Skip to main content
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1986 Jul;83(14):5267–5271. doi: 10.1073/pnas.83.14.5267

Pancreatic B cells possess defense mechanisms against cell-specific toxicity.

D Pipeleers, M Van de Winkel
PMCID: PMC323932  PMID: 2941762

Abstract

Insulin-dependent diabetes develops when more than 90% of the insulin containing B cells are destroyed. The present study investigates whether the target B cells can counteract the damaging effects of cytotoxic substances. Purified islet cells were first exposed for 3-10 min to t-butylhydroperoxide, alloxan, streptozotocin, or B-cell surface antibodies plus complement, then cultured for 20 hr before the percent of dead cells was counted. t-Butylhydroperoxide destroyed all islet cell types whereas the three other agents exerted a dose-dependent toxicity upon islet B cells only. The survival of drug- and complement-treated cells varied with the culture conditions present between the initial cellular attack and the moment of cell death. For the four B-cell toxic agents tested, an increase in medium glucose following any of these treatments reduced the percent of dead cells. This protective effect was not observed with galactose or fructose, nor could it be induced in islet non-B cells; it was additive to the protective action glucose induced during preincubation of the cells prior to their exposure to certain cytotoxic agents such as alloxan. Nicotinamide also enhanced the survival of drug-treated B cells, irrespective of the damaging compound. The vitamin was most effective when applied immediately after the initial drug or complement treatment; it also protected islet non-B cells--in contrast to glucose. The present in vitro study has led to the recognition of defense mechanisms in pancreatic B cells. Physiologic compounds such as glucose and nicotinamide were found to stimulate islet B cells to counteract the damaging effects of B-cell toxic conditions. It is conceivable that the events involved in this protection are implicated in the pathogenesis and/or prevention of insulin-dependent diabetes.

Full text

PDF
5271

Selected References

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

  1. Asayama K., English D., Slonim A. E., Burr I. M. Chemiluminescence as an index of drug-induced free radical production in pancreatic islets. Diabetes. 1984 Feb;33(2):160–163. doi: 10.2337/diab.33.2.160. [DOI] [PubMed] [Google Scholar]
  2. BHATTACHARYA G. Protection against alloxan diabetes by mannose and fructose. Science. 1953 Feb 27;117(3035):230–231. doi: 10.1126/science.117.3035.230. [DOI] [PubMed] [Google Scholar]
  3. Bennett R. A., Pegg A. E. Alkylation of DNA in rat tissues following administration of streptozotocin. Cancer Res. 1981 Jul;41(7):2786–2790. [PubMed] [Google Scholar]
  4. Bhakdi S., Tranum-Jensen J. Membrane damage by complement. Biochim Biophys Acta. 1983 Aug 11;737(3-4):343–372. doi: 10.1016/0304-4157(83)90006-0. [DOI] [PubMed] [Google Scholar]
  5. Borg L. A., Eide S. J., Andersson A., Hellerström C. Effects in vitro of alloxan on the glucose metabolism of mouse pancreatic B-cells. Biochem J. 1979 Sep 15;182(3):797–802. doi: 10.1042/bj1820797. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bottazzo G. F., Mann J. I., Thorogood M., Baum J. D., Doniach D. Autoimmunity in juvenile diabetics and their families. Br Med J. 1978 Jul 15;2(6131):165–168. doi: 10.1136/bmj.2.6131.165. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Colca J. R., Kotagal N., Brooks C. L., Lacy P. E., Landt M., McDaniel M. L. Alloxan inhibition of a Ca2+- and calmodulin-dependent protein kinase activity in pancreatic islets. J Biol Chem. 1983 Jun 25;258(12):7260–7263. [PubMed] [Google Scholar]
  8. Dobersen M. J., Scharff J. E., Ginsberg-Fellner F., Notkins A. L. Cytotoxic autoantibodies to beta cells in the serum of patients with insulin-dependent diabetes mellitus. N Engl J Med. 1980 Dec 25;303(26):1493–1498. doi: 10.1056/NEJM198012253032601. [DOI] [PubMed] [Google Scholar]
  9. Dulin W. E., Wyse B. M. Reversal of streptozotocin diabetes with nicotinamide. Proc Soc Exp Biol Med. 1969 Mar;130(3):992–994. doi: 10.3181/00379727-130-33707. [DOI] [PubMed] [Google Scholar]
  10. Dulin W. E., Wyse B. M. Studies on the ability of compounds to block the diabetogenic activity of streptozotocin. Diabetes. 1969 Jul;18(7):459–466. doi: 10.2337/diab.18.7.459. [DOI] [PubMed] [Google Scholar]
  11. Fariss M. W., Olafsdottir K., Reed D. J. Extracellular calcium protects isolated rat hepatocytes from injury. Biochem Biophys Res Commun. 1984 May 31;121(1):102–110. doi: 10.1016/0006-291x(84)90693-4. [DOI] [PubMed] [Google Scholar]
  12. Gandy S. E., Buse M. G., Crouch R. K. Protective role of superoxide dismutase against diabetogenic drugs. J Clin Invest. 1982 Sep;70(3):650–658. doi: 10.1172/JCI110659. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Geertinger P. Cot death and the third branchial arch. Lancet. 1976 Oct 2;2(7988):716–718. doi: 10.1016/s0140-6736(76)90010-6. [DOI] [PubMed] [Google Scholar]
  14. Gepts W. Pathologic anatomy of the pancreas in juvenile diabetes mellitus. Diabetes. 1965 Oct;14(10):619–633. doi: 10.2337/diab.14.10.619. [DOI] [PubMed] [Google Scholar]
  15. Gorsuch A. N., Spencer K. M., Lister J., McNally J. M., Dean B. M., Bottazzo G. F., Cudworth A. G. Evidence for a long prediabetic period in type I (insulin-dependent) diabetes mellitus. Lancet. 1981 Dec 19;2(8260-61):1363–1365. doi: 10.1016/s0140-6736(81)92795-1. [DOI] [PubMed] [Google Scholar]
  16. Gorus F. K., Malaisse W. J., Pipeleers D. G. Selective uptake of alloxan by pancreatic B-cells. Biochem J. 1982 Nov 15;208(2):513–515. doi: 10.1042/bj2080513. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Grankvist K., Lernmark A., Täljedal I. B. Trypan Blue as a marker of plasma membrane permeability in alloxan-treated mouse islet cells. J Endocrinol Invest. 1979 Apr-Jun;2(2):139–145. doi: 10.1007/BF03349305. [DOI] [PubMed] [Google Scholar]
  18. Grankvist K., Marklund S., Sehlin J., Täljedal I. B. Superoxide dismutase, catalase and scavengers of hydroxyl radical protect against the toxic action of alloxan on pancreatic islet cells in vitro. Biochem J. 1979 Jul 15;182(1):17–25. doi: 10.1042/bj1820017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Grankvist K., Marklund S., Täljedal I. B. Superoxide dismutase is a prophylactic against alloxan diabetes. Nature. 1981 Nov 12;294(5837):158–160. doi: 10.1038/294158a0. [DOI] [PubMed] [Google Scholar]
  20. Gunnarsson R., Berne C., Hellerström C. Cytotoxic effects of streptozotocin and N-nitrosomethylurea on the pancreatic B cells with special regard to the role of nicotinamide-adenine dinucleotide. Biochem J. 1974 Jun;140(3):487–494. doi: 10.1042/bj1400487. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Gunnarsson R. Inhibition of insulin biosynthesis by alloxan, streptozotocin, and N-nitrosomethylurea. Mol Pharmacol. 1975 Nov;11(6):759–765. [PubMed] [Google Scholar]
  22. Heikkila R. E., Winston B., Cohen G. Alloxan-induced diabetes-evidence for hydroxyl radical as a cytotoxic intermediate. Biochem Pharmacol. 1976 May 1;25(9):1085–1092. doi: 10.1016/0006-2952(76)90502-5. [DOI] [PubMed] [Google Scholar]
  23. Helgason T., Jonasson M. R. Evidence for a food additive as a cause of ketosis-prone diabetes. Lancet. 1981 Oct 3;2(8249):716–720. doi: 10.1016/s0140-6736(81)91048-5. [DOI] [PubMed] [Google Scholar]
  24. Huang S. W., Maclaren N. K. Insulin-dependent diabetes: a disease of autoaggression. Science. 1976 Apr 2;192(4234):64–66. doi: 10.1126/science.769160. [DOI] [PubMed] [Google Scholar]
  25. Irvine W. J., McCallum C. J., Gray R. S., Campbell C. J., Duncan L. J., Farquhar J. W., Vaughan H., Morris P. J. Pancreatic islet-cell antibodies in diabetes mellitus correlated with the duration and type of diabetes, coexistent autoimmune disease, and HLA type. Diabetes. 1977 Feb;26(2):138–147. doi: 10.2337/diab.26.2.138. [DOI] [PubMed] [Google Scholar]
  26. Kanatsuna T., Baekkeskov S., Lernmark A., Ludvigsson J. Immunoglobulin from insulin-dependent diabetic children inhibits glucose-induced insulin release. Diabetes. 1983 Jun;32(6):520–524. doi: 10.2337/diab.32.6.520. [DOI] [PubMed] [Google Scholar]
  27. Karam J. H., Lewitt P. A., Young C. W., Nowlain R. E., Frankel B. J., Fujiya H., Freedman Z. R., Grodsky G. M. Insulinopenic diabetes after rodenticide (Vacor) ingestion: a unique model of acquired diabetes in man. Diabetes. 1980 Dec;29(12):971–978. doi: 10.2337/diab.29.12.971. [DOI] [PubMed] [Google Scholar]
  28. Kiesel U., Kolb H. Suppressive effect of antibodies to immune response gene products on the development of low-dose streptozotocin-induced diabetes. Diabetes. 1983 Sep;32(9):869–871. doi: 10.2337/diab.32.9.869. [DOI] [PubMed] [Google Scholar]
  29. Lacy P. E., Kostianovsky M. Method for the isolation of intact islets of Langerhans from the rat pancreas. Diabetes. 1967 Jan;16(1):35–39. doi: 10.2337/diab.16.1.35. [DOI] [PubMed] [Google Scholar]
  30. Lendrum R., Walker G., Gamble D. R. Islet-cell antibodies in juvenile diabetes mellitus of recent onset. Lancet. 1975 Apr 19;1(7912):880–882. doi: 10.1016/s0140-6736(75)91683-9. [DOI] [PubMed] [Google Scholar]
  31. Lernmark A., Freedman Z. R., Hofmann C., Rubenstein A. H., Steiner D. F., Jackson R. L., Winter R. J., Traisman H. S. Islet-cell-surface antibodies in juvenile diabetes mellitus. N Engl J Med. 1978 Aug 24;299(8):375–380. doi: 10.1056/NEJM197808242990802. [DOI] [PubMed] [Google Scholar]
  32. Lernmark A., Hägglöf B., Freedman Z., Irvine J., Ludvigsson J., Holmgren G. A prospective analysis of antibodies reacting with pancreatic islet cells in insulin-dependent diabetic children. Diabetologia. 1981 Apr;20(4):471–474. doi: 10.1007/BF00253410. [DOI] [PubMed] [Google Scholar]
  33. Maclaren N. K., Huang S. W., Fogh J. Antibody to cultured human insulinoma cells in insulin-dependent diabetes. Lancet. 1975 May 3;1(7914):997–1000. doi: 10.1016/s0140-6736(75)91945-5. [DOI] [PubMed] [Google Scholar]
  34. Maes E., Pipeleers D. Effects of glucose and 3',5'-cyclic adenosine monophosphate upon reaggregation of single pancreatic B-cells. Endocrinology. 1984 Jun;114(6):2205–2209. doi: 10.1210/endo-114-6-2205. [DOI] [PubMed] [Google Scholar]
  35. Malaisse W. J. Alloxan toxicity to the pancreatic B-cell. A new hypothesis. Biochem Pharmacol. 1982 Nov 15;31(22):3527–3534. doi: 10.1016/0006-2952(82)90571-8. [DOI] [PubMed] [Google Scholar]
  36. Malaisse W. J., Malaisse-Lagae F., Sener A., Pipeleers D. G. Determinants of the selective toxicity of alloxan to the pancreatic B cell. Proc Natl Acad Sci U S A. 1982 Feb;79(3):927–930. doi: 10.1073/pnas.79.3.927. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Pipeleers D. G., Pipeleers-Marichal M. A. A method for the purification of single A, B and D cells and for the isolation of coupled cells from isolated rat islets. Diabetologia. 1981 Jun;20(6):654–663. doi: 10.1007/BF00257436. [DOI] [PubMed] [Google Scholar]
  38. Pipeleers D. G., Schuit F. C., in't Veld P. A., Maes E., Hooghe-Peters E. L., Van de Winkel M., Gepts W. Interplay of nutrients and hormones in the regulation of insulin release. Endocrinology. 1985 Sep;117(3):824–833. doi: 10.1210/endo-117-3-824. [DOI] [PubMed] [Google Scholar]
  39. Pipeleers D. G., in't Veld P. A., Van de Winkel M., Maes E., Schuit F. C., Gepts W. A new in vitro model for the study of pancreatic A and B cells. Endocrinology. 1985 Sep;117(3):806–816. doi: 10.1210/endo-117-3-806. [DOI] [PubMed] [Google Scholar]
  40. Rossini A. A., Like A. A., Dulin W. E., Cahill G. F., Jr Pancreatic beta cell toxicity by streptozotocin anomers. Diabetes. 1977 Dec;26(12):1120–1124. doi: 10.2337/diab.26.12.1120. [DOI] [PubMed] [Google Scholar]
  41. Sandler S., Andersson A. The partial protective effect of the hydroxyl radical scavenger dimethyl urea on streptozotocin-induced diabetes in the mouse in vivo and in vitro. Diabetologia. 1982 Oct;23(4):374–378. doi: 10.1007/BF00253747. [DOI] [PubMed] [Google Scholar]
  42. Schein P. S., Cooney D. A., McMenamin M. G., Anderson T. Streptozotocin diabetes--further studies on the mechanism of depression of nicotinamide adenine dinucleotide concentrations in mouse pancreatic islets and liver. Biochem Pharmacol. 1973 Oct 15;22(20):2625–2631. doi: 10.1016/0006-2952(73)90071-3. [DOI] [PubMed] [Google Scholar]
  43. Scheynius A., Täljedal I. B. On the mechanism of glucose protection against alloxan toxicity. Diabetologia. 1971 Aug;7(4):252–255. doi: 10.1007/BF01211877. [DOI] [PubMed] [Google Scholar]
  44. Schlager S. I., Ohanian S. H., Borsos T. Correlation between the ability of tumor cells to resist humoral immune attack and their ability to synthesize lipid. J Immunol. 1978 Feb;120(2):463–471. [PubMed] [Google Scholar]
  45. Slonim A. E., Surber M. L., Page D. L., Sharp R. A., Burr I. M. Modification of chemically induced diabetes in rats by vitamin E. Supplementation minimizes and depletion enhances development of diabetes. J Clin Invest. 1983 May;71(5):1282–1288. doi: 10.1172/JCI110878. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Srikanta S., Ganda O. P., Gleason R. E., Jackson R. A., Soeldner J. S., Eisenbarth G. S. Pre-type I diabetes. Linear loss of beta cell response to intravenous glucose. Diabetes. 1984 Aug;33(8):717–720. doi: 10.2337/diab.33.8.717. [DOI] [PubMed] [Google Scholar]
  47. Svenningsen A., Dyrberg T., Gerling I., Lernmark A., Mackay P., Rabinovitch A. Inhibition of insulin release after passive transfer of immunoglobulin from insulin-dependent diabetic children to mice. J Clin Endocrinol Metab. 1983 Dec;57(6):1301–1304. doi: 10.1210/jcem-57-6-1301. [DOI] [PubMed] [Google Scholar]
  48. Swenne I. The role of glucose in the in vitro regulation of cell cycle kinetics and proliferation of fetal pancreatic B-cells. Diabetes. 1982 Sep;31(9):754–760. doi: 10.2337/diab.31.9.754. [DOI] [PubMed] [Google Scholar]
  49. Tjälve H., Wilander E., Johansson E. B. Distribution of labelled streptozotocin in mice: uptake and retention in pancreatic islets. J Endocrinol. 1976 Jun;69(3):455–456. doi: 10.1677/joe.0.0690455. [DOI] [PubMed] [Google Scholar]
  50. Tomita T., Lacy P. E., Natschinsky F. M., McDaniel M. L. Effect of alloxan on insulin secretion in isolated rat islets perifused in vitro. Diabetes. 1974 Jun;23(6):517–524. doi: 10.2337/diab.23.6.517. [DOI] [PubMed] [Google Scholar]
  51. Uchigata Y., Yamamoto H., Kawamura A., Okamoto H. Protection by superoxide dismutase, catalase, and poly(ADP-ribose) synthetase inhibitors against alloxan- and streptozotocin-induced islet DNA strand breaks and against the inhibition of proinsulin synthesis. J Biol Chem. 1982 Jun 10;257(11):6084–6088. [PubMed] [Google Scholar]
  52. Van De Winkel M., Pipeleers D. Autofluorescence-activated cell sorting of pancreatic islet cells: purification of insulin-containing B-cells according to glucose-induced changes in cellular redox state. Biochem Biophys Res Commun. 1983 Jul 29;114(2):835–842. doi: 10.1016/0006-291x(83)90857-4. [DOI] [PubMed] [Google Scholar]
  53. Van De Winkel M., Smets G., Gepts W., Pipeleers D. Islet cell surface antibodies from insulin-dependent diabetics bind specifically to pancreatic B cells. J Clin Invest. 1982 Jul;70(1):41–49. doi: 10.1172/JCI110601. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Van de Winkle M., Maes E., Pipeleers D. Islet cell analysis and purification by light scatter and autofluorescence. Biochem Biophys Res Commun. 1982 Jul 30;107(2):525–532. doi: 10.1016/0006-291x(82)91523-6. [DOI] [PubMed] [Google Scholar]
  55. Wilson G. L., Patton N. J., McCord J. M., Mullins D. W., Mossman B. T. Mechanisms of streptozotocin- and alloxan-induced damage in rat B cells. Diabetologia. 1984 Dec;27(6):587–591. doi: 10.1007/BF00276973. [DOI] [PubMed] [Google Scholar]
  56. Yamada K., Nonaka K., Hanafusa T., Miyazaki A., Toyoshima H., Tarui S. Preventive and therapeutic effects of large-dose nicotinamide injections on diabetes associated with insulitis. An observation in nonobese diabetic (NOD) mice. Diabetes. 1982 Sep;31(9):749–753. doi: 10.2337/diab.31.9.749. [DOI] [PubMed] [Google Scholar]
  57. Yoon J. W., Austin M., Onodera T., Notkins A. L. Isolation of a virus from the pancreas of a child with diabetic ketoacidosis. N Engl J Med. 1979 May 24;300(21):1173–1179. doi: 10.1056/NEJM197905243002102. [DOI] [PubMed] [Google Scholar]
  58. Yoon J. W., McClintock P. R., Onodera T., Notkins A. L. Virus-induced diabetes mellitus. XVIII. Inhibition by a nondiabetogenic variant of encephalomyocarditis virus. J Exp Med. 1980 Oct 1;152(4):878–892. doi: 10.1084/jem.152.4.878. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Yoon J. W., Notkins A. L. Virus-induced diabetes in mice. Metabolism. 1983 Jul;32(7 Suppl 1):37–40. doi: 10.1016/s0026-0495(83)80009-2. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES