J R Soc Med 2004;97:511-520
doi:10.1258/jrsm.97.11.511
© 2004 Royal Society of Medicine
Metabolic syndrome: maladaptation to a modern world
Terence J Wilkin MD FRCP
Linda D Voss PhD
Department of Endocrinology & Metabolism, Peninsula Medical School
(Plymouth campus), Level 7, Derriford Hospital, Plymouth PL6 8DH, UK
Correspondence to: Prof TJ Wilkine-mail
t.wilkin{at}pms.ac.uk
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INTRODUCTION
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For the public, obesity is largely a cosmetic issue. For the
doctor, it
underlies disturbances of lipid and glucose metabolism
that are posing one of
the greatest threats to health the world
has known. Diabetes, cardiovascular
disease, cancers and anovulation
are the principal manifestations. Insulin
resistance, consequent
upon obesity, causes them and metabolic syndrome is the
term
used to describe them. Metabolic syndrome results from the maladaptation
to
overnutrition of genes selected to survive
undernutrition. Obesity
is a disease—a classic interaction
between genes and a
changed environment. This review attempts to give the
metabolic
syndrome perspective and to explain its impact on modern
medicine.
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OBESITY IS AFFECTING THE WHOLE OF SOCIETY, NOT JUST A SECTOR OF IT
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Metabolic syndrome, referred to variously as insulin resistance
syndrome or
syndrome X, represents a conjunction of several
metabolic disturbances and is
very much a product of our
time.
1 It is clearly
associated with obesity and, insofar as it seldom
occurs in people of low body
mass and can be improved by weight
loss, may well be caused by obesity. Data
from around the industrialized
world suggest that obesity rates have tripled
in a generation,
2 so
that obesity and its likely causes are an appropriate place
to start in any
consideration of the metabolic syndrome.
The upward shift in body mass of industrialized societies over the past 25
years has been
dramatic.3 The
median body mass index (BMI) of the UK population in the 1970s was around 23,
meaning that half the adult population just 30 years ago had a BMI below 23.
An important question for health managers is whether the fat alone have become
fatter, or the population as a
whole.4 In the
former case, intervention might reasonably be focused on the heaviest 20%,
with little fear that the rest would catch up. If, on the other hand, the
whole population were gaining weight, public health strategists would face a
quite different problem. Even if a policy successfully helped the heaviest to
lose weight, their place would be taken by others. One approach to answering
the question involves comparison of the mean and median BMI over time. Lack of
change in the median, while the mean increased, would suggest that only those
of already high BMI were gaining weight, whereas movement of the median with
the mean would indicate that the population as a whole was affected. The data
are clear3
(Figure 1). The median BMI of
the UK population by the late 1990s had risen from 23 to 26: over 60% of the
adult population was now overweight by World Health Organization (WHO)
standards. The median BMI of UK adults, which a generation ago was little
different from that in the 19th century when Quetelet first proposed the BMI
as a measure of
fatness,4 now
announces an epidemic of obesity.
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Figure 1. The shift in distribution of BMI of UK adults between the 1970s (black)
and the 1990s (open).
Both the median and the mean have moved, suggesting that the whole of
society is involved. Modified from ref.
3
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OBESITY IS A TRUE DISEASE INVOLVING GENES AND ENVIRONMENT
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Why should this transformation have occurred? A generation is
less than a
second on the scale of evolutionary time, so genetic
change is unlikely to be
responsible for such a rapid emergence
of obesity. Change in environment is
the more likely cause.
It is reasonable to assume that mankind evolved on
limited nutrition.
For hunter-gatherers, excess would have been the exception.
With
limited food availability as a survival pressure, Darwinians
would argue
that survivors selectively carried genes for efficient
storage of excess
calories as fat. The advantage of being able
to create energy stores is still
evident in some preindustrialized
populations, where seasonal availability of
food is still associated
with striking variation in body weight—and
survival.
5
Mankind as a whole entered the 20th century well adapted to privation, but
the people of industrialized and industrializing nations were about to
encounter an environmental change of a speed hitherto unmatched in
evolutionary history. The turning point was probably the Second World War,
with the rapidly rising prosperity of the ‘westernized’ nations
that followed it. The mass ownership of personal transport, processing of
food, consumption of carbonated sodas and increasingly sedentary
occupations—a process dubbed ‘coca-colonization’ by Paul
Zimmet6—have
together conspired to achieve an unprecedented change in environment over a
very short period. ‘Progress’ has made energy dense foods
available to the masses at low cost and with minimum effort. The result was
predictable but not predicted—an effect on society more devastating yet
than the Medical Nemesis envisaged in the 1960s by Ivan
Illich.7 Equipped
with genes ideally suited to—and expressly selected for—the
storage of fat, modern man now inhabits a land of plenty. Worse still, we do
not possess genes to control obesity, because weight excess was never until
now a pressure on survival. Fatness in the 21st century may not reflect the
gluttony about which society has been so judgmental since Shakespeare’s
caricature of Sir John
Falstaff,8 but
rather a genotype for evolutionary survival wholly maladapted to its new
environment.
Everything points to excess weight gain as a societal disorder and not the
preserve of a few. BMI is a continuum and obesity is merely a category
assigned to a particular BMI, which more and more of the population are
reaching. Given this perspective, society and its medical profession may need
to revise their view of the fat as feckless, and understand that obesity is a
disease in the truest sense—a classic interaction between nature and
nurture, susceptibility and risk, genes and environment. We need to think anew
about environmental engineering for obesity, in much the same way as we have
with smoking. Change will come with concern, but concern only with awareness.
Awareness means education, but our understanding of the metabolic syndrome and
what underlies it has emerged so recently that even the medical profession
remains in large part unaware. Metabolic syndrome is fast becoming the
industrialized world’s primary cause of morbidity and mortality,
outstripping infection, accidents and smoking-related diseases. The WHO now
views overnutrition—not undernutrition—as the principal cause of
global malnutrition.
While the industrialized world is already trying to cope, metabolic
syndrome presents an even greater threat to industrializing nations because
the time-scale over which their life-styles have been
‘westernized’ is that much shorter and the maladaptation that much
greater.
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OBESITY IS LARGELY RESPONSIBLE FOR INSULIN RESISTANCE
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As mentioned earlier, the public perceives obesity mainly as
a cosmetic
issue, and this may explain why most of those who
attend weight management
clinics are female. For doctors, it
is a metabolic issue. Some researchers
express concern that
obesity also has important psychological effects, but
there
is little evidence that this is the case. Most of the data on
this
matter come from weight management clinics, where referral
bias is a major
confounder. Population studies suggest that
weight excess has limited impact
on personal
wellbeing.
9 In
metabolic
terms, however, a BMI of 25 (WHO definition of overweight, currently
involving
around 60% of young UK females and 70% of males) already portends
a
risk of type 2 diabetes five times that of BMI 22 or less,
and a BMI of 30
(currently 20% young UK females and 22% males)
some 28 times
greater.
10,11
Diabetes is associated with a 2–4
times excess risk of cardiac
mortality. What is the connection
between BMI, diabetes and cardiovascular
disease?
Figure 2 illustrates the
negative feedback loop that controls the concentration of blood sugar.
Feedback loops are ubiquitous in nature and in engineering design. They are
used to maintain the product they control (sodium, potassium, glucose) within
narrow limits, whatever the
perturbation.12 In
the case of glucose, the islets release insulin, which controls the flux of
glucose in and out of the tissues. The flux results in a concentration of
blood glucose that modulates the release of insulin according to a set-point.
Several tissues respond to insulin, principal among them fat, liver and
muscle. Since there are only two components in the loop, there are essentially
only two things that can go wrong—either the islets or the tissues fail
to function. Loss of islet function (strictly beta-cell function) is typified
by type 1 diabetes in children, where the beta cell mass is destroyed by the
immune system. The kinetic that follows is straightforward: the blood insulin
level falls and, as a result, the blood glucose levels rise.
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Figure 2. Schematic representation of the feedback loop controlling blood
glucose.
If the islets fail (type 1 diabetes), glucose rises because insulin falls.
If the tissues fail (type 2 diabetes), insulin rises because glucose rises
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Failure of the tissues, the other cause of control loop breakdown, is not
due to anatomical loss as in type 1 diabetes but to functional loss. The
tissues lose sensitivity to insulin—a phenomenon referred to as insulin
resistance. The principal cause of insulin resistance is weight gain and the
result, once blood sugar exceeds a threshold defined by the WHO, is type 2
diabetes. The kinetics of loop function in type 2 diabetes, however, are quite
different from those in type 1. The beta cells remain functional in insulin
resistance, and respond to rising glucose by producing more insulin to
overcome the resistance. For every quantum rise in body mass there is a rise
in insulin resistance which weakens the loop’s control over blood
glucose. The glucose level rises slightly, but the beta cells are highly
sensitive to any change and respond to a linear rise in glucose with a
geometric rise in insulin. Of course, the islets cannot continue to respond to
rising insulin resistance forever, and eventually their function saturates. At
saturation, control of glucose is lost and diabetes ensues, but the levels of
insulin are high, not low. They are considerably higher than those of a
healthy person, but still not high enough to overcome the resistance that
drives them. The crucial difference between type 2 diabetes and type 1
diabetes is hyperinsulinaemia.
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INSULIN RESISTANCE IS RESPONSIBLE FOR THE METABOLIC SYNDROME
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For decades, medicine saw the relationship between insulin and
glucose as
one confined to diabetes. In reality, the hyperinsulinaemia
of insulin
resistance is associated with a range of apparently
disparate disturbances
that include hyperglycaemia, hypercholesterolaemia
(particularly LDL),
hypertriglyceridaemia, hypertension, hyperviscosity
(raised haematocrit),
hypercoagulability (raised liver-derived
plasminogen activator inhibitor-1)
and hyperuricaemia. Each
of these disturbances poses a cardiovascular risk in
its own
right, but together they are catastrophic to the macrovascular
system.
Although an understanding of the relationship between
insulin resistance and
metabolic disturbance is (appropriately)
attributed to Reaven, with his
seminal Banting lecture to the
American Diabetes Association in
1988,
1 Himsworth had
noted
50 years earlier that some diabetic patients required increasing
amounts
of insulin and appeared to become increasingly insensitive
or
‘resistant’.
13
The classic disturbances of the metabolic syndrome may be viewed as spokes
of a metabolic wheel where insulin, which drives all of them, lies at the hub
(Figure 3). Several important
points emerge from this representation. First, the insulin levels that turn
the wheel will not rise unless the glucose rises first. Glucose is the
mediator of the high insulin levels and metabolic disturbances that
characterize insulin resistance. However, such is the nature of the feedback
loop that the insulin levels may be very high before glucose control (the
connection between insulin and glucose) is lost. As a result, disturbances in
the other spokes of the wheel may be far advanced before the patient becomes,
by WHO definition, diabetic. It will also be clear that hypercholesterolaemia,
hypertension etc, are not complications of diabetes but associations, mutually
dependent on a common process. This is important, because the high glucose
levels could be reduced clinically by raising the insulin levels still further
(e.g. by use of a sulphonylurea), which might reduce HbA1C but advance the
other spokes of the metabolic wheel still further.
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Figure 3. The metabolic wheel. Insulin resistance at its centre simultaneously
drives a number of metabolic processes. The spokes are each linked through the
hub, rather than to each other. PAI-1=plasminogen activator inhibitor 1;
PCV=haematocrit
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It is the combination of factors in the metabolic syndrome that so
threatens cardiovascular health. People with isolated components are at lower
risk, reflected in the scores used to guide the clinical use of
cholesterol-lowering
statins.14 The
level of hypertriglyceridaemia cannot be used to stratify the risk of heart
disease, but hypertriglyceridaemia in the presence of hypertension or
hypercholesterolaemia makes the chance of a hyperinsulinaemic connection more
likely. Bonora’s analysis of the Bruneck study is highly
instructive.15 Some
27% of the hypercholesterolaemic population of this town in the Dolomites had
lone hypercholesterolaemia which was not associated with insulin resistance
and posed little threat to cardiovascular health. Fasting triglycerides, on
the other hand, were raised in the absence of other metabolic disturbances in
only one case out of 75. In other words, hypertriglyceridaemia is a useful
means of distinguishing syndromic hypercholesterolaemia (or hypertension or
hyperandrogenaemia) from lone disturbances. Finally, the changes in lipids
linked to weight excess, insulin resistance and the metabolic syndrome (high
triglycerides, low HDL-cholesterol, small dense LDL-cholesterol) are not
driven primarily by dietary intake. The key event in pathogenetic terms is
probably resistance to insulin of adipose tissue hormone-sensitive lipase,
which normally keeps a lid on
lipolysis.16 The
resultant release of free fatty acids into the blood is thought to generate
systemic insulin resistance (by the cycle of competition between glucose and
free fatty acids described by Philip Randle in the 1960s). The situation is
analogous to glucose intolerance revealed by, but not caused by, high sugar
intake. Both respond to weight loss and a fall in insulin resistance.
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CANCERS, METABOLIC DYSOVULATION AND PRE-ECLAMPSIA ARE ALSO COMPONENTS OF THE METABOLIC SYNDROME
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The metabolic syndrome has been referred to as the deadly quartet
and even
‘the deadly
sextet’.
17 It
is now clear,
however, that there are even more than six components to the
insulin
resistance syndrome. What was originally termed Stein–Leventhal
syndrome,
and subsequently polycystic ovary syndrome (PCOS), now appears
to be
a metabolic disorder of ovarian function driven by high
insulin
levels.
18 Women
derive their oestrogen by enzymatic
conversion from androgen, and
hyperinsulinaemia raises the production
of androgen by the thecal cells of the
ovary.
19 The
androgen/oestrogen
imbalance blocks follicle development at an early stage,
leading
to anovulation, the cysts and the characteristic phenotype of
hirsutism,
acne and greasy skin. Since menstruation follows ovulation,
women
with PCOS are typically amenorrhoeic. The ovarian cysts
that give the syndrome
its name are coincidental, and pelvic
ultrasound has given place to clinical
and biochemical criteria
for diagnosis. PCOS is probably better termed
metabolic dysovulation,
and is an early expression of insulin resistance. The
waist
circumference of such women is greater than that of fertile
controls,
and the risk of future diabetes and heart disease
is
increased.
20
Metabolic dysovulation may now affect up to
6% of women of childbearing
age,
22,23
a figure that represents
more than twice the current overall prevalence of
type 2 diabetes.
If 6% of the female population is all of a sudden unable to
ovulate,
obesity and the metabolic syndrome it causes may have brought
about
in just 25 years the most rapid change to the gene pool
in evolutionary
time.
Hypertension has long been associated with insulin resistance. Recently, it
has become clear that preeclampsia is commoner in women with metabolic
dysovulation and is likewise associated with insulin
resistance.24
Obesity and insulin resistance not only reduce fertility but also introduce
specific risks when pregnancy is achieved.
The list of comorbidities associated with obesity is a long one, and an
increasing number are linked to insulin resistance. Colorectal cancer was the
first malignancy to be associated with insulin
resistance,25 and
others more recently reported include breast
cancer26 and
endometrial
carcinoma27—although
here the tumorigenic factor may be the high oestrogen associated with
metabolic dysovulation, rather than the insulin-like growth factors that are
thought to operate in the other cancers. A most intriguing question is whether
mood, in what is sometimes referred to as our ‘low-mood society’,
may relate to insulin resistance. Notwithstanding the selection biases
mentioned earlier, the issue has been taken
seriously.28
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FAT DISTRIBUTION IS KEY TO INSULIN RESISTANCE
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Some 60 years ago, Professor Jean Vague from Marseille on the
Mediterranean
coast of France made a seminal observation. Those
overweight patients
attending his diabetic clinic whose fat
distribution was upper abdominal
(
les pommes) were more susceptible
to the morbidities of obesity than
those whose fat was deposited
in the buttocks and thighs (
les
poires). The observation was
published first in French, and its
dissemination was limited
as a result, but when it appeared nine years later
in the
American Journal of Human
Nutrition,
29
the implications became clear
to all. Upper abdominal obesity tends to be the
male distribution,
and gluteofemoral the female, though not exclusively. The
distributions
are largely hormone dependent, since prepubertal boys and girls
of
a given BMI show little difference in waist circumference or
waist–hip
ratio, whereas their parents clearly
do.
30 Furthermore,
the
woman’s lower distribution of fat tends to redistribute
into the
abdomen after the
menopause,
31 which
may explain the
relative cardiovascular protection that the female enjoys
during
her childbearing years, and its subsequent loss.
Abdominal fat tends to be located within the abdominal cavity, around the
digestive organs, whereas gluteofemoral fat is subcutaneous
(Figure 4). This fundamental
distinction explains much of the difference in cardiovascular risk between
males and females. Until recently, fat was viewed as merely a repository of
excess calories, but it is now recognized as the largest endocrine organ in
the
body.32,33
While both visceral and subcutaneous fat are secretory (e.g.
leptin),34 visceral
fat is the source of inflammatory mediators such as tumour necrosis
factor-
and
interleukin-6,35
and of a novel adipocytokine called
adiponectin.36
Visceral secretions are carried directly to the liver by a privileged
route—the portal vein—and the liver is an important site of
insulin action.
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Figure 4. A transverse abdominal CT scan showing intraabdominal visceral fat in
black (area 13459 mm2, metabolically harmful) but, in addition, a
substantial amount of subcutaneous fat (area 5823 mm2,
metabolically harmless)
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Adiponectin is unique in being negatively regulated in obesity: levels fall
with increasing adiposity and seem to be inversely associated with glucose,
insulin, triglyceride and
BMI.37,38
Furthermore, the administration of adiponectin to animals increases insulin
sensitivity.39 By
accelerating tissue fat oxidation, the cytokine reduces circulating fatty acid
levels and reduces the intracellular triglyceride content of liver and muscle.
It also suppresses the expression of adhesion molecules in vascular epithelial
cells and cytokine production from macrophages, thus down-regulating the
inflammatory processes that characterize the early phases of
atherosclerosis.40
Adiponectin concentrations are higher in females than in males, and they are
increased by insulin sensitizing drugs such as the
thiazolidinediones.41,42
Adiponectin is produced predominantly by visceral
fat,43 and appears
to be an important component of the final common pathway to insulin
resistance.
Whether visceral fat alone causes insulin resistance is nevertheless still
uncertain. It may simply coexist with some other primary process. For example,
intramyocellular fat in the skeletal muscles may be
important,44 or
fatty infiltration of the liver could be the mechanism responsible.
Nonalcoholic steatohepatitis, which commonly accompanies obesity, is
associated with inflammation and may explain the disturbed hepatic enzymes and
raised C-reactive protein (CRP) commonly seen in such
patients.45 When an
isolated raised CRP, in the apparent absence of inflammation, is found in
‘screening’ tests for non-specific symptoms, this may be the
explanation.
The late Per Bjorntorp conceived a quite different view of insulin
resistance, starting with chronic stress as the
driver.46 Comparing
the centripetal fat distribution and metabolic disturbances of
metabolic-syndrome patients with those of Cushing’s syndrome, he argued
that stress may so alter the diurnal patterns of cortisol release as to create
a mildly cushingoid state. Hydrocortisone is known to stimulate appetite and
to increase insulin resistance, and disturbances of corticotropin release and
control are characteristic of the obese (and stressed) state. The difficulty,
as so often, is in teasing out cause and effect.
CT scanning of the abdomen in the horizontal plane, and use of software to
calculate per cent fat mass (adiposity), is the ‘gold standard’
measure of visceral adiposity but expensive to apply clinically. BMI, although
a proxy for adiposity, crucially says nothing about its distribution, and
several studies have underlined the importance of fat distribution in clinical
assessment of metabolic risk. Carey and colleagues used dual energy X-ray
absorptiometry and the hyperinsulinaemic clamp (the best measure of insulin
resistance) to establish the relationship between the two in people of varying
BMI (Figure
5).47
While there was a close linear correlation between per cent abdominal fat and
insulin resistance, BMI was of little help in distinguishing those with high
from those with low insulin resistance. Indeed, some of those with the highest
insulin resistance (and highest visceral fat mass) had normal BMI, and some of
those with the lowest were obese. This study identifies very clearly the
clinical importance of the distinction between fat mass and fat distribution.
Someone of relatively low BMI may nevertheless carry most of what little fat
they have in the abdomen (extreme ‘apple’, sometimes referred to
as the ‘obese non-obese’), while a person of high BMI, officially
obese, may carry very little visceral fat (extreme ‘pear’).
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Figure 5. The relationship between visceral adiposity (% central abdominal fat),
BMI and insulin resistance. BMI does not inform on fat distribution and is
a poor proxy for insulin resistance (After Ref.
47)
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Zavaroni and his colleagues used CT to determine visceral adiposity in
healthy factory workers, this time incorporating a fasting blood sample for
lipids and the insulin response to glucose as a measure of insulin
resistance.48 Two
groups were matched exactly for age (mean 39 years) and for BMI (mean 24.7),
but differed in per cent body fat that was abdominal—those below the
median, and those above. The difference in metabolic status was striking
(Box 1), with significantly
higher insulin resistance and cardiovascular risk in the group whose body fat
was predominantly visceral.
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Box 1. The metabolic status of two groups of men matched for age and BMI, but
of different fat distribution (After Ref.
48)
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The combination of wide girth as a proxy for visceral obesity and raised
triglycerides to indicate its metabolic impact has led to the notion of the
‘hypertriglyceridaemic waist’. In a useful review of the concept,
Despres and colleagues report that the combination of a waist circumference
greater than 90 cm and a fasting triglyceride level greater than 2.2 mmol/L
places men in the top quartile of coronary
risk.49 This
approach may be simpler than the Framingham risk calculator, applies to
contemporary data (the Framingham cohort was recruited more than 40 years ago)
and uses an index of the metabolic syndrome (triglyceride) that is seldom
raised on its own. A tape measure around the waist is a reliable surrogate for
visceral fat
mass,50 and waist
alone is probably a better measure than the waist–hip ratio, for which
variable pelvic width is a
confounder.51
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INSULIN RESISTANCE IS A METABOLIC RISK EVEN IN CHILDREN
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Type 2 diabetes, which a generation ago was referred to as
‘adult-onset’,
‘late-onset’ or
‘maturity-onset’, is
now affecting adolescents and
children.
52,53
Children are crossing
weight centiles faster than any other age group and over
a quarter
are now overweight at school
entry.
26
Type 2 diabetes is the outcome of a process, not the process itself. The
process is that of insulin resistance and, given our understanding that
clinical diabetes is preceded by a symptom-free period of rising insulin
resistance, there is mounting interest in how early the process really begins.
For more than a decade, the published work has dwelt on poor gestational
nutrition—for which low birthweight is a proxy—as the factor
principally responsible for programming metabolic disturbances later in
life.54 This was
the basis for the ‘Barker hypothesis’ (thrifty genotype
hypothesis) for insulin resistance later in
life.55 However,
important caveats have emerged in the application of this hypothesis to the
insulin resistance that now pervades the industrialized world. The data
largely relate to cohorts born in the first half of the 20th century, some of
them before the First World War. The low birthweights of historical cohorts
are no longer common in the industrialized world, while the metabolic
disturbances attributed to them, such as diabetes and cardiovascular disease,
are increasing. A new paradigm is needed to reconcile rising insulin
resistance with rising—not falling—birthweight.
The 20th century saw unprecedented changes in western lifestyle and quality
of obstetric care, and low birthweight has been replaced by a progressive rise
in postnatal weight. Across the century, there were many who were subject to
both poor maternal nutrition (low birthweight) and excess nutrition later in
life (high current weight). Although a contributor, low birthweight may
nevertheless have received undue
emphasis,56 and
excess weight acquired after birth (centile crossing) appears now to be the
more important
factor.57 What
still remains unclear is the relative importance of the factors that lead to
insulin resistance in children—genetics, maternal
weight/nutrition/glycaemia, infant weight gain, fat patterning in childhood,
physical activity, food choice.
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METABOLIC SYNDROME DOES NOT EXCLUDE TYPE 1 DIABETES
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However much stress is placed upon the loop that controls blood
glucose,
diabetes does not develop until the beta cells are
no longer able to deliver
sufficient insulin. Diabetes, of whatever
kind, is ultimately a disorder of
beta cell insufficiency. While
the world has focused on the exponential rise
in type 2 diabetes
associated with excess weight gain and insulin resistance,
less
attention has been paid to a parallel rise in the incidence
of type 1
diabetes.
58 A
unifying concept, the ‘accelerator
hypothesis’, attempts to
explain this
observation.
59 It
proposes
that type 1 and type 2 diabetes are the same disorder of insulin
resistance,
set against different genetic backgrounds. Those who develop
type
1 diabetes are growing up in the same obesigenic environment
as the remainder
of society—indeed, they are heavier as
toddlers than those who do
not.
60,61
Insulin resistance leads
to metabolic upregulation and increased
immunogenicity of the
beta cell. It is the increased immunogenicity, the
hypothesis
argues, that accelerates immune-mediated beta cell death in
those
with a genetically more intense immune response. Given
a range of genetically
determined immune responsiveness in the
population and progressively rising
immunogenicity of the beta
cell mediated by insulin resistance, the hypothesis
predicts
an increasing prevalence of type 1 diabetes, an earlier age
at
presentation as the process that causes it is accelerated,
and the involvement
of progressively lower risk genotypes. Ultimately,
the population at large
might be at risk from an immune response
to the beta cell if the drive from
insulin resistance became
sufficiently widespread. Two independent studies
have shown
that type 1 diabetes presents not just more frequently but also
earlier
in heavier children (true
acceleration),
62,63
the recruitment
of lower risk genotypes has recently been
reported,
64 and
teenagers
presenting with type 2 diabetes can be seropositive for
islet-related
autoantibodies.
65,66
Insulin
resistance is increasingly viewed as a pro-inflammatory
state,
67 and the
accelerator hypothesis draws together both types of
diabetes into a single
inflammatory entity differing only in
its tempo of development. The practical
implication of the hypothesis
is that type 1 diabetes, like type 2, may be
amenable to lifestyle
correction.
68
It is not rare to initiate insulin treatment with 10 units per day in a
young patient with type 1 diabetes only to find, when the lean adolescent
becomes an obese adult, that the dose requirement is ten times greater. The
type 1 patient is now as insulin resistant and hyperinsulinaemic as the type
2; only the source of the insulin is different. The value of a diagnostic
label lies in guiding appropriate treatment, but the classification
traditionally applied to diabetes is being stretched to its limit when the
obese patient with type 1 diabetes acquires the risk factors for
cardiovascular disease normally attributed to type 2. His health risks derive
mostly from insulin resistance, and his management needs are arguably more
metabolic than glycaemic.
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THE KEY TO MANAGEMENT OF THE METABOLIC SYNDROME IS WEIGHT REDUCTION
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Reducing blood glucose by addressing insulin resistance will
benefit every
spoke on the metabolic wheel. The sequence is
crucial, and has important
implications for management. The
mortality of type 2 diabetes is largely
macrovascular and related
to dyslipidaemia (some have sought to label the
condition ‘diabetes
lipidus’ in recognition of the
fact
69). More than
half
of all hypertension is attributable to insulin resistance, and
hypertension
is a major contributor to the arteriopathy of diabetes.
Guidelines
from the UK’s National Institute for Clinical Excellence
are
currently ‘glucocentric’. They view type 2 diabetes
essentially as
a disease of raised blood sugar, the primary
aim being to lower HbAc1. They
recommend beta cell stimulators
(sulphonylureas) as first-line agents in those
who are not
‘overweight’,
70
implying
that type 2 diabetes in those whose BMI is < 25 kg/m
2
may
not be related to insulin resistance. The data from Carey and
Zavaroni
cited earlier, however, suggest that BMI is a poor
indicator of insulin
resistance, and people with a BMI of 25
kg/m
2 already have a
five-fold increased population risk of
diabetes.
10 High
blood sugars are important to the development of microvascular
disease, but
sulphonylureas will raise rather than reduce insulin
levels and are, in any
case, of only temporary benefit because
they quickly exhaust the beta
cells.
71
Predictably perhaps,
hypertension in type 2 diabetes does not improve with
further
stimulation of the beta cell, while it falls in response to
insulin-lowering
strategies such as weight
loss,
72 physical
activity
73 and
insulin-sensitizing
agents.
74
As the management of diabetes is traditionally aimed at individual spokes
of the wheel rather than at the hub that drives them, patients frequently
receive multiple treatments individually destined to reduce blood pressure,
blood sugar, blood cholesterol, blood coagulability and weight. It must be
assumed that multiple drug interventions are advised because good-quality
evidence for alternative approaches is limited. Two large studies have
nevertheless shown how effective lifestyle intervention can
be75,76—though
whether at greater or lesser cost than polypharmacy is uncertain. Another
reason for the piecemeal approaches may be the traditional organization of
specialist clinics—weight management, hypertension, infertility,
diabetes, lipid—at different times, in different places and under
different clinicians. Perhaps an insulin resistance clinic (the
‘metabolic clinic’), to manage the cause underlying all of these
disorders, would offer focus, efficiency and better allocation of funds.
Weight gain and insulin resistance are the principal cause of metabolic
syndrome, and weight loss should be the first line of management, with all the
dietetic and psychology skills at hand to achieve it. Paradoxically, dietetics
is often the most difficult service in the National Health Service to finance
for weight management. Exercise reduces insulin resistance independently of
its action on body
weight,77 and this
is important, but physical activity is effective only for as long as it lasts,
and is less efficient in achieving weight loss than calorie reduction. Some
70–75% of energy expenditure is obligatory in the form of resting energy
requirements, so that a doubling of physical activity does not double energy
expenditure. Halving food intake will necessarily halve calorie intake, and
portion size is possibly the most important modifiable factor in the
management of obesity.
Two classes of insulin-sensitizing medication are available. Metformin has
been available for 50 years or more and, strictly speaking, reduces hepatic
glucose release rather than insulin
resistance.78 The
thiazolidinedione drugs stimulate peroxisome proliferator-activated receptors,
and act quite differently by controlling the genes involved in fatty acid
metabolism.79 The
obese patient with type 1 diabetes is deficient in endogenous insulin and
resistant to exogenous insulin. It is both rational and effective to reduce
this patient’s insulin needs with insulin sensitizing drugs. Blood
glucose control becomes easier and, more importantly, insulin levels
fall.80
Metabolic dysovulation is recognized increasingly as a disorder of insulin
resistance,81 and
affected women are increasingly asking the medical profession to prescribe
insulin sensitizers to assist
conception.82 What
cannot be obtained through the doctor is often procured from the internet.
Once pregnant, however, these women will understandably abandon the medication
and perhaps unwittingly embark on a pregnancy that is high-risk for both
mother and child. High insulin resistance is associated with an increased risk
to the mother of hypertension, gestational diabetes, pre-eclampsia and
caesarean section. The fetus is exposed to developmental defects, macrosomia,
pre-eclampsia and possibly metabolic disease later in life. Studies in Pima
Indians suggest that those born after a mother becomes diabetic have a greater
risk of weight gain and diabetes than those born before maternal development
of diabetes.83
These are important considerations in view of the ready availability of
metformin and the glitazones.
|
CONCLUSION
|
|---|
Metabolic syndrome has immense implications for national budgets,
because
its macrovascular complications are chronic and expensive
to manage. They
cause loss of productivity and seriously affect
wellbeing and self-fulfilment.
It is a central issue in public
health, and the politics of coping with it are
difficult and
complex. One thing is certain: our current understanding of
metabolic
syndrome came from painstaking research, and our ability to
deal
with it will only come from more of the same. Five-a-day
fruit campaigns and
break-time fruit for children for children
are not enough: a government
campaign for awareness at least
as powerful as the anti-AIDS campaign of the
1980s is needed
to shift public attitudes and behaviour.
|
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INTRODUCTION
OBESITY IS AFFECTING THE...
