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Glucocorticoid generation in the adrenals and
adipose tissue in obesity
Brian Walker Endocrinology UnitUniversity of Edinburgh
Cushing’s or Metabolic Syndrome?
• Similarities
• The clinical problem – telling them apart
• Does cortisol contribute to Metabolic Syndrome?
• Can manipulating cortisol treat Metabolic Syndrome?
?�Cardiovascular Disease
��+ other features
��Glucose
intolerance
��Hypertension
��Dyslipidaemia
+ Two from:
��Central obesity
Cushing’s
Syndrome
Metabolic
Syndrome (IDF)
RR (95%CI)
106421.6.4.2.1
1.52 (1.47-1.58)
1.78 (1.69-1.87)
4.83 (4.24-5.51)
1.00
Low topical
Medium <7.5
High >7.5
NoneCrude
MEMO
Dose of glucocorticoids and all cardiovascular events
0.99 (0.95-1.03)
1.03 (0.96-1.10)
2.70 (2.33-3.13)
1.00Low
Medium
High
NoneAdjusted*
*Age, gender, social deprivation, cardiovascular drug use, HRT & OCP, NSAIDs, DMARDs, bronchodilators, non-cardiovascular hospitalisation in the 6 months prior to study entry, diabetes mellitus, cancer, renal disease, interaction between exposure and cardiovascular drug use, propensity score
Wei et al Ann Int Med 2004
Cushing’s or Metabolic Syndrome?
• Similarities
• The clinical problem – telling them apart
• Does cortisol contribute to Metabolic Syndrome?
• Can manipulating cortisol treat Metabolic Syndrome?
HPA axis abnormalities in Metabolic Syndrome
• + Increased urinary free cortisol excretion› Marin Metabolism 1992; Pasquali JCEM 1993
• + Loss of diurnal cortisol variation› Rosmond JCEM 1998
• (Increased responses to CRH/AVP and ACTH)› Pasquali Horm Metab Res 2000
• Normal response to dexamethasone at conventional doses
› Chalew Obes Res 1995; Pasquali JCEM 2002
Conclusion – how do you tell?
• Use dexamethasone suppression at conventional doses
Pasquali, R. et al. J Clin Endocrinol Metab 2002;87:166-175
n=13 n=21n=36 n=51
Variation in cortisol suppression explained by:
• Gender• [dexamethasone]• not BMI
Cushing’s or Metabolic Syndrome?
• Similarities
• The clinical problem – telling them apart
• Does cortisol contribute to Metabolic Syndrome?
• Can manipulating cortisol treat Metabolic Syndrome?
Blood cortisol and cardiovascular risk
Umea
Edinburgh
Sheffield
London
Hertfordshire
Preston
Uppsala
Phoenix
Plasma [cortisol] and cardiovascular risk factors
1.8
2
2.2
2.4
<250 -300 -350 -400 >400 All
120
140
160
180
200
Fasting120 min in OGTT
5
5.5
6
6.5
7
7.5
0.95
1.05
1.15
1.25
1.35
1.45
1.55
1.65
<250 -300 -350 -400 >400 All
Systolic blood pressure
(mmHg)
Plasma glucose
se Triglyceride Insulin resistance
(HOMA index)
p<0.03 p<0.001
p<0.04
p<0.05 p<0.03
<250 -300 -350 -400 >400 All <250 -300 -350-400 >400 All
Fasting 0900 h plasma [cortisol] (nM)
84 6662
6395
370
Phillips et al JCEM 1998
Cortisol metabolites & familial BP
5ß-THF
5α-THF
THE
0
1
2
3
4
5U
rinary
excre
tion (
mg/d
ay) NS *
*
C Low Low
D Low High
AHigh Low
B High High
Offspring Parents
O A BC D
P
F E
5βTHF 5αTHF THE
Walker et al Hypertension 1998
HPA axis in leaninsulin resistance syndrome
ACTH
Cortisol
CRH
Central drive
Negative
Feedback
(dexamethasone)
NORMAL
Habituation
IMPAIRED
• Stress?
• Programming?
SynACTHen response
ENHANCED
Reynolds JCEM 2001a, 2001b
Brunner Circulation 2002
Phillips Hypertension 2000Amplified by obesity?
Cortisol in obesity in men
N Sweden (28-65 y) n=33 p<0.01
Preston (47-56 y) n=31 p=0.30
Sheffield (69-74y) n=87 p<0.02
Hertfordshire (60-65y) n=140 p=0.06
Overall r=+0.19, 217µg/cm, p<0.001
Waist circumference (cm)
Total cortisol metabolites (mg/d)
0
10
20
30
40
50
70 80 90 100 110 120 130
0900 h plasma [cortisol] (nM)
0
200
400
600
800
1000
60 70 80 90 100 110 120 130 140
Waist circumference (cm)
N Sweden (25-65 y) n=147 p=0.67
Preston (45-55 y) n=133 p<0.01
Hertfordshire (60-65 y) n=203 p=0.06
Overall r=-0.17, 2nM/cm, p<0.001
5α-Reductase 1 is increased in obesity
0
0.5
1
1.5
2
Lean Obese
mRNA
0.0
0.2
0.4
0.6
0.8
1.0
Lean Obese
protein
* *
0
0.05
0.10
0.15**
5alpha-D4-Cortisol
Excretion
Human Zucker obese rat
Lean Obese
Consequences of enhanced cortisol clearancein obesity
ACTH
Cortisol
CRH
Central drive
Negative
Feedback
Clearance5α-Reductase 1
Adrenal Androgens
GR activation?
Cushing’s or Metabolic Syndrome?
• Similarities
• The clinical problem – telling them apart
• Does cortisol contribute to Metabolic Syndrome?
• Can manipulating cortisol treat Metabolic Syndrome?
Hypothalamic-pituitary-adrenal-tissue axis
ACTH
Cortisol
CRH
Central drive
Negative
Feedback
Tissue responses
Steroid hormone action
11β-HSD2 in kidneyStewart, Edwards et al.
Cortisol (F)
Cortisone (E)
MR
F
E
11HSD2
Na retentionHypertension
Congenitaldeficiency
Inhibitionwith liquorice
Impaired in 1/3
of patients
with hypertension
F
E
11HSD1
LiverAdipose
CNS
GR
Cortisol (F)
Cortisone (E)
MR
F
E
11HSD2
Kidney
Lessons from 11HSD1 transgenic mice
non-Tg Tg
AP2-11HSD1 TGMasuzaki Science 2001
• Obese
• Hypertensive
• Diabetic
wild type
11ß-HSD1-/-
1412108642025
30
35
40
45
weeks on high fat diet
weig
ht
(g)
** *
*
11HSD1 ‘knockouts’Kotelevtsev PNAS 1997
Morton Diabetes 2004
Protected from:
• Obesity
• Diabetes
• dyslipidaemia80
100
120
140
160
180
12:00 pm12:00 am12:00 pm12:00 am12:00 pm12:00 am
• hypertensive• Fatty liver• hyperinsulinaemic• dyslipidaemia• not obese• not diabetic
ApoE-11HSD1 TGPaterson PNAS 2004
Quantifying cortisol regeneration in humans
O
HO OHCO
CH2OH
O
OHCO
CH2OH
D
CH2OH
O
OHCO
O
CH2OH
O
OHCO
O
OH
O
HOCO
CH2OH
O
CO
CH2OH
D4 cortisol
D3 cortisone
D3 cortisol
D
D2
D
D2
D
D2
Andrew et al JCEM 2002
0
2
4
6
8
10
Placebo CBX
D3-cortisol production
nmol/min
Regional cortisol production in humans
Cortisol
Cortisone
D4-Cortisol
D4-Cortisol
D3-Cortisone
D3-Cortisol
Visceralfat
other
Fat
etc
Liver
Kidney
Adrenals
~38 nmol/min
~11 nmol/min
Basu et al
Diabetes 2004
Cortisone
~15 nmol/min
~30 nmol/min
[Cortisol] 118nM
[Cortisol]
155nM
45 nmol/min
Andrew et al
Diabetes 2005
~2nmol/
min/kg
Andersson et al
unpublished
Highest
100
300
500
700
0 60 120 180 240
Time after oral cortisone (min)
Plasma cortisol (nmol/L)
LowestMiddle34 (16) men in
tertiles of BMI:
Tissue-specific dysregulationof 11-HSD1 in obese men
Liver
0
5
10
15
20
25
30
35
40
0 3 6 20 30
Incubation time (h)
%11-HSD1 activity
sc adipose tissue
Rask et al. JCE&M 2001
SC adipose 11HSD1 in obesity - microdialysis
Skin
Adiposeinterstitial
fluid
Tracer3Hcortisone Analysis
3Hcortisol
Dialysismembrane
3H4-cortisone
to 3H4-cortisol
0
10
20
30
40
Lean Obese
*
Sandeep et al Diabetes 2005
11HSD1 in human obesity
cortisol
cortisone
11HSD1
Carbenoxolone
2
2
C O H
C H
C H
C O
O
2
H
CO H
O
2
Drug discovery
Potent selective inhibitors of 11HSD1 in mice
eg Biovitrum/Amgen, Merck, Johnson & Johnson, Wyeth, Abbott ….
• Lower blood glucose in KKAy, ob/ob, db/db, DIO
• Lower body weight
• Atheroprotective eg in ApoE -/- mice
Alberts et al Diabetologia 2002; Endocrinology 2003;
Vosatka J Exp Med 2005
Clinical
DevelopmentTarget Biology
Lead
Finding
In vitro
& In Vivo
Models
Drug
Candidate
Lead
Optimisation
Key points
• Glucocorticoids cause cardiovascular disease
• Dexamethasone discriminates Cushing’s vs Metabolic Syndrome
• Plasma cortisol:
› elevated in Metabolic Syndrome
› lower in obesity
• Liver glucocorticoid action depends on:
› 11HSD1 in visceral adipose
› 5α-reductase 1 in liver?
• 11HSD1 generates more cortisol within adipose tissue in obesity
• 11HSD1 inhibitors may be useful in Metabolic Syndrome
Thanks!Edinburgh
Jonathan Seckl
Nik Morton
John Mullins
Ruth Andrew
Dawn Livingstone
Paddy Hadoke
Natalie Homer
Ken Smith
Rob Andrews
Greg Jones
Rebecca Reynolds
Thekkepat Sandeep
Gary Small
Debbie Wake
Alison Ayres
Wendy Barron
Jill Campbell
Scott Denham
UmeaTommy Olsson
Stefan Soderberg
et al
PhoenixAntonio Tataranni
Paska PermanaRobbie Lindsay
SouthamptonDavid Phillips
Cyrus Cooper
Utrecht
Tjeerd van StaaPatrick Souverein
HelsinkiHannele Yki-Jarvinen
Jukka WesterbackaJussi Sutinen
StockholmJohn Wahren
Dundee
Tom MacDonald
Li Wei
LondonEric Brunner
Michael Marmot
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