Logo of jcinvestThe Journal of Clinical InvestigationCurrent IssueArchiveSubscriptionAbout the Journal
J Clin Invest. 1997 Feb 1; 99(3): 414–423.
PMCID: PMC507814

Direct glucocorticoid inhibition of insulin secretion. An in vitro study of dexamethasone effects in mouse islets.


The direct effects of glucocorticoids on pancreatic beta cell function were studied with normal mouse islets. Dexamethasone inhibited insulin secretion from cultured islets in a concentration-dependent manner: maximum of approximately 75% at 250 nM and IC50 at approximately 20 nM dexamethasone. This inhibition was of slow onset (0, 20, and 40% after 1, 2, and 3 h) and only slowly reversible. It was prevented by a blocker of nuclear glucocorticoid receptors, by pertussis toxin, by a phorbol ester, and by dibutyryl cAMP, but was unaffected by an increase in the fuel content of the culture medium. Dexamethasone treatment did not affect islet cAMP levels but slightly reduced inositol phosphate formation. After 18 h of culture with or without 1 microM dexamethasone, the islets were perifused and stimulated by a rise in the glucose concentration from 3 to 15 mM. Both phases of insulin secretion were similarly decreased in dexamethasone-treated islets as compared with control islets. This inhibition could not be ascribed to a lowering of insulin stores (higher in dexamethasone-treated islets), to an alteration of glucose metabolism (glucose oxidation and NAD(P)H changes were unaffected), or to a lesser rise of cytoplasmic Ca2+ in beta cells (only the frequency of the oscillations was modified). Dexamethasone also inhibited insulin secretion induced by arginine, tolbutamide, or high K+. In this case also the inhibition was observed despite a normal rise of cytoplasmic Ca2+. In conclusion, dexamethasone inhibits insulin secretion through a genomic action in beta cells that leads to a decrease in the efficacy of cytoplasmic Ca2+ on the exocytotic process.

Full Text

The Full Text of this article is available as a PDF (229K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • McMahon M, Gerich J, Rizza R. Effects of glucocorticoids on carbohydrate metabolism. Diabetes Metab Rev. 1988 Feb;4(1):17–30. [PubMed]
  • De Feo P, Perriello G, Torlone E, Ventura MM, Fanelli C, Santeusanio F, Brunetti P, Gerich JE, Bolli GB. Contribution of cortisol to glucose counterregulation in humans. Am J Physiol. 1989 Jul;257(1 Pt 1):E35–E42. [PubMed]
  • Boyle PJ, Cryer PE. Growth hormone, cortisol, or both are involved in defense against, but are not critical to recovery from, hypoglycemia. Am J Physiol. 1991 Mar;260(3 Pt 1):E395–E402. [PubMed]
  • CONN JW, FAJANS SS. Influence of adrenal cortical steroids on carbohydrate metabolism in man. Metabolism. 1956 Mar;5(2):114–127. [PubMed]
  • Lenzen S, Bailey CJ. Thyroid hormones, gonadal and adrenocortical steroids and the function of the islets of Langerhans. Endocr Rev. 1984 Summer;5(3):411–434. [PubMed]
  • 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. [PubMed]
  • Matthes H, Kaiser A, Stier U, Riecken EO, Rosewicz S. Glucocorticoid receptor gene expression in the exocrine and endocrine rat pancreas. Endocrinology. 1994 Jul;135(1):476–479. [PubMed]
  • Kalhan SC, Adam PA. Inhibitory effect of prednisone on insulin secretion in man: model for duplication of blood glucose concentration. J Clin Endocrinol Metab. 1975 Sep;41(3):600–610. [PubMed]
  • Dinneen S, Alzaid A, Miles J, Rizza R. Metabolic effects of the nocturnal rise in cortisol on carbohydrate metabolism in normal humans. J Clin Invest. 1993 Nov;92(5):2283–2290. [PMC free article] [PubMed]
  • Plat L, Byrne MM, Sturis J, Polonsky KS, Mockel J, Féry F, Van Cauter E. Effects of morning cortisol elevation on insulin secretion and glucose regulation in humans. Am J Physiol. 1996 Jan;270(1 Pt 1):E36–E42. [PubMed]
  • Longano CA, Fletcher HP. Insulin release after acute hydrocortisone treatment in mice. Metabolism. 1983 Jun;32(6):603–608. [PubMed]
  • Malaisse WJ, Malaisse-Lagae F, McCraw EF, Wright PH. Insulin secretion in vitro by pancreatic tissue from normal, adrenalectomized, and cortisol-treated rats. Proc Soc Exp Biol Med. 1967 Mar;124(3):924–928. [PubMed]
  • Kawai A, Kuzuya N. On the role of glucocorticoid in glucose-induced insulin secretion. Horm Metab Res. 1977 Sep;9(5):361–365. [PubMed]
  • Ogawa A, Johnson JH, Ohneda M, McAllister CT, Inman L, Alam T, Unger RH. Roles of insulin resistance and beta-cell dysfunction in dexamethasone-induced diabetes. J Clin Invest. 1992 Aug;90(2):497–504. [PMC free article] [PubMed]
  • Wang ZL, Bennet WM, Wang RM, Ghatei MA, Bloom SR. Evidence of a paracrine role of neuropeptide-Y in the regulation of insulin release from pancreatic islets of normal and dexamethasone-treated rats. Endocrinology. 1994 Jul;135(1):200–206. [PubMed]
  • Chuthaputti A, Fletcher HP. Effect of hydrocortisone on terbutaline stimulated insulin release from isolated pancreatic islets. Res Commun Chem Pathol Pharmacol. 1987 Sep;57(3):329–341. [PubMed]
  • O'Brien TD, Westermark P, Johnson KH. Islet amyloid polypeptide and insulin secretion from isolated perfused pancreas of fed, fasted, glucose-treated, and dexamethasone-treated rats. Diabetes. 1991 Dec;40(12):1701–1706. [PubMed]
  • Grill V, Rundfeldt M. Abnormalities of insulin responses after ambient and previous exposure to glucose in streptozocin-diabetic and dexamethasone-treated rats. Role of hyperglycemia and increased B-cell demands. Diabetes. 1986 Jan;35(1):44–51. [PubMed]
  • Khan A, Ostenson CG, Berggren PO, Efendic S. Glucocorticoid increases glucose cycling and inhibits insulin release in pancreatic islets of ob/ob mice. Am J Physiol. 1992 Oct;263(4 Pt 1):E663–E666. [PubMed]
  • Billaudel B, Sutter BC. Direct effect of corticosterone upon insulin secretion studied by three different techniques. Horm Metab Res. 1979 Oct;11(10):555–560. [PubMed]
  • Barseghian G, Levine R. Effect of corticosterone on insulin and glucagon secretion by the isolated perfused rat pancreas. Endocrinology. 1980 Feb;106(2):547–552. [PubMed]
  • Barseghian G, Levine R, Epps P. Direct effect of cortisol and cortisone on insulin and glucagon secretion. Endocrinology. 1982 Nov;111(5):1648–1651. [PubMed]
  • Billaudel B, Mathias PC, Sutter BC, Malaisse WJ. Inhibition by corticosterone of calcium inflow and insulin release in rat pancreatic islets. J Endocrinol. 1984 Feb;100(2):227–233. [PubMed]
  • Brunstedt J, Nielsen JH. Direct long-term effect of hydrocortisone on insulin and glucagon release from mouse pancreatic islets in tissue culture. Acta Endocrinol (Copenh) 1981 Apr;96(4):498–504. [PubMed]
  • Chan C, Lejeune J. Reduced sensitivity to dexamethasone of pancreatic islets from obese (fa/fa) rats. Can J Physiol Pharmacol. 1992 Nov;70(11):1518–1522. [PubMed]
  • Pierluissi J, Navas FO, Ashcroft SJ. Effect of adrenal steroids on insulin release from cultured rat islets of Langerhans. Diabetologia. 1986 Feb;29(2):119–121. [PubMed]
  • Stahl M, Cheng H, Linde S, Nielson JH. Cortisol increases the susceptibility of rat islets to interleukin 1. Acta Endocrinol (Copenh) 1991 Oct;125(4):441–448. [PubMed]
  • Henquin JC. D-glucose inhibits potassium efflux from pancreatic islet cells. Nature. 1978 Jan 19;271(5642):271–273. [PubMed]
  • Detimary P, Jonas JC, Henquin JC. Possible links between glucose-induced changes in the energy state of pancreatic B cells and insulin release. Unmasking by decreasing a stable pool of adenine nucleotides in mouse islets. J Clin Invest. 1995 Oct;96(4):1738–1745. [PMC free article] [PubMed]
  • Gilon P, Henquin JC. Influence of membrane potential changes on cytoplasmic Ca2+ concentration in an electrically excitable cell, the insulin-secreting pancreatic B-cell. J Biol Chem. 1992 Oct 15;267(29):20713–20720. [PubMed]
  • Valdeolmillos M, Nadal A, Soria B, García-Sancho J. Fluorescence digital image analysis of glucose-induced [Ca2+]i oscillations in mouse pancreatic islets of Langerhans. Diabetes. 1993 Aug;42(8):1210–1214. [PubMed]
  • Worley JF, 3rd, McIntyre MS, Spencer B, Mertz RJ, Roe MW, Dukes ID. Endoplasmic reticulum calcium store regulates membrane potential in mouse islet beta-cells. J Biol Chem. 1994 May 20;269(20):14359–14362. [PubMed]
  • Hedeskov CJ. Mechanism of glucose-induced insulin secretion. Physiol Rev. 1980 Apr;60(2):442–509. [PubMed]
  • Henquin JC, Lambert AE. Bicarbonate modulation of glucose-9nduced biphasic insulin release by rat islets. Am J Physiol. 1976 Sep;231(3):713–721. [PubMed]
  • Berridge MJ, Dawson RM, Downes CP, Heslop JP, Irvine RF. Changes in the levels of inositol phosphates after agonist-dependent hydrolysis of membrane phosphoinositides. Biochem J. 1983 May 15;212(2):473–482. [PMC free article] [PubMed]
  • Martin TF. Measurement of phospholipid turnover in cultured hormone responsive pituitary cells. Methods Enzymol. 1986;124:424–442. [PubMed]
  • Gao ZY, Gilon P, Henquin JC. The role of protein kinase-C in signal transduction through vasopressin and acetylcholine receptors in pancreatic B-cells from normal mouse. Endocrinology. 1994 Jul;135(1):191–199. [PubMed]
  • Henquin JC. Effects of trifluoperazine and pimozide on stimulus-secretion coupling in pancreatic B-cells. Suggestion for a role of calmodulin? Biochem J. 1981 Jun 15;196(3):771–780. [PMC free article] [PubMed]
  • Moguilewsky M, Philibert D. RU 38486: potent antiglucocorticoid activity correlated with strong binding to the cytosolic glucocorticoid receptor followed by an impaired activation. J Steroid Biochem. 1984 Jan;20(1):271–276. [PubMed]
  • Hamamdzic D, Duzic E, Sherlock JD, Lanier SM. Regulation of alpha 2-adrenergic receptor expression and signaling in pancreatic beta-cells. Am J Physiol. 1995 Jul;269(1 Pt 1):E162–E171. [PubMed]
  • Nakaki T, Nakadate T, Kato R. Alpha 2-adrenoceptors modulating insulin release from isolated pancreatic islets. Naunyn Schmiedebergs Arch Pharmacol. 1980 Aug;313(2):151–153. [PubMed]
  • Jonas JC, Plant TD, Henquin JC. Imidazoline antagonists of alpha 2-adrenoceptors increase insulin release in vitro by inhibiting ATP-sensitive K+ channels in pancreatic beta-cells. Br J Pharmacol. 1992 Sep;107(1):8–14. [PMC free article] [PubMed]
  • Katada T, Ui M. Islet-activating protein. Enhanced insulin secretion and cyclic AMP accumulation in pancreatic islets due to activation of native calcium ionophores. J Biol Chem. 1979 Jan 25;254(2):469–479. [PubMed]
  • Panten U, Christians J, von Kriegstein E, Poser W, Hasselblatt A. Effect of carbohydrates upon fluorescence of reduced pyridine nucleotides from perifused isolated pancreatic islets. Diabetologia. 1973 Dec;9(6):477–482. [PubMed]
  • Bretherton-Watt D, Ghatei MA, Bloom SR, Jamal H, Ferrier GJ, Girgis SI, Legon S. Altered islet amyloid polypeptide (amylin) gene expression in rat models of diabetes. Diabetologia. 1989 Dec;32(12):881–883. [PubMed]
  • Orland MJ, Permutt MA. Comparative modulations of insulin secretion, pancreatic insulin content, and proinsulin mRNA in rats. Effects of 50% pancreatectomy and dexamethasone administration. Diabetes. 1991 Feb;40(2):181–189. [PubMed]
  • Welsh M, Weber T, Wrange O, Nielsen DA, Matthieu M, Steiner DF. Regulation of insulin gene expression by dexamethasone, Ca2+ and a phorbol ester. Biomed Biochim Acta. 1988;47(4-5):299–303. [PubMed]
  • Philippe J, Giordano E, Gjinovci A, Meda P. Cyclic adenosine monophosphate prevents the glucocorticoid-mediated inhibition of insulin gene expression in rodent islet cells. J Clin Invest. 1992 Dec;90(6):2228–2233. [PMC free article] [PubMed]
  • Ohneda M, Johnson JH, Inman LR, Unger RH. GLUT-2 function in glucose-unresponsive beta cells of dexamethasone-induced diabetes in rats. J Clin Invest. 1993 Oct;92(4):1950–1956. [PMC free article] [PubMed]
  • TäljedalIB Presence, induction and possible role of glucose 6-phosphatase in mammalian pancreatic islets. Biochem J. 1969 Sep;114(2):387–394. [PMC free article] [PubMed]
  • Khan A, Hong-Lie C, Landau BR. Glucose-6-phosphatase activity in islets from ob/ob and lean mice and the effect of dexamethasone. Endocrinology. 1995 May;136(5):1934–1938. [PubMed]
  • Saito N, Guitart X, Hayward M, Tallman JF, Duman RS, Nestler EJ. Corticosterone differentially regulates the expression of Gs alpha and Gi alpha messenger RNA and protein in rat cerebral cortex. Proc Natl Acad Sci U S A. 1989 May;86(10):3906–3910. [PMC free article] [PubMed]
  • Kawai Y, Arinze IJ. Glucocorticoid regulation of G-protein subunits in neonatal liver. Mol Cell Endocrinol. 1993 Jan;90(2):203–209. [PubMed]
  • Seaquist ER, Walseth TF, Redmon JB, Robertson RP. G-protein regulation of insulin secretion. J Lab Clin Med. 1994 Mar;123(3):338–345. [PubMed]
  • Myrsén U, Ahrén B, Sundler F. Neuropeptide Y is expressed in subpopulations of insulin- and non-insulin-producing islet cells in the rat after dexamethasone treatment: a combined immunocytochemical and in situ hybridisation study. Regul Pept. 1995 Dec 7;60(1):19–31. [PubMed]
  • Zawalich WS, Zawalich KC, Kelley GG. Regulation of insulin release by phospholipase C activation in mouse islets: differential effects of glucose and neurohumoral stimulation. Endocrinology. 1995 Nov;136(11):4903–4909. [PubMed]
  • Tamagawa T, Niki H, Niki A. Insulin release independent of a rise in cytosolic free Ca2+ by forskolin and phorbol ester. FEBS Lett. 1985 Apr 22;183(2):430–432. [PubMed]
  • Gembal M, Detimary P, Gilon P, Gao ZY, Henquin JC. 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. [PMC free article] [PubMed]

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


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • Cited in Books
    Cited in Books
    PubMed Central articles cited in books
  • Compound
    PubChem Compound links
  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...