Buradasınız

ROLE OF 11 β-HYDROXYSTEROID DEHYDROGENASE INHIBITORS IN METABOLIC SYNDROME AND ITS EXPANSION IN OTHER THERAPEUTIC OPTIONS

Journal Name:

Publication Year:

Abstract (2. Language): 
The metabolic syndrome is a constellation of interrelated metabolic risk factors that appear to promote the development of diabetes and cardiovascular disease. These risk factors include abdominal obesity, insulin resistance, hypertension and dyslipidemia. This article was aimed to review the pathophysiological and pharmaco therapeutic aspects of 11beta-Hydroxysteroid dehydrogenase (11beta-HSD). It catalyzes the interconversion of glucocorticoids through the activity of two isozymes: type 1 (11beta-HSD1) and type 2 (11beta-HSD2). 11beta-HSD1 converts inactive glucocorticoid to the active form, whereas 11beta-HSD2 converts active glucocorticoid to the inactive form. Glucocorticoids play a pivotal role in regulating fat metabolism, function and distribution. Evidence has accumulated that enzyme activity of 11beta-HSD1, which regenerates active glucocorticoids from inactive forms and plays a central role in regulating intracellular glucocorticoid concentration, is commonly elevated in fat depots from obese individuals. This suggests a role for local glucocorticoid reactivation in obesity and the Metabolic Syndrome. 11beta-HSD1 knockout mice resist visceral fat accumulation and insulin resistance even on a high-fat diet. In summary, 11beta-HSD1 is a promising pharmaceutical target for the treatment of the Metabolic Syndrome. Animal studies and pharmacological experiments suggest further unrelated target areas, for example improvement of cognitive function and treatment of glaucoma, osteoporosis due to the role of glucocorticoids and cellular activation by 11beta-HSD1 in these pathologies.
78
99

REFERENCES

References: 

1. Adcock IM, Cosio B, Tsaprouni L, Barnes
PJ, Ito K: Redox Regulation of Histone
Deacetylases and Glucocorticoid-Mediated
Inhibition of the Inflammatory Response.
Antioxidant & Redox Signaling 2005; 7(1-2):
144-152.
2. Adcock IM, Ito K, Barnes PJ
Glucocorticoids: Effects on Gene
Transcription. Proc. Am. Thorac.Soc. 2004;
1(3): 247-254.
3. Barnes PJ, Adcock I: Anti-inflammatory
actions of steroids: molecular mechanisms.
Trends. Pharmacol. Sci. 1993; 14(12): 436-
441.
4. Nonogaki K, Iguchi A: Role of central
neural mechanisms in the regulation of
hepatic glucose metabolism. Life Sci. 1997;
60(11): 797-807.
5. Agarwal AK, Monder C, Eckstein B, White
PC: Cloning and expression of rat cDNA
encoding corticosteroid 11 betadehydrogenase.
J. Biol. Chem. 1989;
264:18939–18943.
6. Albiston AL, Obeyesekere VR, Smith RE,
Krozowski ZS: Cloning and tissue
distribution of the human 11 betahydroxysteroid
dehydrogenase type 2
enzyme. Mol. Cell. Endocrinol. 1994; 105:
R11–R17.
7. Walker BR, JR Seckl: 11betahydroxysteroid
dehydrogenase type 1 as a
novel therapeutic target in metabolic and
Research Article CODEN: IJPRNK ISSN: 2277-8713
Vijaykumar Arumugam, IJPRBS, 2013; Volume 2(5):78-99 IJPRBS
Available Online at www.ijprbs.com
90
neurodegenerative disease. Expert Opin.
Ther. Targets 2003; 7: 771–783.
8. Masuzaki H, Flier JS. Tissue-specific
glucocorticoid reactivating enzyme, 11
beta-hydroxysteroid dehydrogenase type 1
(11 beta- HSD1)–a promising drug target for
the treatment of metabolic syndrome. Curr.
Drug Targets Immune Endocr. Metabol.
Disord. 2003; 3: 255–262.
9. Stewart PM: Tissue-specific Cushing’s
syndrome, 11betahydroxysteroid
dehydrogenases and the redefinition of
corticosteroid hormone action. Eur. J.
Endocrinol. 2003; 149: 163–168.
10. Stewart PM: Tissue-specific Cushing’s
syndrome uncovers a new target in treating
the metabolic syndrome- 11β-
hydroxysteroid dehydrogenase type 1. Clin.
Med. 2005; 5(2): 142-146.
11. Bahr V, Pfeiffer AF, Diederich S: The
metabolic syndrome x and peripheral
cortisol synthesis. Exp. Clin. Endocrinol.
Diabetes 2002; 110(7): 313-318.
12. Thieringer R, Hermanowski-Vosatka A:
Inhibition of 11β-HSD1 as a novel treatment
for the metabolic syndrome: do
glucocorticoids play a role?. Exp. Rev.
Cardiovasc.Ther. 2005; 3(5): 911-924.
13. Tomlinson JW, Walker EA, Bujalska IJ,
Draper N, Lavery GG, Cooper MS, et al: 11β-
Hydroxysteroid Dehydrogenase Type 1: A
Tissue-Specific Regulator of Glucocorticoid
Response. Endocr. Rev. 2004; 25(5): 831-
866.
14. Xiangdong Su, Nigel Vicker, Mark P:
Thomas, Fabienne Pradaux-Caggiano,
Heather Halem, Michael D. Culler, and Barry
V. L. Potter: Discovery of Adamantyl
Heterocyclic Ketones as Potent 11β-
Hydroxysteroid Dehydrogenase Type 1
Inhibitors. Chem. Med. Chem. 2011; 6: 1439
– 1451.
15. Walker BR, Connacher AA, Lindsay RM,
Webb DJ, Edwards CR: Carbenoxolone
increases hepatic insulin sensitivity in man:
a novel role for 11-oxosteroid reductase in
enhancing glucocorticoid receptor
activation. J. Clin. Endocrinol. Metab. 1995;
80: 3155–3159.
16. Seckl JR, Walker BR: 11beta
Hydroxysteroid dehydrogenase type 1—a
tissue-specific amplifier of glucocorticoid
action. Endocrinology 2001; 142: 1371–
1376.
17. Walker BR, Connacher AA, Lindsay RM,
Webb DJ, Edwards CR: Carbenoxolone
18. increases hepatic insulin sensitivity in
man: a novel role for 11-oxosteroid
reductase
19. in enhancing glucocorticoid receptor
activation. J. Clin. Endocrinol. Metab. 1995;
80: 3155–3159.
20. Jamieson PM, Walker BR, Chapman KE,
Andrew R, Rossiter S, Seckl JR: 11 betahydroxysteroid
dehydrogenase type 1 is a
Research Article CODEN: IJPRNK ISSN: 2277-8713
Vijaykumar Arumugam, IJPRBS, 2013; Volume 2(5):78-99 IJPRBS
Available Online at www.ijprbs.com
91
predominant 11 beta-reductase in the
intact perfused rat liver. J. Endocrinol. 2000;
165(3): 685-692.
21. Low SC, Chapman K.E, Edwards CR, Seckl
JR: 'Liver-type' 11β-hydroxysteroid
dehydrogenase cDNA encodes reductase
but not dehydrogenase activity in intact
mammalian COS-7 cells. J. Mol. Endocrinol.
1994; 13(2): 167-174.
22. Jamieson PM, Chapman KE, Edwards CR,
Seckl JR: 11 beta-hydroxysteroid
dehydrogenase is an exclusive 11 betareductase
in primary cultures of rat
hepatocytes: effect of physicochemical and
hormonal manipulations. Endocrinology
1995; 136(11): 4754-4761.
23. Voice MW, Seckl JR, Edwards CR,
Chapman KE: 11b-Hydroxysteroid
dehydrogenase type 1 expression in 2S
FAZA hepatoma cells is hormonally
regulated: a model system for the study of
hepatic glucocorticoid metabolism.
Biochem. J. 1996; 317(Pt 2): 621-625.
24. Kotelevtsev Y, Holmes MC, Burchell A,
Houston PM, Schmoll D , Jamieson P, et al:
11β-Hydroxysteroid dehydrogenase type 1
knockout mice show attenuated
glucocorticoid-inducible responses and
resist hyperglycemia on obesity or stress.
Proc. Natl. Acad. Sci. USA. 1997; 94(26):
14924-14929.
25. Hewitt KN, Walker EA, Stewart PM:
Hexose-6-phosphate dehydrogenase and
redox control of 11 beta hydroxysteroid
dehydrogenase type 1 activity.
Endocrinology 2005;146: 2539–2543.
26. Banhegyi G, Benedetti A, Fulceri R,
Senesi S: Cooperativity between 11betahydroxysteroid
dehydrogenase type 1 and
hexose-6-phosphate dehydrogenase in the
lumen of the endoplasmic reticulum. J. Biol.
Chem. 2004; 279: 27017–27021.
27. Atanasov AG, Nashev LG, Schweizer
RAS, Frick C, Odermatt A: Hexose-6-
phosphate dehydrogenase determines the
reaction direction of 11betahydroxysteroid
Dehydrogenase type 1 as an oxoreductase.
FEBS Lett. 2004; 571(1-3): 129–133.
28. Thieringer R, Le Grand CB, Carbin L, Cai
TQ, Wong B, Wright SD, et al.: 11beta-
Hydroxysteroid dehydrogenase type 1 is
induced in human monocytes upon
differentiation to macrophages. J. Immunol.
2001; 167: 30–35.
29. Hammani MM, Siiteri PK: Regulation of
11 beta hydroxysteroid dehydrogenase
activity in human skin fibroblasts: enzymatic
modulation of glucocorticoid action. J. Clin.
Endocrinol. Metab. 1991; 73: 326–334.
30. Moore JS, Monson JP, Kaltsas G,
Putignano P, Wood PJ, Sheppard MC, et al:
Modulation of 11 beta hydroxysteroid
dehydrogenase isozymes by growth
hormone and insulin-like growth factor: in
vivo and in vitro studies. J. Clin. Endocrinol.
Metab. 1999; 84(11): 4172– 4177.
Research Article CODEN: IJPRNK ISSN: 2277-8713
Vijaykumar Arumugam, IJPRBS, 2013; Volume 2(5):78-99 IJPRBS
Available Online at www.ijprbs.com
92
31. Trainer PJ, Drake WM, Perry LA, Taylor
NF, Besser GM, Monson JP: Modulation of
cortisol metabolism by the growth hormone
receptor antagonist pegvisomant in
patients with acromegaly. J. Clin.
Endocrinol. Metab. 2001; 86: 2989–2992.
32. Berger J, Tanen M, Elbrecht A,
Hermanowski-Vosatka A, Moller DE, Wright
SD. Peroxisome proliferatoractivated
receptor-ligands inhibit adipocyte 11betahydroxysteroid
dehydrogenase type 1
expression and activity. J. Biol. Chem. 2001;
276: 12629–12635.
33. Hermanowski-Vosatka A, Gerhold D,
Mundt SS, Loving VA, Lu M, Y Chen, et al:
PPARalpha agonists reduce 11betahydroxysteroid
dehydrogenase type 1 in the
liver. Biochem. Biophy. Res. Commun. 2000;
279(2): 330–336.
34. Hermanowski-Vosatka A, David G,
Steven SM, Vilert AL, Meiqing L, Yuli C, et al:
PPAR alpha agonists reduce 11betahydroxysteroid
dehydrogenase type 1 in the
liver. Biochem. Biophy. Res. Commun. 2002;
279(2): 330–336.
35. Morton NM, Ramage L, Seckl JR: Downregulation
of adipose 11 beta
hydroxysteroid dehydrogenase type 1 by
high-fat feeding in mice: a potential
adaptive mechanism counteracting
metabolic disease. Endocrinology 2004;
145: 2707–2712.
36. Bujalska IJ, Walker EA, Hewison M,
Stewart PM: A Switch in Dehydrogenase to
Reductase Activity of 11β-Hydroxysteroid
Dehydrogenase Type 1 upon Differentiation
of Human Omental Adipose Stromal Cells.
J.Clin.Endocrinol. Metab. 2002; 87(3): 1205-
1210.
37. 35.Bujalska IJ, Walker EA, Tomlinson JW,
Hewison M, Stewart PM: 11β-
hydroxysteroid dehydrogenase type 1 in
differentiating omental human
preadipocytes: from de-activation to
generation of cortisol. Endocr. Res. 2002;
28(4): 449-461.
38. Tomlinson JW, Sinha B, Bujalska I,
Hewison M, Stewart PM: Expression of
11β-Hydroxysteroid Dehydrogenase Type 1
in Adipose Tissue Is Not Increased in Human
Obesity. J. Clin. Endocrinol. Metab. 2002;
87(12): 5630-5635.
39. Tomlinson JW, Moore J, Cooper MS,
Bujalska I, Shahmanesh M, Burt C, et al:
Regulation of Expression of 11β-
Hydroxysteroid Dehydrogenase Type 1 in
Adipose Tissue: Tissue-Specific Induction by
Cytokines. Endocrinology 2001; 142(5):
1982-1989.
40. Franks PW, Knowler WC, Nair S, Koska J,
Lee YH, Lindsay RS, et al: Interaction
between an 11betaHSD1 gene variant and
birth era modifies the risk of hypertension
in Pima Indians. Hypertension 2004; 44:
681–688.
41. Caramelli E, Strippoli P, Giacomi T DI,
Catleen T, Paolo C, Renato P: Lack of
mutations of type 1 11[beta]-
Research Article CODEN: IJPRNK ISSN: 2277-8713
Vijaykumar Arumugam, IJPRBS, 2013; Volume 2(5):78-99 IJPRBS
Available Online at www.ijprbs.com
93
hydroxysteroid dehydrogenase gene in
patients with abdominal obesity. Endocr.
Res. 2001; 27(1-2): 47–61.
42. Draper N, Echwald SM, Lavery GG,
Walker EA, Fraser R, Davies E, et al:
Association studies between microsatellite
markers within the gene encoding human
11betahydroxysteroid dehydrogenase type
1 and body mass index, waist to hip ratio,
and glucocorticoid metabolism. J. Clin.
Endocrinol. Metab. 2002; 87(11): 4984–
4990.
43. Gelernter-Yaniv L, Feng N, Sebring NG,
Hochberg Z, Yanovski JA: Associations
between polymorphism in the 11 beta
hydroxysteroid dehydrogenase type I gene
and body composition. Int. J. Obes. Relat.
Metab. Disord. 2003; 27: 983–986.
44. Schadt EE, Lamb J, Yang X, Zhu J,
Edwards S, Guhathakurta D, et al: An
integrative genomics approach to infer
causal associations between gene
expression and disease. Nat. Genet. 2005;
37: 710–717.
45. Otieno CJ, Bastiaansen J, Ramos AM,
Rothschild MF: Mapping and association
studies of diabetes related genes in the pig.
Anim. Genet.2005; 36: 36–42.
46. Reus VI, Wolkowitz OM:
Antiglucocorticoid drugs in the treatment of
depression. Expert Opin. Investig. Drugs
2001; 10: 1789–1796.
47. Reus VI, Wolkowitz OM:
Antiglucocorticoid treatment of depression:
double-blind ketoconazole. Biol. Psychol.
1999; 45: 1070–1074.
48. Gaillard RC, Poffet D, Riondel AM,
Saurat JH: RU486 inhibits peripheral effects
of glucocorticoids in humans. J. Clin.
Endocrinol. Metab. 1985; 61: 1009–1011.
49. Jacobson PB, von Geldern TW, Ohman L,
Osterland M, Wang J, Zinker B, et al:
Hepatic glucocorticoid receptor antagonism
is sufficient to reduce elevated hepatic
glucose output and improve glucose control
in animal models of type 2 diabetes. J.
Pharmacol. Exp. Ther. 2005; 314: 191–200.
50. Stewart PM, Wallace AM, Atherden SM,
Shearing CH, Edwards CRW:
Mineralocorticoid activity of
carbenoxolone: contrasting effects of
carbenoxolone and liquorice on 11 beta
hydroxysteroid dehydrogenase activity in
man. Clin. Sci. 1990; 78(1): 49– 54.
51. Andrew R, Smith K, Jones GC, Walker
BR: Distinguishing the activities of 11 beta
hydroxysteroid dehydrogenases in vivo
using isotopically labeled cortisol. J. Clin.
Endocrinol. Metab. 2002; 87: 277–285.
52. Andrews RC, Rooyackers O, Walker BR:
Effects of the 11 beta hydroxysteroid
dehydrogenase inhibitor carbenoxolone on
insulin sensitivity in men with type 2
diabetes. J. Clin. Endocrinol. Metab. 2003;
88: 285–291.
Research Article CODEN: IJPRNK ISSN: 2277-8713
Vijaykumar Arumugam, IJPRBS, 2013; Volume 2(5):78-99 IJPRBS
Available Online at www.ijprbs.com
94
53. Livingstone DE, Walker BR: Is 11 beta
hydroxysteroid dehydrogenase type 1 a
therapeutic target? Effects of
carbenoxolone in lean and obese Zucker
rats. J. Pharmacol. Exp. Ther. 2003; 305:
167–172.
54. Li RS, Nakagawa Y, Nakanishi T, Fujisawa
Y, Ohzeki T. Different responsiveness in
55. body weight and hepatic 11betahydroxysteroid
dehydrogenase (11beta-
HSD) type 1 mrna to 11beta-HSD inhibition
by glycyrrhetinic acid treatment in obese
and lean zucker rats. Metabolism 2004; 53:
600–606.
56. Barf T, Vallgarda J, Emond R, Häggström
C, Kurz G, Nygren A, et al:
Arylsulfonamidothiazoles as a new class of
potential antidiabetic drugs. Discovery of
potent and selective inhibitors of the 11
beta hydroxysteroid dehydrogenase type 1.
J. Med. Chem. 2002; 45: 3813–3815.
57. Xiang J, Ipek M, Suri V, Massefski W, Pan
N, Ge Y, et al: Synthesis and biological
evaluation of sulfonamidooxazoles and keto
sulfones: selective inhibitors of 11 betahydroxysteroid
dehydrogenase type 1.
Bioorg. Med. Chem. Lett. 2005; 15: 2865–
2869.
58. Hult M, Jornvall H, ppermann UCT:
Selective inhibition of human type 1 11bhydroxysteroid
dehydrogenase by synthetic
steroids and xenobiotics. Fed. Eur. Biochem.
Stud. 1998; 441: 25–28.
59. Alberts P, Engblom L, Edling N, Forsgren
M, Klingstrom G, Larsson C, et al: Selective
inhibition of 11betahydroxysteroid
dehydrogenase type 1 decreases blood
glucose concentrations in hyperglycaemic
mice. Diabetologia. 2002; 45(11): 1528–
1532.
60. Alberts P, Nilsson C, Selen G, Engblom
LO, Edling NH, Norling S, et al: Selective
inhibition of 11 beta hydroxysteroid
dehydrogenase type 1 improves hepatic
insulin sensitivity in hyperglycaemic mice
strains. Endocrinology 2003; 144: 4755–
4762.
61. Hermanowski-Vosatka A, Balkovec JM,
Cheng K, Chen HY, Hernandez M, Koo GC,
et al: 11 beta HSD1 inhibition ameliorates
metabolic syndrome and prevents
progression of atherosclerosis in mice. J.
Exp. Med. 2005; 202: 517–527.
62. Walker BR, Yau JL, Brett LP, Seckl JR,
Monder C, Williams BC, et al: 11 beta-
Hydroxysteroid dehydrogenase in vascular
smooth muscle and heart: implications for
cardiovascular responses to glucocorticoids.
Endocrinology 1991; 129: 3305–3312.
63. Hadoke PWF, Christy C, Kotelevtsev YV,
Brent CW, Christopher JK, Jonathan RS, et
al: Endothelial cell dysfunction in mice after
transgenic knockout of type 2, but not type
1, 11beta- hydroxysteroid dehydrogenase.
Circulation. 2001; 104(23): 2832–2837.
64. Small GR, Hadoke PW, Sharif I, Dover
AR, Armour D, Kenyon CJ, et al: Preventing
Research Article CODEN: IJPRNK ISSN: 2277-8713
Vijaykumar Arumugam, IJPRBS, 2013; Volume 2(5):78-99 IJPRBS
Available Online at www.ijprbs.com
95
regeneration of glucocorticoids by 11 beta
hydroxysteroid dehydrogenase type 1
enhances angiogenesis. Proc. Natl. Acad.
Sci. USA 2005; 102: 12165–12170.
65. Thieringer R, Hermanowski-Vosatka A:
Inhibition of 11β-HSD1 as a novel treatment
for the metabolic syndrome: do
glucocorticoids play a role?. Exp. Rev.
Cardiovasc. Ther. 2005; 3(5): 911-924.
66. Wang MS, Shi H, Wang KS, Reidenberg
MM: Inhibition of 11β-hydroxysteroid
dehydrogenase in guinea pig kidney by
three bioflavonoids and their interactions
with gossypol. Acta Pharmacol. Sin. 2002;
23(1), 92-96.
67. Thieringer R, Le Grand CB, Carbin L, Cai
TQ, Wong B, Wright SD, et al: 11beta-
Hydroxysteroid dehydrogenase type 1 is
induced in human monocytes upon
differentiation tomacrophages. J. Immunol.
2001; 167: 30–35.
68. Walker BR, Yau JL, Brett LP, Seckl JR,
Monder C, Williams BC, et al: 11 beta
Hydroxysteroid dehydrogenasein vascular
smooth muscle and heart: implications for
cardiovascular responses to glucocorticoids.
Endocrinology 1991; 129: 3305–3312.
69. Hadoke PWF, Christy C, Kotelevtsev YV,
Williams BC, Kenyon CJ, Seckl JR, et al:
Endothelial cell dysfunction in mice after
transgenic knockout of type 2, but not type
1, 11 beta hydroxysteroid dehydrogenase.
Circulation 2001; 104(23):2832–2837.
70. Small GR, Hadoke PW, Sharif I, Dover
AR, Armour D, Kenyon CJ, et al: Preventing
regeneration of glucocorticoids by 11 beta
hydroxysteroid dehydrogenase type 1
enhances angiogenesis. Proc. Natl. Acad.
Sci. USA 2005; 102: 12165–12170.
71. Harris HJ, Kotelevtsev YV, Mullins JJ,
Seckl JR, Holmes MC: Intracellular
Regeneration of Glucocorticoids by 11β-
Hydroxysteroid Dehydrogenase (11β-HSD)-1
Plays a Key Role in Regulation of the
Hypothalamic-Pituitary-Adrenal Axis:
Analysis of 11β-HSD-1-Deficient Mice.
Endocrinology 2001; 142(1): 114–120.
72. Yau JL, Noble J, Kenyon CJ, Hibberd C,
Kotelevtsev Y, Mullins JJ, et al: Lack of tissue
glucocorticoid reactivation in 11 beta
hydroxysteroid dehydrogenase type 1
knockout mice ameliorates age-related
learning impairments. Proc. Natl. Acad. Sci.
USA 2001; 98(8): 4716–4721.
73. Sandeep TC, Yau JL, MacLullich AM,
Noble J, Deary IJ, Walker BR, et al: 11 beta
hydroxysteroid dehydrogenase inhibition
improves cognitive function in healthy
elderly men and type 2 diabetics. Proc. Natl.
Acad. Sci. USA 2004; 101: 6734–6739.
74. Stulnig TM, Oppermann U, Steffensen
KR, Schuster GU, Gustafsson JA: Diabetes
2002; 51(8): 2426-2433.
75. Cao G, Liang Y, Broderick CL, Oldham
BA, Beyer TP, Schmidt RJ, et al: Antidiabetic
Action of a Liver X Receptor Agonist
Mediated By Inhibition of Hepatic
Research Article CODEN: IJPRNK ISSN: 2277-8713
Vijaykumar Arumugam, IJPRBS, 2013; Volume 2(5):78-99 IJPRBS
Available Online at www.ijprbs.com
96
Gluconeogenesis. J. Biol. Chem. 2003;
278(2): 1131-1136.
76. Laffitte BA , Chao LC, Li J, Walczak R,
Hummasti S, Joseph SB, et al: Activation of
liver X receptor improves glucose tolerance
through coordinate regulation of glucose
metabolism in liver and adipose tissue.
Proc. Natl. Acad. Sci. USA 2003; 100(9):
5419-5424.
77. Kurukulasuriya R, Link JT, Madar DJ, Pei
Z, Richards SJ, Rohde J , et al: Potential
drug targets and progress towards
pharmacologic inhibition of hepatic glucose
production. Curr. Med. Chem. 2003; 10(2):
123-153.
78. Link JT: Pharmacological regulation of
hepatic glucose production. Curr. Opin.
Investig. Drugs 2003; 4(4): 421-429.
79. Jacobson PB, von Geldern TW, Ohman L,
Osterland M, Wang J, Zinker B, et al:
Hepatic Glucocorticoid Receptor
Antagonism Is Sufficient to Reduce Elevated
Hepatic Glucose Output and Improve
Glucose Control in Animal Models of Type 2
Diabetes. J. Pharmacol. Exp. Ther. 2005;
314(1): 191-200.
80. Valsamakis G, Anwar A, Tomlinson JW,
Shackleton CH, McTernan PG, Chetty R, et
al: 11β-Hydroxysteroid Dehydrogenase
Type 1 Activity in Lean and Obese Males
with Type 2 Diabetes Mellitus. J. Clin.
Endocrinol. Metab. 2004; 89(9): 4755-4761.
81. Basu R, Singh RJ, Basu A, Chittilapilly EG,
Johnson CM, Toffolo G, et al: Splanchnic
cortisol production occurs in humans –
evidence for conversion of cortisone to
cortisol via the 11 beta hydroxysteroid
dehydrogenase type 1 pathway. Diabetes
2004; 53: 2051–2059.
82. Liu Y, Nakagawa Y, Wang Y, Li R, Li X, T
Ohzeki et al: Leptin activation of
corticosterone production in hepatocytes
may contribute to the reversal of obesity
and hyperglycemia in leptin-deficient ob/ob
mice. Diabetes 2003; 52(6): 1409–1416.
83. Tomlinson JW, Moore JS, Clark PM,
Holder G, Shakespeare L, Stewart PM, et al:
Weight loss increases 11betahydroxysteroid
dehydrogenase type 1
expression in human adipose tissue. J. Clin.
Endocrinol. Metab. 2004; 89: 2711–2716.
84. Engeli S, Böhnke J, Feldpausch M,
Gorzelniak K, Heintze U, Janke J, et al:
Regulation of 11 beta hydroxysteroid
dehydrogenase genes in human adipose
tissue: influence of central obesity and
weight loss. Obes. Res. 2004; 12: 9–17.
85. De Kloet, Vreugdenhil ER: Stress in the
brain. Eur. J. Pharmacol.2000; 405(1-3):
187-198.
86. De Kloet, Vreugdenhil ER: Hormones
and the stressed brain. Ann. N.Y. Acad. Sci.
2004(1018): 1-15.
87. De Kloet, Vreugdenhil ER, Oitzl E, Joels
M: Brain Corticosteroid Receptor Balance in
Research Article CODEN: IJPRNK ISSN: 2277-8713
Vijaykumar Arumugam, IJPRBS, 2013; Volume 2(5):78-99 IJPRBS
Available Online at www.ijprbs.com
97
Health and Disease. Endocr. Rev. 1998;
19(3): 269-301.
88. Moisan MP, Seckl JR: Edwards CR. 1lβ-
Hydroxysteroid Dehydrogenase Bioactivity
and Messenger RNA Expression in Rat
Forebrain: Localization in Hypothalamus,
Hippocampus, and Cortex. Endocrinology
1990; 127(3): 1450-1455.
89. Low SC, Moisan MP, Noble JM, Edwards
CR, Seckl JR: Glucocorticoids Regulate
Hippocampal 11β-Hydroxysteroid
Dehydrogenase Activity and Gene
Expression in vivo in the Rat. J.
Neuroendocrinol. 1994; 6(3): 285-290.
90. Rajan V, Edwards CR, Seckl JR: 11 beta-
Hydroxysteroid dehydrogenase in cultured
hippocampal cells reactivates inert 11-
dehydrocorticosterone, potentiating
neurotoxicity. J. Neurosci. 1996; 16(1): 65-
70.
91. Yau JL, Noble J, Kenyon CJ, Hibberd C,
Kotelevtsev Y, Mullins JJ, et al: Lack of
tissue glucocorticoid reactivation in 11β-
hydroxysteroid dehydrogenase type 1
knockout mice ameliorates age-related
learning impairments. Proc. Natl. Acad. Sci.
USA 2001; 98(8): 4716-4721.
92. Sandeep TC, Yau JL, MacLullich AM,
Noble J, Deary IJ, Walker BR, et al: 11β-
Hydroxysteroid dehydrogenase inhibition
improves cognitive function in healthy
elderly men and type 2 diabetics. Proc. Natl.
Acad. Sci. USA.2004; 101(17): 6734-6739.
93. de Quervain DJ, Poirier R, Wollmer MA,
Grimaldi LM, Tsolaki M, Streffer JR, et al:
Glucocorticoid-related genetic susceptibility
for Alzheimer's disease. Hum. Mol.
Genet.2004; 13(1): 47-52.
94. Rauz S, Walker EA, Shackleton CH,
Hewison M, Murray PI, Stewart PM:
Expression and Putative Role of 11β-
Hydroxysteroid Dehydrogenase Isozymes
within the Human Eye. Invest. Ophthalmol.
Vis. Sci.2001; 42(9): 2037-2042.
95. Rauz S, Cheung CM, Wood PJ, Coca-
Prados M, Walker EA, Murray P I, et al:
Inhibition of 11β-hydroxysteroid
dehydrogenase type 1 lowers intraocular
pressure in patients with ocular
hypertension. QJM 2003; 96(7): 481-490.
96. Barnes PJ, Adcock IM. How Do
Corticosteroids Work in Asthma? Ann.
Intern. Med. 2003; 139(5 Pt1): 359-370.
97. Barnes PJ, Adcock IM: Steroid resistance
in asthma. QJM 1995; 88(7): 455-468.
98. Wilckens T: Glucocorticoids and immune
function: physiological relevance and
pathogenic potential of hormonal
dysfunction. Trends Pharmacol. Sci. 1995;
16(6): 193-197.
99. Wilckens T, De Rijk R: Glucocorticoids
and immune function: unknown dimensions
and new frontiers. Immunol. Today 1997;
18(9): 418-424.
100. Munck A, Naray-Fejes-Toth A: The ups
and downs of glucocorticoid physiology
Research Article CODEN: IJPRNK ISSN: 2277-8713
Vijaykumar Arumugam, IJPRBS, 2013; Volume 2(5):78-99 IJPRBS
Available Online at www.ijprbs.com
98
Permissive and suppressive effects
revisited. Mol. Cell Endocrinol 1992; 90(1):
C1-4.
101. Zhou Z, Shackleton CH, Pahwa S,
White PC, Speiser PW: Prominent sex
steroid metabolism in human lymphocytes.
Mol. Cell Endocrinol. 1998; 138(1-2): 61-69.
102. Hennebold JD, Ryu SY, Mu HH,
Galbraith A, Daynes RA: 11 betahydroxysteroid
dehydrogenase modulation
of glucocorticoid activities in lymphoid
organs. Am. J. Physiol. 1996; 270(6 Pt 2):
R1296-1306.
103. Freeman L, Hewison M, Hughes SV,
Evans KN, Hardie D, Means TK, et al:
Expression of 11β-hydroxysteroid
dehydrogenase type 1 permits regulation of
glucocorticoid bioavailability by human
dendritic cells. Blood 2005; 106(6): 2042-
2049.
104. Teelucksingh S, Mackie AD, Burt D,
McIntyre MA, Brett L, Edwards CR:
Potentiation of hydrocortisone activity in
skin by glycyrrhetinic acid. Lancet 1990;
335(8697): 1060-1063.
105. Hennebold JD, Mu HH, Poynter ME,
Chen XP, Daynes RA: Active catabolism of
glucocorticoids by 11 beta-hydroxysteroid
dehydrogenase in vivo is a necessary
requirement for natural resistance to
infection with Listeria monocytogenes. Int.
Immunol. 1997; 9(1): 105-115.
106. Manelli F, Giustina A: Glucocorticoidinduced
osteoporosis. Trends. Endocrinol.
Metab. 2000; 11(3): 79-85.
107. Doga M, Bonadonna S, Burattin A,
Carpinteri R, Manelli F, Giustina A:
Bisphosphonates in the treatment of
glucocorticoid-induced osteoporosis. Front.
Horm. Res. 2002; 30: 150-164.
108. Cooper MS, Rabbitt EH, Goddard PE,
Bartlett WA, Hewison M, Stewart PM: 11β-
Hydroxysteroid Dehydrogenase Type 1
Activity Increases With Age and
Glucocorticoid Exposure. J. Bone Miner.
Res. 2002; 17(6): 979-986.
109. Cooper MS, Walker EA, Bland R, Fraser
WD, Hewison M, Stewart PM: Expression
and functional consequences of 11β-
hydroxysteroid dehydrogenase activity in
human bone. Bone 2000; 27(3): 375-381.
110. Cooper MS, Blumsohn A, Goddard PE,
Bartlett WA, Shackleton CH, Eastell R, et al:
11β-Hydroxysteroid Dehydrogenase Type 1
Activity Predicts the Effects of
Glucocorticoids on Bone. J. Clin. Endocrinol.
Metab. 2003; 88(8): 3874-3877.
111. Justesen J, Mosekilde L, Holmes M,
Stenderup K, Gasser J, Mullins JJ, et al: Mice
Deficient in 11β-Hydroxysteroid
Dehydrogenase Type 1 Lack Bone Marrow
Adipocytes, but Maintain Normal Bone
Formation. Endocrinology 2004; 145(4):
1916-1925.

Thank you for copying data from http://www.arastirmax.com