Cortisol— cause and cure for metabolic syndrome?

Cortisol
Special
Oxford, report
Diabetic
DME Report
Blackwell
0742-3071
23 and
UK metabolicLtd
Medicine
Publishing
Publishing, syndrome B. R. Walker
2006

B. R. Walker

Endocrinology Unit, Centre for Cardiovascular
Science, University of Edinburgh, Queen’s Medical
Research Institute, Edinburgh, UK
Accepted 3 July 2006
Abstract
Similarities between the metabolic syndrome and Cushing’s syndrome, and
reversibility of the features of Cushing’s syndrome, suggest that cortisol may
contribute to the pathophysiology of both conditions and that reducing cortisol
action may provide a novel therapeutic approach in the metabolic syndrome.
There is substantial evidence that circulating cortisol concentrations are higher
in people with hypertension and glucose intolerance. The basis for this activation
of the hypothalamic–pituitary–adrenal axis remains uncertain, but it may be
attributable to ‘programming’ effects of events in early life, since it is associated
with low birth weight. In obese people, intracellular cortisol levels within adipose
tissue are further amplified by increased local regeneration of cortisol by the
enzyme 11β-HSD type 1. In mice, transgenic manipulations of 11β-HSD1 have
potent effects on obesity and associated features of the metabolic syndrome.
Promising preclinical data suggest that novel 11β-HSD1 inhibitors will have a
role in lowering intracellular cortisol levels as a treatment for the metabolic
syndrome. In addition to their metabolic effects, glucocorticoids act in the blood
vessel wall. Pharmacoepidemiological studies suggest that glucocorticoid excess
is an independent risk factor for cardiovascular disease. Recent data suggest that
11β-HSD1 within the blood vessel wall influences vascular remodelling and
angiogenesis, for example in the myocardium following coronary artery occlusion.
Thus, glucocorticoid signalling provides a potentially tractable system to influence
both risk factors for, and the outcome of, Type 2 diabetes and cardiovascular
disease.
Diabet. Med. 23, 1281–1288 (2006)
Keywords glucocorticoids, 11β-hydroxysteroid dehydrogenase, metabolic
syndrome, cardiovascular disease
Abbreviations 11HSDs, 11β-hydroxysteroid dehydrogenases; GR, glucocorticoid
receptor; HPA, hypothalamic–pituitary–adrenal

Introduction haemodynamics and fluid balance) and successful resolution

of the otherwise unchecked innate immune response (hence anti-
Cortisol is the major glucocorticoid in humans, secreted from
inflammatory effects). However, if elevated cortisol secretion
the adrenal cortex under the control of the hypothalamic–
is sustained—especially in the context of continued capacity to
pituitary–adrenal (HPA) axis. During acute severe stress (e.g.
eat and thereby sustain high insulin levels—then these effects
major injury or systemic infection), activation of the HPA axis,
become maladaptive and result in the plethora of features
resulting in elevated plasma cortisol levels, is essential for
described in Cushing’s syndrome. These include central obesity,
survival. This allows homeostatic adjustments, including
hypertension, glucose intolerance and dyslipidaemia. The
liberation of fuel (hence effects of cortisol on glucose and fatty
similarities between the features of Cushing’s syndrome and
acid metabolism), protection against shock (hence effects on
those of the metabolic syndrome have led to the suggestion
that subtle abnormalities in cortisol secretion or action may
Correspondence to: Professor Brian R. Walker, Endocrinology Unit, contribute to the links between features of the metabolic
Centre for Cardiovascular Science, University of Edinburgh, Queen’s
Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK. syndrome [1]. Moreover, most of the features of Cushing’s
E-mail: b.walker@ed.ac.uk syndrome are reversible upon removal of glucocorticoid excess,

© 2006 The Author.

Journal compilation © 2006 Diabetes UK. Diabetic Medicine, 23, 1281–1288 1281
 1282 Cortisol and metabolic syndrome • B. R. Walker
Figure 1 Positive correlations between 09.00 h fasting plasma cortisol and features of the metabolic syndrome. Results are from 370 men aged
59–70 years studied in Hertfordshire, England [2]. OGTT, Oral glucose tolerance test; HOMA, homeostasis model assessment.
suggesting that manipulations which reduce cortisol action
might have a role in treatment of the metabolic syndrome.
The HPA axis in the metabolic syndrome
Several groups have attempted to measure indices of HPA
axis activity in cohorts of subjects in whom cardiovascular risk
factors are well characterized. This is not straightforward,
because cortisol levels in blood have wide diurnal variation—
being highest on waking—and may be elevated as a conse-
quence of the psychological stress of having a measurement
taken and in response to food or exercise. Integrated measures
of 24-h cortisol secretion used in the clinical diagnosis of
Cushing’s syndrome may not be sensitive to subtle changes in
the HPA axis: for example, 24-h urine free cortisol comprises
only a tiny fraction of total cortisol secretion.
We have collected evidence that the HPA axis is ‘activated’
in the metabolic syndrome. In cohort studies, we have shown
that 09.00 h plasma cortisol after overnight fasting is elevated
in subjects with relative glucose intolerance, hypertension,
insulin resistance and hypertriglyceridaemia (Fig. 1) [2–6].
This elevation of plasma cortisol in metabolic syndrome
associates with increased cortisol response to low-dose (1 µg)
ACTH1−24, consistent with adrenal hypertrophy [7]. Integrated
cortisol secretion, measured using mass spectrometry to assess
total urinary cortisol metabolite excretion, is variably increased
in subjects with the metabolic syndrome [4,7]. These observa-
tions should not be confused with similar studies undertaken
in subjects with obesity (with or without the metabolic syn-
drome): in obesity, the metabolic clearance rate of cortisol is
increased [8–10], tending to lower plasma cortisol concentration
and obscure the underlying positive association between
plasma cortisol and other features of the metabolic syndrome.
The basis for this activation of the HPA axis in the metabolic
syndrome remains uncertain. We have not found altered
suppression of cortisol in response to ultra-low dose dexame-
thasone [7] and do not favour the hypothesis that negative
feedback control of the HPA axis is altered. It seems likely that
central control of the HPA axis is disrupted but this is difficult
to test. Patients with Type 2 diabetes have higher plasma
cortisol which, unlike control subjects, fails to habituate (i.e. fall)
on repeated measurement [11], suggesting that the response to
the stress of sampling may be exaggerated in the metabolic
syndrome. However, in a case–control study nested in the
Whitehall II study, the elevated cortisol secretion in those with
the metabolic syndrome was not attributable to indices of
economic and psychosocial stress which have been so carefully
documented in that cohort [12].
An alternative explanation is that the HPA axis is permanently
programmed by events in early life. In animals, manipulations
in pregnancy which retard fetal growth and lead to later glucose
intolerance and hypertension in the offspring also lead to life-
long activation of the HPA axis [13]. In humans, low birth
weight is associated not only with the metabolic syndrome but
© 2006 The Author.
Journal compilation © 2006 Diabetes UK. Diabetic Medicine, 23, 1281–1288

Figure 2 Interconversion of cortisol and cortisone by 11β-hydroxysteroid dehydrogenases.
also with elevated plasma cortisol up to 70 years later [2,3].
However, the molecular basis for this putative programming
of HPA function remains elusive.
It has been suggested that therapies which suppress the HPA
axis, for example by inhibiting adrenal biosynthesis of cortisol
with metyrapone or ketoconazole, would be useful in the
metabolic syndrome. Indeed, clinical trials are underway for
this purpose. In the author’s view, this approach is hazardous
since it risks an inadequate cortisol response to the stress of
intercurrent illness or injury and hence risks the clinical
complications of Addisonian crisis.
Tissue responsiveness to glucocorticoids
in metabolic syndrome
Conventional endocrinology deals with levels of hormones
in the blood. However, a new biology has emerged which
describes the intricate control of tissue responsiveness to
hormones, such that tissues—and people—differ in the response
elicited by the same concentration of circulating hormone.
Bioassays, such as the intensity of dermal vasoconstriction
following topical steroid application, suggest that tissue sensi-
tivity to glucocorticoids is increased in subjects with features
of the metabolic syndrome [4,14]. Moreover, polymorphisms
in the glucocorticoid receptor (GR) gene [15], and increased
mRNA for GR in skeletal muscle [16], have been associated
with the metabolic syndrome.
For steroid hormones, a key component conferring tissue
specificity of response is the presence of enzymes within target
cells which either limit or amplify the local intracellular
concentrations of ligand for intracellular receptors. For gluco-
corticoids the relevant enzymes are the 11β-hydroxysteroid
dehydrogenases (11HSDs) [17,18]. These interconvert the active
11hydroxy-steroid cortisol with its inactive 11keto-metabolite
cortisone. 11HSD type 2 is responsible for inactivation of
cortisol in the kidney, thereby protecting mineralocorticoid
receptors from cortisol and allowing selective access of aldos-
terone. Defects in 11HSD2 may be important in a proportion
of patients with salt-sensitive essential hypertension [19,20].
However, it is another isozyme, 11HSD type 1 (11HSD1),
which is of greatest relevance to explaining, and potentially
reversing, the associations between features of the metabolic
syndrome.
© 2006 The Author.
Journal compilation © 2006 Diabetes UK. Diabetic Medicine, 23, 1281–1288
Special report 1283
11β-Hydroxysteroid dehydrogenase type 1
and metabolism
11HSD1 is expressed in many tissues, including adipose tissue
and liver; these tissues are typically abundant in GR but not
mineralocorticoid receptors. For this isozyme, the reaction
direction favours conversion of cortisone to cortisol, thus
potentially amplifying local cortisol concentrations and GR
activation (Fig. 2) [18,21].
The potency of 11HSD1 in determining GR activation in
a tissue-specific manner has been illustrated by experiments
using transgenesis in mice. Mice with overexpression of rat
11HSD1 in adipose tissue, driven by a transgene under the
AP2 promoter, develop central obesity, glucose intolerance,
dyslipidaemia and hypertension [22,23]. Mice with a similar
degree of overexpression of rat 11HSD1 in liver under the
ApoE promoter develop hyperinsulinaemia and hypertension,
but not obesity or glucose intolerance [24]. These data suggest
that the most potent effects of glucocorticoids on the metabolic
syndrome are mediated in adipose tissue. Knockout mice lack-
ing 11HSD1 exhibit protection from features of the metabolic
syndrome, including resistance to obesity and glucose intoler-
ance on a high-fat diet and a favourable serum lipid profile
[25–27].
These striking observations in mice raise important ques-
tions in humans: how important is 11HSD1 in determining
intracellular cortisol concentrations; does increased 11HSD1
cause increased intracellular cortisol and contribute to features
of the metabolic syndrome; and could inhibition of 11HSD1
be a useful therapy to reduce intracellular cortisol concentra-
tions without compromising the ability of the HPA axis to
respond to stress?
Extra-adrenal cortisol regeneration in humans
Measurement of regeneration of cortisol by 11HSD1 in
humans is not straightforward, since many organs may have
the capacity for reversible interconversion of cortisol and
cortisone (if they express both isozymes of 11HSD), or express
other enzymes which inactivate cortisol, obscuring net
generation by 11HSD1. We have recently established a stable
isotope tracer (9,11,12,12-2H4-cortisol) which allows measure-
ment of cortisol regenerated from cortisone (see Fig. 3 and
 1284 Cortisol and metabolic syndrome • B. R. Walker
Figure 3 Metabolism of 2H4-cortisol (D4-cortisol) by 11β-hydroxysteroid dehydrogenases (11HSDs). Note that D3-cortisol is subject to reversible
interconversion while D4-cortisol is not regenerated by 11HSD1. D3-Cortisol and D4-cortisol can be distinguished by mass spectrometry and
discrepancies between them during steady-state infusion used to deduce 11HSD1 reductase activity [28–30,40,41].
legend) [28]. This has been used to show that the splanchnic
circulation produces as much as 25% of the amount of cortisol
produced from the adrenal glands [29]. Moreover, approxi-
mately one-third of the splanchnic production appears to be
from liver and approximately two-thirds from visceral adipose
tissue [30]. These data indicate very substantial peripheral
regeneration of cortisol, sufficient to alter both intracellular
cortisol concentrations and also the concentration of cortisol
in the portal vein. Thus, cortisol can be added to the list of
hormones (which includes adipokines, cytokines and free fatty
acids) which are delivered directly from the visceral adipose
tissue to the liver and may contribute to the insulin resistance
associated with central obesity.
11HSD1 activity in metabolic syndrome
In the metabolic syndrome, dissection of 11HSD1 activity has
been complicated because the changes are tissue specific. Par-
alleling original observations in obese rodents [31], in human
obesity 11HSD1 in liver is decreased [32–34], while 11HSD1
in adipose tissue is increased [33–39]. These balance each
other so that there is no net change in whole-body [40] or
splanchnic [41] cortisol regeneration. However, measure-
ments of intra-adipose cortisol generation using microdialysis
confirm that local regeneration of cortisol from cortisone is
increased (from ∼ 5% in an hour in lean subjects to ∼30% in
obese subjects) [40]. Confusion has arisen in the literature
because the urinary ratios of cortisol and cortisone metabolites
do not always reflect 11HSD1 activity (they are influenced by
several other enzymes); in the author’s view, this ratio should
not be used in isolation to deduce 11HSD1 activity.
As replicated independently by several groups, the increase
in adipose 11HSD1 in obesity is transcriptional [35–39], but
its basis remains uncertain. Genetic studies have shown rela-
tionships between polymorphisms in the gene which encodes
11HSD1 (HSD11B1) and both Type 2 diabetes and hyperten-
sion [42,43], but not obesity. This suggests that 11HSD1 may
determine the metabolic response to obesity rather than causing
obesity per se. A number of studies will be reported soon which
have investigated regulation of 11HSD1 in humans and may
shed light on the response of the enzyme to different nutritional
signals and to inflammatory stimuli.
Inhibition of 11HSD1 as a therapy for metabolic syndrome
Many pharmaceutical companies are developing novel selec-
tive 11HSD1 inhibitors for treatment of Type 2 diabetes and
obesity. Published results in mice are promising, with lowering
of blood glucose and body weight in diabetic and obese strains
[44 – 46].
© 2006 The Author.
Journal compilation © 2006 Diabetes UK. Diabetic Medicine, 23, 1281–1288
 Special report 1285

Figure 4 Amplification of the angiostatic effect of glucocorticoids by 11β-hydroxysteroid dehydrogenase (11HSD) 1 in the blood vessel wall.
Mouse aortic rings were cultured on Matrigel for 7 days and the number of new vessels quantified histologically. New vessel formation was inhibited
by corticosterone (the mouse equivalent of cortisol) and also by 11dehydro-corticosterone (the inert substrate for 11HSD1). The effect of corticosterone
was blocked by the glucocorticoid receptor antagonist RU486. The effect of 11-dehydrocorticosterone was absent in vessels from 11HSD1 knockout
(–/–) mice, which lack the capacity to convert 11dehydro-corticosterone to active corticosterone [59].

While results of administration of these novel inhibitors
in humans are awaited, we have used the liquorice derivative
carbenoxolone as a ‘prototype’ to assess the effects of 11HSD1
inhibition on insulin sensitivity. In healthy volunteers, carbenox-
olone increased whole body insulin sensitivity during eugly-
caemic hyperinsulinaemic clamps [47]. In patients with Type 2
diabetes, this was attributed to reduction of hepatic glucose
output, associated with altered glycogen turnover, but there
was no increase in peripheral glucose uptake [48]. However, in
obese patients without diabetes, carbenoxolone had no effect
on insulin sensitivity [40] and in non-selected patients with
Type 2 diabetes it had no effect on HbA1c [49]. There may be
several reasons for these somewhat disappointing effects
of carbenoxolone, including its relatively low potency for
11HSD1 inhibition and its lack of efficacy in adipose tissue
[40,50]. Inhibition of 11HSD1 in liver but not adipose tissue
may be insufficient in obese people, since the down-regulation
of liver enzyme activity may render these subjects insensitive
to the modest insulin-sensitizing action in liver. Inhibition of
11HSD1 in adipose appears to be a key attribute required of
novel 11HSD1 inhibitors.
Glucocorticoids, 11HSDs and cardiovascular
disease
An unexpected effect of 11HSD1 inhibition in mice is protec-
tion from atherogenesis in ApoE–/– mice [46]. This appears to
be disproportionate to any serum lipid-lowering effect in these
mice, raising the possibility that 11HSD1 may influence
pathophysiology within the vascular wall. This is plausible,
since 11HSD1 is expressed in vascular smooth muscle [51], as
well as in macrophages [52] which invade atheromatous lesions.
The effects of glucocorticoids in blood vessel walls are com-
plex [53–55]. Both GR and mineralocorticoid receptors are
expressed in the vessel wall and a variety of effects of corticos-
teroids on vascular tone have been described. However, less is
known about the influence of glucocorticoids on structural
disease within the vessel wall. Their anti-inflammatory effects
might be expected to protect against atheroma and there is
evidence that glucocorticoids prevent neo-intimal proliferation
following intravascular injury [55]. However, in two large
pharmacoepidemiological studies, we found that subjects treated
with exogenous glucocorticoids had an increase in cardiovas-
cular disease event rate [56,57].
So, is there direct evidence that 11HSDs influence vascular
function or the progression of vascular disease? In studies of
11HSD–/– knockout mice, we showed that vascular function
is altered in 11HSD2–/– mice, consistent with protection of
endothelial cells from excessive exposure to glucocorticoids
[58]. However, 11HSD1–/– mice had normal vascular function
[58]. Regarding vascular disease, we have taken the approach
of investigating vascular proliferation, specifically angiogenesis
in mouse vessels [59]. In isolated aortic rings, cultured on
Matrigel, new vessels are formed (Fig. 4). This angiogenesis is
inhibited by the active 11hydroxy-glucocorticoid corticoster-
one and also by the inert 11keto-steroid substrate for 11HSD1
in mice, 11-dehydrocorticosterone. Moreover, the effect of
11-dehydrocorticosterone is attenuated by carbenoxolone and
absent in vessels from 11HSD1–/– mice. These observations
were replicated in vivo , by measuring angiogenesis in
polyurethane sponges implanted subcutaneously in mice and
assessing the effects of impregnating the sponge with cortisol
or cortisone. Most importantly, the role of 11HSD1 in ampli-
fying the angiostatic effect of glucocorticoids was confirmed in

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Journal compilation © 2006 Diabetes UK. Diabetic Medicine, 23, 1281–1288
 1286 Cortisol and metabolic syndrome • B. R. Walker
mice in which myocardial infarction was induced by coronary
artery ligation: the myocardial angiogenic response and left
ventricular ejection fraction were both greater in 11HSD1–/–
mice than in wild-type controls [59].
These observations suggest that regeneration of glucocorti-
coids within the vessel wall modifies local proliferative responses.
Inhibition of 11HSD1 may therefore be beneficial during
collateral re-perfusion of ischaemic tissue, but the same actions
are of unknown significance in pathogenic angiogenesis, such
as occurs in diabetic retinopathy and in solid tumour growth.
Summary
The role of glucocorticoids in the metabolic syndrome may
best be described as a ‘life-course’ hypothesis, in which events
in early life permanently programme activation of the HPA
axis in later life, with elevated circulating cortisol predisposing
to metabolic syndrome. In later life, dietary and lifestyle fac-
tors which promote obesity also increase intra-adipose cortisol
regeneration by 11HSD1, amplifying the link between obesity
and metabolic syndrome. Excessive exposure to glucocorticoids
ultimately leads to cardiovascular disease.
Fortunately, there is evidence that this system is tractable to
therapy. Inhibition of 11HSD1 offers the potential to reduce
cortisol concentrations within the adipose tissue, portal vein
and liver and hence interrupt the link between obesity and
metabolic syndrome, without preventing appropriate responses
of the HPA axis to intercurrent illness and stress. Ultimately,
this approach may improve outcomes from cardiovascular
disease.
Competing interests
B.R.W. has received research funding from Biovitrum and
Ipsen, and lecture or consultancy fees from Abbott, Amgen,
Biovitrum, Bristol Myers Squibb, Incyte, Johnson and Johnson,
Merck, Syrrx and Vitae. B.R.W. is an inventor on relevant
patents owned by University of Edinburgh.
Acknowledgements
The author is deeply grateful to the many colleagues and
collaborators who contributed to the studies presented in the
Dorothy Hodgkin lecture 2006, of which this article is a
summary. Thanks also to the many contributions from funding
agencies, including notably the British Heart Foundation,
Wellcome Trust and Diabetes UK.
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© 2006 The Author.
Journal compilation © 2006 Diabetes UK. Diabetic Medicine, 23, 1281–1288