Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1997 Nov 15;100(10):2547–2551. doi: 10.1172/JCI119797

Pulsatile insulin release from pancreatic islets with nonoscillatory elevation of cytoplasmic Ca2+.

J Westerlund 1, E Gylfe 1, P Bergsten 1
PMCID: PMC508455  PMID: 9366569

Abstract

The relationship between insulin release and cytoplasmic Ca2+ concentration ([Ca2+]i) was studied in isolated pancreatic islets from ob/ob mice. Although [Ca2+]i was low and stable in the presence of 3 mM glucose, basal insulin release exhibited low amplitude pulsatility, with a frequency of 0.32 +/- 0.04 min-1. Depolarization by raising K+ from 5.9 to 30.9 mM or by the addition of 1 mM tolbutamide caused a pronounced initial insulin pulse followed by declining pulses, but there was no change in frequency. This decline in amplitude of the insulin pulses was prevented in similar experiments performed in the presence of 11 mM glucose. Corresponding measurements of [Ca2+]i in islets exposed to tolbutamide or the high K+ concentration revealed stable elevations without oscillations. Although the [Ca2+]i level is an important determinant for the rate of secretion, the results indicate that pulsatile insulin release does not always depend on [Ca2+]i oscillations. It is suggested that cyclic generation of ATP may fuel pulsatile release under conditions when [Ca2+]i remains stable.

Full Text

The Full Text of this article is available as a PDF (165.0 KB).

Selected References

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

  1. Ashcroft F. M., Rorsman P. Electrophysiology of the pancreatic beta-cell. Prog Biophys Mol Biol. 1989;54(2):87–143. doi: 10.1016/0079-6107(89)90013-8. [DOI] [PubMed] [Google Scholar]
  2. Bergsten P., Grapengiesser E., Gylfe E., Tengholm A., Hellman B. Synchronous oscillations of cytoplasmic Ca2+ and insulin release in glucose-stimulated pancreatic islets. J Biol Chem. 1994 Mar 25;269(12):8749–8753. [PubMed] [Google Scholar]
  3. Bergsten P., Hellman B. Glucose-induced amplitude regulation of pulsatile insulin secretion from individual pancreatic islets. Diabetes. 1993 May;42(5):670–674. doi: 10.2337/diab.42.5.670. [DOI] [PubMed] [Google Scholar]
  4. Bergsten P. Slow and fast oscillations of cytoplasmic Ca2+ in pancreatic islets correspond to pulsatile insulin release. Am J Physiol. 1995 Feb;268(2 Pt 1):E282–E287. doi: 10.1152/ajpendo.1995.268.2.E282. [DOI] [PubMed] [Google Scholar]
  5. Chow R. H., Lund P. E., Löser S., Panten U., Gylfe E. Coincidence of early glucose-induced depolarization with lowering of cytoplasmic Ca2+ in mouse pancreatic beta-cells. J Physiol. 1995 Jun 15;485(Pt 3):607–617. doi: 10.1113/jphysiol.1995.sp020756. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Devis G., Somers G., Van Obberghen E., Malaisse W. J. Calcium antagonists and islet function. I. Inhibition of insulin release by verapamil. Diabetes. 1975 Jun;24(6):247–251. doi: 10.2337/diabetes.24.6.247. [DOI] [PubMed] [Google Scholar]
  7. Dryselius S., Lund P. E., Gylfe E., Hellman B. Variations in ATP-sensitive K+ channel activity provide evidence for inherent metabolic oscillations in pancreatic beta-cells. Biochem Biophys Res Commun. 1994 Nov 30;205(1):880–885. doi: 10.1006/bbrc.1994.2746. [DOI] [PubMed] [Google Scholar]
  8. Gembal M., Detimary P., Gilon P., Gao Z. Y., Henquin J. C. Mechanisms by which glucose can control insulin release independently from its action on adenosine triphosphate-sensitive K+ channels in mouse B cells. J Clin Invest. 1993 Mar;91(3):871–880. doi: 10.1172/JCI116308. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Goodner C. J., Sweet I. R., Harrison H. C., Jr Rapid reduction and return of surface insulin receptors after exposure to brief pulses of insulin in perifused rat hepatocytes. Diabetes. 1988 Oct;37(10):1316–1323. doi: 10.2337/diab.37.10.1316. [DOI] [PubMed] [Google Scholar]
  10. Goodner C. J., Walike B. C., Koerker D. J., Ensinck J. W., Brown A. C., Chideckel E. W., Palmer J., Kalnasy L. Insulin, glucagon, and glucose exhibit synchronous, sustained oscillations in fasting monkeys. Science. 1977 Jan 14;195(4274):177–179. doi: 10.1126/science.401543. [DOI] [PubMed] [Google Scholar]
  11. Grapengiesser E., Gylfe E., Hellman B. Glucose-induced oscillations of cytoplasmic Ca2+ in the pancreatic beta-cell. Biochem Biophys Res Commun. 1988 Mar 30;151(3):1299–1304. doi: 10.1016/s0006-291x(88)80503-5. [DOI] [PubMed] [Google Scholar]
  12. Grill V., Cerasi E. Activation by glucose of adenyl cyclase in pancreatic islets of the rat. FEBS Lett. 1973 Jul 15;33(3):311–314. doi: 10.1016/0014-5793(73)80218-2. [DOI] [PubMed] [Google Scholar]
  13. Grodsky G. M., Bennett L. L. Cation requirements for insulin secretion in the isolated perfused pancreas. Diabetes. 1966 Dec;15(12):910–913. doi: 10.2337/diab.15.12.910. [DOI] [PubMed] [Google Scholar]
  14. Grynkiewicz G., Poenie M., Tsien R. Y. A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem. 1985 Mar 25;260(6):3440–3450. [PubMed] [Google Scholar]
  15. Gylfe E., Grapengiesser E., Hellman B. Propagation of cytoplasmic Ca2+ oscillations in clusters of pancreatic beta-cells exposed to glucose. Cell Calcium. 1991 Feb-Mar;12(2-3):229–240. doi: 10.1016/0143-4160(91)90023-8. [DOI] [PubMed] [Google Scholar]
  16. Gylfe E. Nutrient secretagogues induce bimodal early changes in cytoplasmic calcium of insulin-releasing ob/ob mouse beta-cells. J Biol Chem. 1988 Sep 25;263(27):13750–13754. [PubMed] [Google Scholar]
  17. Hellman B., Idahl L. A., Lernmark A., Täljedal I. B. The pancreatic beta-cell recognition of insulin secretagogues: does cyclic AMP mediate the effect of glucose? Proc Natl Acad Sci U S A. 1974 Sep;71(9):3405–3409. doi: 10.1073/pnas.71.9.3405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hellman B. Studies in obese-hyperglycemic mice. Ann N Y Acad Sci. 1965 Oct 8;131(1):541–558. doi: 10.1111/j.1749-6632.1965.tb34819.x. [DOI] [PubMed] [Google Scholar]
  19. Jaspan J. B., Lever E., Polonsky K. S., Van Cauter E. In vivo pulsatility of pancreatic islet peptides. Am J Physiol. 1986 Aug;251(2 Pt 1):E215–E226. doi: 10.1152/ajpendo.1986.251.2.E215. [DOI] [PubMed] [Google Scholar]
  20. Lang D. A., Matthews D. R., Burnett M., Turner R. C. Brief, irregular oscillations of basal plasma insulin and glucose concentrations in diabetic man. Diabetes. 1981 May;30(5):435–439. doi: 10.2337/diab.30.5.435. [DOI] [PubMed] [Google Scholar]
  21. Lang D. A., Matthews D. R., Burnett M., Ward G. M., Turner R. C. Pulsatile, synchronous basal insulin and glucagon secretion in man. Diabetes. 1982 Jan;31(1):22–26. doi: 10.2337/diab.31.1.22. [DOI] [PubMed] [Google Scholar]
  22. Lang D. A., Matthews D. R., Peto J., Turner R. C. Cyclic oscillations of basal plasma glucose and insulin concentrations in human beings. N Engl J Med. 1979 Nov 8;301(19):1023–1027. doi: 10.1056/NEJM197911083011903. [DOI] [PubMed] [Google Scholar]
  23. Lefèbvre P. J., Paolisso G., Scheen A. J., Henquin J. C. Pulsatility of insulin and glucagon release: physiological significance and pharmacological implications. Diabetologia. 1987 Jul;30(7):443–452. doi: 10.1007/BF00279610. [DOI] [PubMed] [Google Scholar]
  24. Matthews D. R., Naylor B. A., Jones R. G., Ward G. M., Turner R. C. Pulsatile insulin has greater hypoglycemic effect than continuous delivery. Diabetes. 1983 Jul;32(7):617–621. doi: 10.2337/diab.32.7.617. [DOI] [PubMed] [Google Scholar]
  25. Milner R. D., Hales C. N. The role of calcium and magnesium in insulin secretion from rabbit pancreas studied in vitro. Diabetologia. 1967 Mar;3(1):47–49. doi: 10.1007/BF01269910. [DOI] [PubMed] [Google Scholar]
  26. O'Rahilly S., Turner R. C., Matthews D. R. Impaired pulsatile secretion of insulin in relatives of patients with non-insulin-dependent diabetes. N Engl J Med. 1988 May 12;318(19):1225–1230. doi: 10.1056/NEJM198805123181902. [DOI] [PubMed] [Google Scholar]
  27. Paolisso G., Sgambato S., Torella R., Varricchio M., Scheen A., D'Onofrio F., Lefèbvre P. J. Pulsatile insulin delivery is more efficient than continuous infusion in modulating islet cell function in normal subjects and patients with type 1 diabetes. J Clin Endocrinol Metab. 1988 Jun;66(6):1220–1226. doi: 10.1210/jcem-66-6-1220. [DOI] [PubMed] [Google Scholar]
  28. Peiris A. N., Stagner J. I., Vogel R. L., Nakagawa A., Samols E. Body fat distribution and peripheral insulin sensitivity in healthy men: role of insulin pulsatility. J Clin Endocrinol Metab. 1992 Jul;75(1):290–294. doi: 10.1210/jcem.75.1.1619021. [DOI] [PubMed] [Google Scholar]
  29. Pralong W. F., Spät A., Wollheim C. B. Dynamic pacing of cell metabolism by intracellular Ca2+ transients. J Biol Chem. 1994 Nov 4;269(44):27310–27314. [PubMed] [Google Scholar]
  30. Pørksen N., Munn S., Steers J., Vore S., Veldhuis J., Butler P. Pulsatile insulin secretion accounts for 70% of total insulin secretion during fasting. Am J Physiol. 1995 Sep;269(3 Pt 1):E478–E488. doi: 10.1152/ajpendo.1995.269.3.E478. [DOI] [PubMed] [Google Scholar]
  31. Renström E., Eliasson L., Bokvist K., Rorsman P. Cooling inhibits exocytosis in single mouse pancreatic B-cells by suppression of granule mobilization. J Physiol. 1996 Jul 1;494(Pt 1):41–52. doi: 10.1113/jphysiol.1996.sp021474. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Stagner J. I., Samols E., Weir G. C. Sustained oscillations of insulin, glucagon, and somatostatin from the isolated canine pancreas during exposure to a constant glucose concentration. J Clin Invest. 1980 Apr;65(4):939–942. doi: 10.1172/JCI109750. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Trube G., Rorsman P., Ohno-Shosaku T. Opposite effects of tolbutamide and diazoxide on the ATP-dependent K+ channel in mouse pancreatic beta-cells. Pflugers Arch. 1986 Nov;407(5):493–499. doi: 10.1007/BF00657506. [DOI] [PubMed] [Google Scholar]
  34. Westerlund J., Hellman B., Bergsten P. Pulsatile insulin release from mouse islets occurs in the absence of stimulated entry of Ca2+. J Clin Invest. 1996 Apr 15;97(8):1860–1863. doi: 10.1172/JCI118616. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Yaseen M. A., Pedley K. C., Howell S. L. Regulation of insulin secretion from islets of Langerhans rendered permeable by electric discharge. Biochem J. 1982 Jul 15;206(1):81–87. doi: 10.1042/bj2060081. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES