans. Biophys J 48: 741–749PubMedGoogle Scholar
  34. 34.
    Hansford RG (1980) Control of mitochondrial substrate oxidation. Curr Top Bioenerg 10: 217–278Google Scholar
  35. 35.
    Aw TY, Jones DP (1985) ATP concentration gradients in cytosol of liver cells during hypoxia. Am J Physiol 249: C 385-C 392Google Scholar
  36. 36.
    Jackson JE, Bressler R (1981) Clinical pharmacology of suifonylurea hypoglycaemic agents: part 1. Drugs 22: 211–245PubMedGoogle Scholar
  37. 37.
    Zini R, d'Athis P, Hoareau A, Tillement JP (1976) Binding of four sulphonamides to human albumin. Europ J Clin Pharmacol 10: 139–145Google Scholar
  38. 38.
    Matschinsky FM (1972) Enzymes, metabolites, and cofactors involved in intermediary metabolism of islets of Langerhans. In: Steiner DF, Freinkel N (eds) Handbook of physiology, Section 7, Vol 1. American Physiological Society, Washington DC, pp 199–214Google Scholar
  39. 39.
    Henquin JC, Meissner HP (1984) Significance of ionic fluxes and changes in membrane potential for stimulus-secretion coupling in pancreatic B-cells. Experientia 40: 1043–1052PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1986

Authors and Affiliations

  • U. Panten
    • 1
  • B. J. Zünkler
    • 1
  • S. Scheit
    • 1
  • K. Kirchhoff
    • 1
  • S. Lenzen
    • 1
  1. 1.Institute of Pharmacology and ToxicologyUniversity of GöttingenGöttingenFRG

Personalised recommendations