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. 1998 May 15;101(10):2174–2181. doi: 10.1172/JCI1567

Glucocorticoid exposure in late gestation permanently programs rat hepatic phosphoenolpyruvate carboxykinase and glucocorticoid receptor expression and causes glucose intolerance in adult offspring.

M J Nyirenda 1, R S Lindsay 1, C J Kenyon 1, A Burchell 1, J R Seckl 1
PMCID: PMC508805  PMID: 9593773

Abstract

Low birth weight in humans is predictive of insulin resistance and diabetes in adult life. The molecular mechanisms underlying this link are unknown but fetal exposure to excess glucocorticoids has been implicated. The fetus is normally protected from the higher maternal levels of glucocorticoids by feto-placental 11beta-hydroxysteroid dehydrogenase type-2 (11beta-HSD2) which inactivates glucocorticoids. We have shown previously that inhibiting 11beta-HSD2 throughout pregnancy in rats reduces birth weight and causes hyperglycemia in the adult offspring. We now show that dexamethasone (a poor substrate for 11beta-HSD2) administered to pregnant rats selectively in the last week of pregnancy reduces birth weight by 10% (P < 0.05), and produces adult fasting hyperglycemia (treated 5.3+/-0.3; control 4.3+/-0.2 mmol/ liter, P = 0.04), reactive hyperglycemia (treated 8.7+/-0.4; control 7.5+/-0.2 mmol/liter, P = 0.03), and hyperinsulinemia (treated 6.1+/-0.4; control 3.8+/-0.5 ng/ml, P = 0.01) on oral glucose loading. In the adult offspring of rats exposed to dexamethasone in late pregnancy, hepatic expression of glucocorticoid receptor (GR) mRNA and phosphoenolpyruvate carboxykinase (PEPCK) mRNA (and activity) are increased by 25% (P = 0.01) and 60% (P < 0.01), respectively, while other liver enzymes (glucose-6-phosphatase, glucokinase, and 11beta-hydroxysteroid dehydrogenase type-1) are unaltered. In contrast dexamethasone, when given in the first or second week of gestation, has no effect on offspring insulin/glucose responses or hepatic PEPCK and GR expression. The increased hepatic GR expression may be crucial, since rats exposed to dexamethasone in utero showed potentiated glucose responses to exogenous corticosterone. These observations suggest that excessive glucocorticoid exposure late in pregnancy predisposes the offspring to glucose intolerance in adulthood. Programmed hepatic PEPCK overexpression, perhaps mediated by increased GR, may promote this process by increasing gluconeogenesis.

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Selected References

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  1. Agarwal A. K., Monder C., Eckstein B., White P. C. Cloning and expression of rat cDNA encoding corticosteroid 11 beta-dehydrogenase. J Biol Chem. 1989 Nov 15;264(32):18939–18943. [PubMed] [Google Scholar]
  2. Ballard F. J., Hanson R. W. Phosphoenolpyruvate carboxykinase and pyruvate carboxylase in developing rat liver. Biochem J. 1967 Sep;104(3):866–871. doi: 10.1042/bj1040866. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Barker D. J., Bull A. R., Osmond C., Simmonds S. J. Fetal and placental size and risk of hypertension in adult life. BMJ. 1990 Aug 4;301(6746):259–262. doi: 10.1136/bmj.301.6746.259. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Barker D. J., Gluckman P. D., Godfrey K. M., Harding J. E., Owens J. A., Robinson J. S. Fetal nutrition and cardiovascular disease in adult life. Lancet. 1993 Apr 10;341(8850):938–941. doi: 10.1016/0140-6736(93)91224-a. [DOI] [PubMed] [Google Scholar]
  5. Brown R. W., Chapman K. E., Kotelevtsev Y., Yau J. L., Lindsay R. S., Brett L., Leckie C., Murad P., Lyons V., Mullins J. J. Cloning and production of antisera to human placental 11 beta-hydroxysteroid dehydrogenase type 2. Biochem J. 1996 Feb 1;313(Pt 3):1007–1017. doi: 10.1042/bj3131007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Burchell A., Hume R., Burchell B. A new microtechnique for the analysis of the human hepatic microsomal glucose-6-phosphatase system. Clin Chim Acta. 1988 Apr 15;173(2):183–191. doi: 10.1016/0009-8981(88)90256-2. [DOI] [PubMed] [Google Scholar]
  7. Chang A. Y., Schneider D. I. Abnormalities in hepatic enzyme activities during development of diabetes in db mice. Diabetologia. 1970 Jun;6(3):274–278. doi: 10.1007/BF01212238. [DOI] [PubMed] [Google Scholar]
  8. Cole T. J., Blendy J. A., Monaghan A. P., Schmid W., Aguzzi A., Schütz G. Molecular genetic analysis of glucocorticoid signaling during mouse development. Steroids. 1995 Jan;60(1):93–96. doi: 10.1016/0039-128x(94)00009-2. [DOI] [PubMed] [Google Scholar]
  9. Consoli A., Nurjhan N., Reilly J. J., Jr, Bier D. M., Gerich J. E. Mechanism of increased gluconeogenesis in noninsulin-dependent diabetes mellitus. Role of alterations in systemic, hepatic, and muscle lactate and alanine metabolism. J Clin Invest. 1990 Dec;86(6):2038–2045. doi: 10.1172/JCI114940. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Davidson A. L., Arion W. J. Factors underlying significant underestimations of glucokinase activity in crude liver extracts: physiological implications of higher cellular activity. Arch Biochem Biophys. 1987 Feb 15;253(1):156–167. doi: 10.1016/0003-9861(87)90648-5. [DOI] [PubMed] [Google Scholar]
  11. Desai M., Crowther N. J., Ozanne S. E., Lucas A., Hales C. N. Adult glucose and lipid metabolism may be programmed during fetal life. Biochem Soc Trans. 1995 May;23(2):331–335. doi: 10.1042/bst0230331. [DOI] [PubMed] [Google Scholar]
  12. Edwards C. R., Benediktsson R., Lindsay R. S., Seckl J. R. Dysfunction of placental glucocorticoid barrier: link between fetal environment and adult hypertension? Lancet. 1993 Feb 6;341(8841):355–357. doi: 10.1016/0140-6736(93)90148-a. [DOI] [PubMed] [Google Scholar]
  13. Fowden A. L., Mijovic J., Silver M. The effects of cortisol on hepatic and renal gluconeogenic enzyme activities in the sheep fetus during late gestation. J Endocrinol. 1993 May;137(2):213–222. doi: 10.1677/joe.0.1370213. [DOI] [PubMed] [Google Scholar]
  14. Friedman J. E., Yun J. S., Patel Y. M., McGrane M. M., Hanson R. W. Glucocorticoids regulate the induction of phosphoenolpyruvate carboxykinase (GTP) gene transcription during diabetes. J Biol Chem. 1993 Jun 15;268(17):12952–12957. [PubMed] [Google Scholar]
  15. Garcia Ruiz J. P., Ingram R., Hanson R. W. Changes in hepatic messenger RNA for phosphoenolpyruvate carboxykinase (GTP) during development. Proc Natl Acad Sci U S A. 1978 Sep;75(9):4189–4193. doi: 10.1073/pnas.75.9.4189. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gearing K. L., Cairns W., Okret S., Gustafsson J. A. Heterogeneity in the 5' untranslated region of the rat glucocorticoid receptor mRNA. J Steroid Biochem Mol Biol. 1993 Nov;46(5):635–639. doi: 10.1016/0960-0760(93)90192-y. [DOI] [PubMed] [Google Scholar]
  17. Girard J. Control of fetal and neonatal glucose metabolism by pancreatic hormones. Baillieres Clin Endocrinol Metab. 1989 Nov;3(3):817–836. doi: 10.1016/s0950-351x(89)80055-2. [DOI] [PubMed] [Google Scholar]
  18. Goland R. S., Jozak S., Warren W. B., Conwell I. M., Stark R. I., Tropper P. J. Elevated levels of umbilical cord plasma corticotropin-releasing hormone in growth-retarded fetuses. J Clin Endocrinol Metab. 1993 Nov;77(5):1174–1179. doi: 10.1210/jcem.77.5.8077309. [DOI] [PubMed] [Google Scholar]
  19. Gustafsson J. A., Stenberg A. Neonatal programming of androgen responsiveness of liver of adult rats. J Biol Chem. 1974 Feb 10;249(3):719–723. [PubMed] [Google Scholar]
  20. HARRIS G. W. SEX HORMONES, BRAIN DEVELOPMENT AND BRAIN FUNCTION. Endocrinology. 1964 Oct;75:627–648. doi: 10.1210/endo-75-4-627. [DOI] [PubMed] [Google Scholar]
  21. Hales C. N., Barker D. J., Clark P. M., Cox L. J., Fall C., Osmond C., Winter P. D. Fetal and infant growth and impaired glucose tolerance at age 64. BMJ. 1991 Oct 26;303(6809):1019–1022. doi: 10.1136/bmj.303.6809.1019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Hales C. N., Barker D. J. Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia. 1992 Jul;35(7):595–601. doi: 10.1007/BF00400248. [DOI] [PubMed] [Google Scholar]
  23. Imai E., Stromstedt P. E., Quinn P. G., Carlstedt-Duke J., Gustafsson J. A., Granner D. K. Characterization of a complex glucocorticoid response unit in the phosphoenolpyruvate carboxykinase gene. Mol Cell Biol. 1990 Sep;10(9):4712–4719. doi: 10.1128/mcb.10.9.4712. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Jamieson P. M., Chapman K. E., Edwards C. R., Seckl J. R. 11 beta-hydroxysteroid dehydrogenase is an exclusive 11 beta- reductase in primary cultures of rat hepatocytes: effect of physicochemical and hormonal manipulations. Endocrinology. 1995 Nov;136(11):4754–4761. doi: 10.1210/endo.136.11.7588203. [DOI] [PubMed] [Google Scholar]
  25. Kotelevtsev Y., Holmes M. C., Burchell A., Houston P. M., Schmoll D., Jamieson P., Best R., Brown R., Edwards C. R., Seckl J. R. 11beta-hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress. Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14924–14929. doi: 10.1073/pnas.94.26.14924. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Lambillotte C., Gilon P., Henquin J. C. Direct glucocorticoid inhibition of insulin secretion. An in vitro study of dexamethasone effects in mouse islets. J Clin Invest. 1997 Feb 1;99(3):414–423. doi: 10.1172/JCI119175. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Langley-Evans S. C. Hypertension induced by foetal exposure to a maternal low-protein diet, in the rat, is prevented by pharmacological blockade of maternal glucocorticoid synthesis. J Hypertens. 1997 May;15(5):537–544. doi: 10.1097/00004872-199715050-00010. [DOI] [PubMed] [Google Scholar]
  28. Langley-Evans S. C., Phillips G. J., Benediktsson R., Gardner D. S., Edwards C. R., Jackson A. A., Seckl J. R. Protein intake in pregnancy, placental glucocorticoid metabolism and the programming of hypertension in the rat. Placenta. 1996 Mar-Apr;17(2-3):169–172. doi: 10.1016/s0143-4004(96)80010-5. [DOI] [PubMed] [Google Scholar]
  29. Levitt N. S., Lindsay R. S., Holmes M. C., Seckl J. R. Dexamethasone in the last week of pregnancy attenuates hippocampal glucocorticoid receptor gene expression and elevates blood pressure in the adult offspring in the rat. Neuroendocrinology. 1996 Dec;64(6):412–418. doi: 10.1159/000127146. [DOI] [PubMed] [Google Scholar]
  30. Liggins G. C. Adrenocortical-related maturational events in the fetus. Am J Obstet Gynecol. 1976 Dec 1;126(7):931–941. doi: 10.1016/0002-9378(76)90680-3. [DOI] [PubMed] [Google Scholar]
  31. Lindsay R. S., Lindsay R. M., Waddell B. J., Seckl J. R. Prenatal glucocorticoid exposure leads to offspring hyperglycaemia in the rat: studies with the 11 beta-hydroxysteroid dehydrogenase inhibitor carbenoxolone. Diabetologia. 1996 Nov;39(11):1299–1305. doi: 10.1007/s001250050573. [DOI] [PubMed] [Google Scholar]
  32. Lucas P. C., Granner D. K. Hormone response domains in gene transcription. Annu Rev Biochem. 1992;61:1131–1173. doi: 10.1146/annurev.bi.61.070192.005411. [DOI] [PubMed] [Google Scholar]
  33. MacPhee I. A., Antoni F. A., Mason D. W. Spontaneous recovery of rats from experimental allergic encephalomyelitis is dependent on regulation of the immune system by endogenous adrenal corticosteroids. J Exp Med. 1989 Feb 1;169(2):431–445. doi: 10.1084/jem.169.2.431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. McCaffrey J., Hamilton J. W. Development regulation of basal and hormone-inducible phosphoenolpyruvate carboxykinase gene expression in chick embryo liver in vivo. Arch Biochem Biophys. 1994 Feb 15;309(1):10–17. doi: 10.1006/abbi.1994.1076. [DOI] [PubMed] [Google Scholar]
  35. McCance D. R., Pettitt D. J., Hanson R. L., Jacobsson L. T., Knowler W. C., Bennett P. H. Birth weight and non-insulin dependent diabetes: thrifty genotype, thrifty phenotype, or surviving small baby genotype? BMJ. 1994 Apr 9;308(6934):942–945. doi: 10.1136/bmj.308.6934.942. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Meaney M. J., Aitken D. H., van Berkel C., Bhatnagar S., Sapolsky R. M. Effect of neonatal handling on age-related impairments associated with the hippocampus. Science. 1988 Feb 12;239(4841 Pt 1):766–768. doi: 10.1126/science.3340858. [DOI] [PubMed] [Google Scholar]
  37. Miesfeld R., Okret S., Wikström A. C., Wrange O., Gustafsson J. A., Yamamoto K. R. Characterization of a steroid hormone receptor gene and mRNA in wild-type and mutant cells. Nature. 1984 Dec 20;312(5996):779–781. doi: 10.1038/312779a0. [DOI] [PubMed] [Google Scholar]
  38. Murphy B. E., Clark S. J., Donald I. R., Pinsky M., Vedady D. Conversion of maternal cortisol to cortisone during placental transfer to the human fetus. Am J Obstet Gynecol. 1974 Feb 15;118(4):538–541. doi: 10.1016/s0002-9378(16)33697-3. [DOI] [PubMed] [Google Scholar]
  39. O'Brien R. M., Granner D. K. Regulation of gene expression by insulin. Biochem J. 1991 Sep 15;278(Pt 3):609–619. doi: 10.1042/bj2780609. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Panarelli M., Holloway C. D., Barr A. B., Fraser R., Kenyon C. J. Differences in temperature-sensitive receptor binding of glucocorticoids in spontaneously hypertensive and normotensive Wistar-Kyoto rats. Steroids. 1995 Jan;60(1):73–75. doi: 10.1016/0039-128x(94)00011-z. [DOI] [PubMed] [Google Scholar]
  41. Peterson G. L. A simplification of the protein assay method of Lowry et al. which is more generally applicable. Anal Biochem. 1977 Dec;83(2):346–356. doi: 10.1016/0003-2697(77)90043-4. [DOI] [PubMed] [Google Scholar]
  42. Petrescu I., Bojan O., Saied M., Bârzu O., Schmidt F., Kühnle H. F. Determination of phosphoenolpyruvate carboxykinase activity with deoxyguanosine 5'-diphosphate as nucleotide substrate. Anal Biochem. 1979 Jul 15;96(2):279–281. doi: 10.1016/0003-2697(79)90582-7. [DOI] [PubMed] [Google Scholar]
  43. Philippidis H., Ballard F. J. The development of gluconeogenesis in rat liver. Effects of glucagon and ether. Biochem J. 1970 Nov;120(2):385–392. doi: 10.1042/bj1200385. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Pilkis S. J., Granner D. K. Molecular physiology of the regulation of hepatic gluconeogenesis and glycolysis. Annu Rev Physiol. 1992;54:885–909. doi: 10.1146/annurev.ph.54.030192.004321. [DOI] [PubMed] [Google Scholar]
  45. Price W. A., Stiles A. D., Moats-Staats B. M., D'Ercole A. J. Gene expression of insulin-like growth factors (IGFs), the type 1 IGF receptor, and IGF-binding proteins in dexamethasone-induced fetal growth retardation. Endocrinology. 1992 Mar;130(3):1424–1432. doi: 10.1210/endo.130.3.1371449. [DOI] [PubMed] [Google Scholar]
  46. Purdy L. P., Metzger B. E. Influences of the intrauterine metabolic environment on adult disease: what may we infer from size at birth? Diabetologia. 1996 Sep;39(9):1126–1130. doi: 10.1007/BF00400665. [DOI] [PubMed] [Google Scholar]
  47. Rajkumar K., Barron D., Lewitt M. S., Murphy L. J. Growth retardation and hyperglycemia in insulin-like growth factor binding protein-1 transgenic mice. Endocrinology. 1995 Sep;136(9):4029–4034. doi: 10.1210/endo.136.9.7544274. [DOI] [PubMed] [Google Scholar]
  48. Reinisch J. M., Simon N. G., Karow W. G., Gandelman R. Prenatal exposure to prednisone in humans and animals retards intrauterine growth. Science. 1978 Oct 27;202(4366):436–438. doi: 10.1126/science.705336. [DOI] [PubMed] [Google Scholar]
  49. Rosella G., Zajac J. D., Kaczmarczyk S. J., Andrikopoulos S., Proietto J. Impaired suppression of gluconeogenesis induced by overexpression of a noninsulin-responsive phosphoenolpyruvate carboxykinase gene. Mol Endocrinol. 1993 Nov;7(11):1456–1462. doi: 10.1210/mend.7.11.8114759. [DOI] [PubMed] [Google Scholar]
  50. Ross E. J., Marshall-Jones P., Friedman M. Cushing's syndrome: diagnostic criteria. Q J Med. 1966 Apr;35(138):149–192. [PubMed] [Google Scholar]
  51. Schmidt T. J., Meyer A. S. Autoregulation of corticosteroid receptors. How, when, where, and why? Receptor. 1994 Winter;4(4):229–257. [PubMed] [Google Scholar]
  52. Stewart P. M., Rogerson F. M., Mason J. I. Type 2 11 beta-hydroxysteroid dehydrogenase messenger ribonucleic acid and activity in human placenta and fetal membranes: its relationship to birth weight and putative role in fetal adrenal steroidogenesis. J Clin Endocrinol Metab. 1995 Mar;80(3):885–890. doi: 10.1210/jcem.80.3.7883847. [DOI] [PubMed] [Google Scholar]
  53. Strähle U., Schmidt A., Kelsey G., Stewart A. F., Cole T. J., Schmid W., Schütz G. At least three promoters direct expression of the mouse glucocorticoid receptor gene. Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):6731–6735. doi: 10.1073/pnas.89.15.6731. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Suh D. S., Rechler M. M. Hepatocyte nuclear factor 1 and the glucocorticoid receptor synergistically activate transcription of the rat insulin-like growth factor binding protein-1 gene. Mol Endocrinol. 1997 Nov;11(12):1822–1831. doi: 10.1210/mend.11.12.0021. [DOI] [PubMed] [Google Scholar]
  55. Valdez R., Athens M. A., Thompson G. H., Bradshaw B. S., Stern M. P. Birthweight and adult health outcomes in a biethnic population in the USA. Diabetologia. 1994 Jun;37(6):624–631. doi: 10.1007/BF00403383. [DOI] [PubMed] [Google Scholar]
  56. Valera A., Pujol A., Pelegrin M., Bosch F. Transgenic mice overexpressing phosphoenolpyruvate carboxykinase develop non-insulin-dependent diabetes mellitus. Proc Natl Acad Sci U S A. 1994 Sep 13;91(19):9151–9154. doi: 10.1073/pnas.91.19.9151. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Weinstein S. P., Paquin T., Pritsker A., Haber R. S. Glucocorticoid-induced insulin resistance: dexamethasone inhibits the activation of glucose transport in rat skeletal muscle by both insulin- and non-insulin-related stimuli. Diabetes. 1995 Apr;44(4):441–445. doi: 10.2337/diab.44.4.441. [DOI] [PubMed] [Google Scholar]
  58. Yamagata K., Oda N., Kaisaki P. J., Menzel S., Furuta H., Vaxillaire M., Southam L., Cox R. D., Lathrop G. M., Boriraj V. V. Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3) Nature. 1996 Dec 5;384(6608):455–458. doi: 10.1038/384455a0. [DOI] [PubMed] [Google Scholar]

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