Horm Metab Res 2009; 41(12): 899-904
DOI: 10.1055/s-0029-1234071
Humans, Clinical

© Georg Thieme Verlag KG Stuttgart · New York

Effect of RU486 on Hepatic and Adipocyte Gene Expression Improves Diabetes Control in Obesity-type 2 Diabetes

A. I. Taylor1 , N. Frizzell1 , A. M. McKillop1 , P. R. Flatt1 , V. A. Gault1
  • 1The SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, UK
Further Information

Publication History

received 09.04.2009

accepted 07.07.2009

Publication Date:
10 August 2009 (online)

Abstract

Cortisol has wide-ranging actions, namely in gluconeogenesis and glycogenesis and exerts its effects through the glucocorticoid receptor. In the present study, we examined effects of glucocorticoid receptor blockade on type 2 diabetes control using the antagonist, RU486. Obese diabetic mice received daily injections of vehicle or RU486 over 28 days. Food intake, body weight, and plasma glucose were measured frequently. At 28 days, glucose tolerance, insulin sensitivity, and plasma triglycerides were assessed. Epididymal white adipose tissue and liver were excised for measurement of gene expression. Daily administration of RU486 had no effect on body weight or food intake, but plasma glucose concentrations were significantly lowered (1.4–1.6-fold; p<0.05 to p<0.001). Glucose concentrations were also significantly reduced (2.2-fold; p<0.001) following a glucose challenge. Similarly, exogenous insulin evoked a significantly greater reduction in plasma glucose (3.6-fold; p<0.01). Gene expression analysis revealed a significant reduction in hepatic mRNA of key enzymes, namely PEPCK-C (25%; p<0.01) and G6 Pase (32%; p<0.01) and also 11β-HSD1 (18%; p<0.05). Investigation of adipose tissue gene expression also demonstrated reduced expression in 11β-HSD1 (47%; p<0.05) and LPL (47%; p<0.001). These data demonstrate wide-ranging effects of glucocorticoid receptor antagonism on gene expression and metabolism, illustrating the therapeutic potential of specific glucocorticoid receptor antagonists in obesity-related diabetes.

References

  • 1 Schoneveld OJ, Gaemers IC, Lamers WH. Mechanisms of glucocorticoid signalling.  Biochem Biophys Acta. 2004;  1680 114-128
  • 2 Kassel O, Herrlich P. Crosstalk between the glucocorticoid receptor and other transcription factors: Molecular aspects.  Mol Cell Endocrinol. 2007;  275 13-29
  • 3 Kino T. Tissue Glucocorticoid sensitivity: Beyond stochastic regulation on the diverse actions of glucocorticoids.  Horm Metab Res. 2007;  39 420-424
  • 4 Friedman JE, Yun JS, Patel YM, McGrane MM, Hanson RW. Glucocortocoids regulate the induction of phosphoenolpyruvate carboxykinase (GTP) gene transcription during diabetes.  J Biol Chem. 1993;  268 12952-12957
  • 5 Pilkis SJ, Granner DK. Molecular physiology of the regulation of hepatic gluconeogenesis and glycolysis.  Annu Rev Physiol. 1992;  54 885-909
  • 6 McKay LI, Cidlowski JA. Molecular control of immune/inflammatory responses: interactions between nuclear factor-kappa B and steroid receptor-signalling pathways.  Endocrinol Rev. 1999;  20 435-459
  • 7 Herbert J, Goodyer IM, Grossman AB, Hastings MH, de Kloet ER, Lightman SL, Lupien SJ, Roozendaal B, Seckl JR. Do corticosteroids damage the brain?.  J Neuroendocrinol. 2006;  18 393-411
  • 8 Sivagurunathan S, Muir MM, Brennan TC, Seale JP, Mason RS. Influence of glucocorticoids on human osteoclast generation and activity.  J Bone Miner Res. 2005;  20 390-398
  • 9 Matero F, Boscaro M. Glucocorticoid-dependent hypertension.  J Steroid Biochem Mol Biol. 1992;  43 409-413
  • 10 Pasquali R, Vicennati V. The abdominal obesity phenotype and insulin resistance are associated with abnormalities of the hypothalamic-pituitary adrenal axis in humans.  Horm Metab Res. 2000;  32 521-525
  • 11 Mahajan DK, London SN. Mifepristone (RU486): A review.  Fertil Steril. 1997;  68 967-976
  • 12 Johanssen S, Allolio B. Mifepristone (RU486) in Cushing's Syndrome.  Eur J Endocrinol. 2007;  157 561-569
  • 13 Cadepond F, Ulmann A, Baulieu EE. RU486 (Mifepristone): Mechanism of action and clinical uses.  Annu Rev Med. 1997;  48 129-156
  • 14 Jay MA, Ren J. Peroxisome proliferator-activated receptor (PPAR) in metabolic syndrome and type 2 diabetes mellitus.  Curr Diabetes Rev. 2007;  3 33-39
  • 15 Livingstone DE, Walker BR. Is 11beta-hydroxysteroid dehydrogenase type 1 a therapeutic target? Effects of carbenoxolone in lean and obese Zucker rats.  J Pharmacol Exp Therap. 2003;  305 167-172
  • 16 Kim W, Egan JM. The role of incretins in glucose homeostasis and diabetes treatment.  Pharmacol Rev. 2008;  60 470-512
  • 17 Bailey CJ, Flatt PR. Animal syndromes resembling type 2 diabetes. In: Pickup JC, Williams G (eds) Textbook of Diabetes (3rd ed). Oxford: Blackwell Science Ltd. 2003: 25.1-25.30
  • 18 Bailey CJ, Flatt PR, Atkins TW. Influence of genetic background and age on the expression of the obese hyperglycaemic syndrome in Aston ob/ob mice.  Int J Obesity. 1982;  6 11-21
  • 19 Gettys TW, Watson PM, Taylor IL, Collins S. RU-486 (Mifepristone) ameliorates diabetes but does not correct deficient β-adrenergic signalling in adipocytes from mature C57BL/J6-ob/ob mice.  Int J Obesity. 1997;  21 865-873
  • 20 Flatt PR, Bailey CJ. Abnormal plasma glucose and insulin responses in heterozygous lean (ob/+) mice.  Diabetologia. 1981;  20 573-577
  • 21 McClean PL, Irwin N, Cassidy RS, Holst JJ, Gault VA, Flatt PR. GIP receptor antagonism reverses obesity, insulin resistance, and associated metabolic disturbances induced in mice by prolonged consumption of high-fat diet.  Am J Physiol Endocrinol Metab. 2007;  293 1746-1755
  • 22 Saltiel AR, Kahn R. Insulin signalling and the regulation of glucose and lipid metabolism.  Nature. 2001;  414 799-806
  • 23 Dirlewanger M, Schneiter PH, Paquot N, Jequier E, Rey V, Tappy L. Effects of glucocorticoids on hepatic sensitivity to insulin and glucagon in man.  Clin Nutr. 2000;  19 29-34
  • 24 Rognstad R. Rate-limiting steps in metabolic pathways.  J Biol Chem. 1979;  254 1875-1878
  • 25 Imai E, Stromstedt PE, Quinn PG, Carlstedt-Duke J, Gustafsson JA, Granner DK. Characterization of a complex glucocorticoid response unit in the phosphoenolpyruvate carboxykinase gene.  Mol Cell Biol. 1990;  10 4172-4179
  • 26 Vander Kooi BT, Onuma H, Oeser JK, Svitek CA, Allen SR, Vander Kooi CW, Chazin WJ, O’Brien RM. The Glucose-6-Phosphatase catalytic subunit gene promoter contains both positive and negative glucocorticoid response elements.  Mol Endocrinol. 2005;  19 3001-3022
  • 27 Liu Y, Nakagawa Y, Wang Y, Sakurai R, Tripathi PV, Lufty K, Friedman TC. Increased glucocorticoid receptor and 11{beta}-hydroxysteroid dehydrogenase type 1 expression in hepatocytes may contribute to the phenotype of type 2 diabetes in db/db mice.  Diabetes. 2005;  54 32-40
  • 28 Friedman JE, Sun Y, Ishizuka T, Farrell CJ, McCormack SE, Herron LM, Hakimi P, Lechner P, Yun JS. Phosphoenolpyruvate carboxykinase (GTP) gene transcription and hyperglycemia are regulated by glucocorticoids in genetically obese db/db transgenic mice.  J Biol Chem. 1997;  272 31475-31481
  • 29 Gómez-Valadés AG, Méndez-Lucas A, Vidal-Alabró A, Blasco FX, Chillon M, Bartrons R, Bermúdez J, Perales JC. Pck1 gene silencing in the liver improves glycemia control, insulin sensitivity, and dyslipidemia in db/db mice.  Diabetes. 2008;  57 2199-2210
  • 30 Liu Y, Nakagawa Y, Wang Y, Liu L, Du H, Wang W, Ren X, Lufty K, Friedman TC. Reduction of hepatic glucocorticoid receptor and hexose-6-phosphate dehydrogenase expression ameliorates diet-induced obesity and insulin resistance in mice.  J Mol Endocrinol. 2008;  41 53-64
  • 31 Jiang W, Fiordeliso JJ, Allan G, Linton O, Tannenbaum P, Xu J, Zhu P, Gunnet J, Demarest K, Lundeen S, Sui Z. Discovery of novel phosphorus-containing steroids as selective glucocorticoid receptor antagonist.  Bioorg Med Chem Lett. 2007;  17 1471-1474
  • 32 Alberts P, Nilsson C, Selen G, Engblom LO, Edling NH, Norling S, Klingström G, Larsson C, Forsgren M, Ashkzari M, Nilsson CE, Fiedler M, Bergqvist E, Ohmen B, Bjorkstrand E, Abrahmsen LB. Selective inhibition of 11 beta-hydroxysteroid dehydrogenase type 1 improves hepatic insulin sensitivity in hyperglycemic mice strains.  Endocrinology. 2003;  144 4755-4762
  • 33 Picard F, Wanatabe M, Schoonjans K, Lydon J, O’Malley BW, Auwerx J. Progesterone receptor knockout mice have an improved glucose homeostasis secondary to β-cell proliferation.  Proc Natl Acad Sci USA. 2002;  99 15644-15648
  • 34 Langley SC, York, DA. Effects of antiglucocorticoid RU 486 on development of obesity in obese fa/fa Zucker rats.  Am J Physiol. 1990;  259 539-544
  • 35 Fried SK, Russell CD, Grauso NL, Brolin RE. Lipoprotein lipase regulation by insulin and glucocorticoid in subcutaneous and omental adipose tissues of obese women and men.  J Clin Invest. 1993;  92 2191-2198
  • 36 Ong JM, Simsolo RB, Saffari B, Kern PA. The regulation of lipoprotein lipase gene expression by dexamethasone in isolated rat adipocytes.  Endocrinology. 1992;  130 2310-2316
  • 37 Ottosson M, Mårin P, Karason K, Elander A, Björntorp P. Blockade of the glucocorticoid receptor with RU 486: effects in vitro and in vivo on human adipose tissue lipoprotein lipase activity.  J Clin Endocrinol Metab. 1995;  78 375-380
  • 38 Bailey CJ, Day C, Bray GA, Lipson LG, Flatt PR. Role of adrenal glands in the development of abnormal glucose and insulin homeostasis in genetically obese (ob/ob) mice.  Horm Metab Res. 1986;  18 357-360

Correspondence

V. A. Gault

The SAAD Centre for Pharmacy and Diabetes

School of Biomedical Sciences

University of Ulster

Coleraine BT52 1SA

Northern Ireland

UK

Phone: +28/7032 33 22

Fax: +28/7032 49 65

Email: va.gault@ulster.ac.uk

    >