Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1992 Dec;90(6):2228–2233. doi: 10.1172/JCI116108

Cyclic adenosine monophosphate prevents the glucocorticoid-mediated inhibition of insulin gene expression in rodent islet cells.

J Philippe 1, E Giordano 1, A Gjinovci 1, P Meda 1
PMCID: PMC443373  PMID: 1334972

Abstract

Dexamethasone negatively regulates insulin gene expression in HIT-15 cells. In vivo, however, an excess of glucocorticoids results in an increase in insulin biosynthesis and peripheral hyperinsulinemia. To resolve this contradiction, we have studied the effects of dexamethasone in primary rat islet cells. We show here that dexamethasone decreases insulin mRNA levels in single islet cells, as in HIT-15 cells, but does not affect these levels in reaggregated islet cells and increases them in intact islets of Langerhans. Because cAMP is an important regulator of insulin gene expression and intracellular cAMP content may be decreased in single beta cells, we investigated whether cAMP could prevent the inhibitory effect of dexamethasone on insulin mRNA levels. In the presence of cAMP analogues, the inhibitory action of dexamethasone was not only prevented, but insulin mRNA increased to levels comparable to those observed when cAMP analogues were used alone. We conclude that the insulin gene is negatively regulated by dexamethasone in single islet cells, but that other factors such as cAMP prevent this effect when the native environment of islet cells is preserved. Our results indicate that insulin gene regulation is influenced by cell to cell contacts within the islet, and that intracellular cAMP levels might be influential in this regulation.

Full text

PDF
2232

Images in this article

2229Image
on p.2229
2229Image
on p.2229
2229Image
on p.2229
2229Image
on p.2229
2229Image
on p.2229
2230Image
on p.2230
2230Image
on p.2230
2230Image
on p.2230
2230Image
on p.2230
2231Image
on p.2231
2231Image
on p.2231

Selected References

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

  1. Ashcroft S. J., Hammonds P., Harrison D. E. Insulin secretory responses of a clonal cell line of simian virus 40-transformed B cells. Diabetologia. 1986 Oct;29(10):727–733. doi: 10.1007/BF00870283. [DOI] [PubMed] [Google Scholar]
  2. Bosco D., Orci L., Meda P. Homologous but not heterologous contact increases the insulin secretion of individual pancreatic B-cells. Exp Cell Res. 1989 Sep;184(1):72–80. doi: 10.1016/0014-4827(89)90365-0. [DOI] [PubMed] [Google Scholar]
  3. Charles M. A., Lawecki J., Pictet R., Grodsky G. M. Insulin secretion. Interrelationships of glucose, cyclic adenosine 3:5-monophosphate, and calcium. J Biol Chem. 1975 Aug 10;250(15):6134–6140. [PubMed] [Google Scholar]
  4. Denner L. A., Weigel N. L., Maxwell B. L., Schrader W. T., O'Malley B. W. Regulation of progesterone receptor-mediated transcription by phosphorylation. Science. 1990 Dec 21;250(4988):1740–1743. doi: 10.1126/science.2176746. [DOI] [PubMed] [Google Scholar]
  5. Drucker D. J., Campos R., Reynolds R., Stobie K., Brubaker P. L. The rat glucagon gene is regulated by a protein kinase A-dependent pathway in pancreatic islet cells. Endocrinology. 1991 Jan;128(1):394–400. doi: 10.1210/endo-128-1-394. [DOI] [PubMed] [Google Scholar]
  6. Fischer B., Rausch U., Wollny P., Westphal H., Seitz J., Aumüller G. Immunohistochemical localization of the glucocorticoid receptor in pancreatic beta-cells of the rat. Endocrinology. 1990 May;126(5):2635–2641. doi: 10.1210/endo-126-5-2635. [DOI] [PubMed] [Google Scholar]
  7. German M. S., Moss L. G., Rutter W. J. Regulation of insulin gene expression by glucose and calcium in transfected primary islet cultures. J Biol Chem. 1990 Dec 25;265(36):22063–22066. [PubMed] [Google Scholar]
  8. Gold G., Qian R. L., Grodsky G. M. Insulin biosynthesis in HIT cells. Effects of glucose, forskolin, IBMX, and dexamethasone. Diabetes. 1988 Feb;37(2):160–165. doi: 10.2337/diab.37.2.160. [DOI] [PubMed] [Google Scholar]
  9. Hammonds P., Schofield P. N., Ashcroft S. J., Sutton R., Gray D. W. Regulation and specificity of glucose-stimulated insulin gene expression in human islets of Langerhans. FEBS Lett. 1987 Oct 19;223(1):131–137. doi: 10.1016/0014-5793(87)80523-9. [DOI] [PubMed] [Google Scholar]
  10. Hill R. S., Oberwetter J. M., Boyd A. E., 3rd Increase in cAMP levels in beta-cell line potentiates insulin secretion without altering cytosolic free-calcium concentration. Diabetes. 1987 Apr;36(4):440–446. doi: 10.2337/diab.36.4.440. [DOI] [PubMed] [Google Scholar]
  11. Jungmann R. A., Wang X. S., Milkowski D. M., Short M. L. Glucocorticoid induction of CRE-binding protein isoform mRNAs in rat C6 glioma cells. Nucleic Acids Res. 1992 Feb 25;20(4):825–829. doi: 10.1093/nar/20.4.825. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Knepel W., Chafitz J., Habener J. F. Transcriptional activation of the rat glucagon gene by the cyclic AMP-responsive element in pancreatic islet cells. Mol Cell Biol. 1990 Dec;10(12):6799–6804. doi: 10.1128/mcb.10.12.6799. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Lenzen S., Bailey C. J. Thyroid hormones, gonadal and adrenocortical steroids and the function of the islets of Langerhans. Endocr Rev. 1984 Summer;5(3):411–434. doi: 10.1210/edrv-5-3-411. [DOI] [PubMed] [Google Scholar]
  14. Meda P., Amherdt M., Perrelet A., Orci L. Metabolic coupling between cultured pancreatic b-cells. Exp Cell Res. 1981 Jun;133(2):421–430. doi: 10.1016/0014-4827(81)90335-9. [DOI] [PubMed] [Google Scholar]
  15. Meda P., Bosco D., Chanson M., Giordano E., Vallar L., Wollheim C., Orci L. Rapid and reversible secretion changes during uncoupling of rat insulin-producing cells. J Clin Invest. 1990 Sep;86(3):759–768. doi: 10.1172/JCI114772. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Meda P., Hooghe-Peters E. L., Orci L. Monolayer cultures of adult pancreatic islet cells on osmotically disrupted fibroblasts. Diabetes. 1980 Jun;29(6):497–500. doi: 10.2337/diab.29.6.497. [DOI] [PubMed] [Google Scholar]
  17. Nielsen D. A., Welsh M., Casadaban M. J., Steiner D. F. Control of insulin gene expression in pancreatic beta-cells and in an insulin-producing cell line, RIN-5F cells. I. Effects of glucose and cyclic AMP on the transcription of insulin mRNA. J Biol Chem. 1985 Nov 5;260(25):13585–13589. [PubMed] [Google Scholar]
  18. Philippe J., Missotten M. Dexamethasone inhibits insulin biosynthesis by destabilizing insulin messenger ribonucleic acid in hamster insulinoma cells. Endocrinology. 1990 Oct;127(4):1640–1645. doi: 10.1210/endo-127-4-1640. [DOI] [PubMed] [Google Scholar]
  19. Philippe J., Missotten M. Functional characterization of a cAMP-responsive element of the rat insulin I gene. J Biol Chem. 1990 Jan 25;265(3):1465–1469. [PubMed] [Google Scholar]
  20. 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]
  21. Power R. F., Lydon J. P., Conneely O. M., O'Malley B. W. Dopamine activation of an orphan of the steroid receptor superfamily. Science. 1991 Jun 14;252(5012):1546–1548. doi: 10.1126/science.2047861. [DOI] [PubMed] [Google Scholar]
  22. Sutton R., Peters M., McShane P., Gray D. W., Morris P. J. Isolation of rat pancreatic islets by ductal injection of collagenase. Transplantation. 1986 Dec;42(6):689–691. doi: 10.1097/00007890-198612000-00022. [DOI] [PubMed] [Google Scholar]
  23. Ullrich S., Wollheim C. B. Islet cyclic AMP levels are not lowered during alpha 2-adrenergic inhibition of insulin release. J Biol Chem. 1984 Apr 10;259(7):4111–4115. [PubMed] [Google Scholar]
  24. Welsh M., Nielsen D. A., MacKrell A. J., Steiner D. F. Control of insulin gene expression in pancreatic beta-cells and in an insulin-producing cell line, RIN-5F cells. II. Regulation of insulin mRNA stability. J Biol Chem. 1985 Nov 5;260(25):13590–13594. [PubMed] [Google Scholar]
  25. Welsh M., Weber T., Wrange O., Nielsen D. A., Matthieu M., Steiner D. F. Regulation of insulin gene expression by dexamethasone, Ca2+ and a phorbol ester. Biomed Biochim Acta. 1988;47(4-5):299–303. [PubMed] [Google Scholar]
  26. Wollheim C. B., Meda P., Halban P. A. Isolation of pancreatic islets and primary culture of the intact microorgans or of dispersed islet cells. Methods Enzymol. 1990;192:188–223. doi: 10.1016/0076-6879(90)92071-k. [DOI] [PubMed] [Google Scholar]

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

RESOURCES