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Diagnosis, epidemiology and pathogenesis of diabetes mellitus:

an update for psychiatrists


Richard I. G. Holt
BJP 2004, 184:s55-s63.
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B R I T I S H J O U R N A L O F P S YC H I AT RY ( 2 0 0 4 ) , 1 8 4 ( s u p p l . 4 7 ) , s 5 5 ^ s 6 3

Diagnosis, epidemiology and pathogenesis therefore to provide an update on current


thinking about diabetes for practising psy-
chiatrists, in order to improve the physical
of diabetes mellitus: an update for psychiatrists health of their patients. Since type 2 dia-
betes is the primary cause of concern for
RICHARD I. G. HOLT
patients with schizophrenia, it is the main
focus of this review.

METHOD

The current diabetes literature, the Na-


tional Service Framework for Diabetes,
Background Diabetes mellitus is a Diabetes mellitus is a complex metabolic
the National Institute for Clinical Excel-
complex metabolic disorder characterised disorder characterised by persistent hyper-
lence guidance on the management of dia-
glycaemia resulting from defects in insulin
by persistent hyperglycaemia.The betes and literature produced by Diabetes
secretion, insulin action or both. The two
prevalence of diabetes is increased in UK were reviewed.
main types of diabetes mellitus are type 1
people with schizophrenia. (formerly known as insulin-dependent
diabetes), and type 2 (formerly known as RESULTS
Aims To provide an update of current non-insulin-dependent diabetes). Type 1
thinking in diabetes for practising diabetes is caused by the autoimmune A brief history of diabetes
psychiatrists. destruction of the b-cells of the pancreatic The oldest description of diabetes as a
islets, whereas type 2 diabetes results from polyuric state dates back to 1550 BC in an-
Method Literature review. both impaired insulin secretion and resis- cient Egypt. The word diabetes, derived
tance to the action of insulin. Diabetes from the Greek meaning siphon or pass
Results Diabetes is a costly condition in affects around 3% of the adult UK through, was first used by Aretaeus of
individual, social and economic terms, and population (Bennett et al, al, 1995). As the Cappadocia in the 2nd century AD when
the global burden of diabetes is increasing prevalence increases with age, the lifetime he gave a clinical description of the disease.
risk of developing diabetes is around 10% In the 5th and 6th centuries, Indian physi-
in most populations.The insidious onset
(Neil et al,
al, 1987). cians recognised the sweet, honey-like taste
and asymptomatic nature of diabetes Diabetes is associated with premature of urine from polyuric patients, which
results in many people remaining undiag- mortality, predominantly through athero- attracted ants and insects. The Indian de-
nosed and at great risk of developing sclerotic vascular disease (World Health scriptions of diabetes mellitus also recog-
life-threatening vascular complications. Organization/International Diabetes Fed- nised the distinction between two forms of
eration, 1999). Microvascular complica- diabetes: one in older, fatter people, and
Lifestyle and pharmacological inter-
tions, which affect the small blood vessels the other in thin people who rapidly
ventions can reduce incident diabetes and in the eye, kidney and nerves, are associated succumbed to their illness.
delay its progression. with considerable morbidity. The economic The sweetness in the urine was redis-
and social costs of diabetes are enormous, covered by the Englishman Thomas Willis,
Conclusions Public health policies are both for health care services and through physician to King Charles II in the 17th
urgently required to encourage people to loss of productivity. In developed countries, century, who also noted the importance
follow a healthy lifestyle.Primary 10% or more of the total health budget is of lifestyle when he remarked that the pre-
spent on the management of diabetes and valence of diabetes was increasing because
prevention strategies for diabetes should
its complications (Jonsson, 2002; Zimmet of good fellowship and gusling down
target individuals at especially high riskof
risk of et al,
al, 2003). chiefly of unalloyed wine. A century later,
developing type 2 diabetes, including The prevalence of type 2 diabetes is Matthew Dobson in 1776 showed that the
those with severe mental illness. increased in patients with schizophrenia urinary sweetness was caused by sugar and
compared with the general population was associated with a rise in blood sugar.
Declaration of interest R.I.G.H. has (Holt et al,
al, 2004). Although many factors, At the turn of the 18th century, John
received educational grants and fees for including genetic and lifestyle issues, contri- Rollo was the first person to use the term
bute to this association, there has been a diabetes mellitus (honey) to distinguish
lecturing and consultancy work from Eli
recent surge in interest in the subject the condition from diabetes insipidus
Lilly & Co. because of the possible link between the (tasteless).
use of atypical antipsychotic drugs and the Claude Bernard, a French physiologist,
development of diabetes. The increased made several important advances in the
prevalence of type 2 diabetes among people 19th century when he discovered that
with schizophrenia has implications for sugar was stored in the liver in the form
the delivery of care by psychiatrists, as of glycogen, and that transfixion of the
well as for diabetologists and general medulla in conscious rabbits caused hyper-
practitioners. The purpose of this paper is glycaemia. Paul Langerhans, also working

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T
Table
able 1 1999 World Health Organization diagnostic criteria for diabetes mellitus (World Health Organiza- fasting glycaemia and impaired glucose
tion, 1999) tolerance; the latter can only be diagnosed
following a 75 g oral glucose tolerance test.
Plasma glucose concentration Fasting plasma glucose concentration (mmol/l) Impaired fasting glycaemia and impaired
glucose tolerance are not distinct clinical
2 h following a 75 g
entities, but rather risk factors for future
oral glucose test (mmol/l) 56.1 56.1^6.9 57.0
diabetes and cardiovascular disease
57.8 Normal Impaired fasting glycaemia Diabetes (DECODE Study Group, 2001). Indeed,
57.8^11.0 Impaired glucose tolerance Impaired glucose tolerance Diabetes the ADA has suggested that the new term
pre-diabetes be used to describe both
511.1 Diabetes Diabetes Diabetes
these abnormalities (American Diabetes
Association, 2002).
A diagnosis of diabetes has important
in the 19th century, discovered the pan- Diagnosis and Classification of Diabetes social, legal and medical implications for
creatic islets that now bear his name, Mellitus, 1997). In response, the WHO the patient, and it is therefore essential that
although it was Edouard Laguesse in 1893 updated its diagnostic criteria (Table 1). any diagnosis is secure. Diabetes should
who suggested that they were the endocrine According to the 1999 WHO criteria not be diagnosed on the basis of glyco-
tissue of the pancreas. In 1889, Joseph von (which are also endorsed by Diabetes UK), suria, and the blood glucose concentration
Mering and Oskar Minkowski removed the a diagnosis of diabetes is made if the fasting should be measured on a venous plasma
pancreas from a dog and discovered that blood glucose level is 7.0 mmol/l or more, sample in an accredited laboratory (World
the animal developed diabetes, demon- or a random blood glucose test shows a Health Organization, 1999). At present,
strating the important link between the level of 11.1 mmol/l or more. Only one test diabetes cannot be diagnosed by measuring
pancreas and diabetes. is required in a patient with classical glycosylated haemoglobin (HbA1c).
Several workers in different institutions diabetic symptoms; a supplementary test is
followed this observation by attempting to required in asymptomatic individuals. The
isolate the blood glucose lowering agent WHO recommends under these circum- Classification of diabetes
from the pancreas, culminating in the dis- stances that a 75 g oral glucose tolerance
The original WHO classification of dia-
covery of insulin in 1921 by a team based test is performed.
betes introduced in 1980 and revised in
at the University of Toronto, comprising Although the diagnostic criteria of the
1985 was based on clinical characteristics.
Frederick Banting, Charles Best, James WHO have a slightly different emphasis
The two most common types of diabetes
Collip and J. R. Macleod. In 1922, Leonard to those of the ADA, for clinical and
were insulin-dependent diabetes mellitus
Thompson was the first person to receive epidemiological purposes they are essen-
(IDDM) and non-insulin-dependent dia-
insulin, thus transforming the management tially identical, and can be considered to
betes mellitus (NIDDM), and this nomen-
of diabetes forever. represent an international consensus.
clature reflected the need for insulin to
Although insulin has major actions on It is instructive to consider why there
lipid and protein metabolism, this historical has been so much debate about the diag-
perspective explains why the focus of nosis of diabetes. Plasma glucose concentra-
diabetic management has been the normal- tions show a skewed normal distribution in
isation of blood glucose levels and why the the general population, and the delineation
diagnosis of diabetes is based on the finding of abnormal from normal thus becomes
of chronic hyperglycaemia. arbitrary. The WHO and ADA diagnostic
criteria reflect the concentration of plasma
glucose at which there is an association with
Diagnosis of diabetes the development of microvascular com-
Before the late 1970s, there was no consen- plications, particularly retinopathy (Pettitt
sus on the diagnostic criteria for diabetes. et al,
al, 1980). Although the relationship
This led to much confusion and precluded between the exposure to hyperglycaemia
any meaningful comparison of the preva- and microvascular complications is expo-
lence of diabetes within or between popula- nential allowing for a diagnostic cut-off
tions (West, 1975). In 1965 the World at the inflection of the curve the relation-
Health Organization (WHO) prepared its ship between hyperglycaemia and macro-
first expert report on the diagnosis of dia- vascular complications is more linear,
betes, and these diagnostic criteria were suggesting that there is no threshold for Fig. 1 Relationship between glycosylated

subsequently modified and simplified by the development of cardiovascular disease haemoglobin (HbA1c ) and microvascular disease
the WHO and the National Diabetes Group (Fig. 1; Stratton et al,
al, 2000). This implies (black line) and macrovascular complications
in the USA in 1979, 1980 and 1985. The that cardiovascular risk will also increase (myocardial infarction, white line) in 4585 patients
American Diabetes Association (ADA) then with increases in blood glucose concen- with type 2 diabetes (error bars, 95% CI).
proposed diagnostic criteria that placed a trations across the normal population. Reproduced from Stratton et al (2000) BMJ,
BMJ, 321,
321,
greater emphasis on fasting blood glucose The WHO diagnostic criteria also 405
405^^ 412 with permission from the BMJ Publishing
concentration (Expert Committee on the recognise two further categories: impaired Group.

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H I AT R I S T S

survive. The WHO classification also Studies indicate that genetic factors do Table 2 Worldwide prevalence of diabetes
recognised malnutrition-related diabetes not account entirely for the development
mellitus, other types of diabetes mellitus of type 1 diabetes, and several environmen- (n6106) Increase
Prevalence (n
associated with specific conditions, and tal triggers, including viral infections, nutri- (%)
gestational diabetes, which is diabetes diag- tional factors, parental age and low birth 2003 2025
nosed for the first time during pregnancy. weight, have been implicated (Akerblom (predicted)
In 1997, the ADA proposed a classification et al,
al, 2002).
that distinguished the types of diabetes Asia 81.8 156.1 91
according to aetiology, and this was sub- Europe 38.2 44.2 16
Type 2 diabetes
sequently endorsed by the WHO (see North America 25.0 39.7 59
Epidemiology
Appendix) (Expert Committee on the South America 10.4 19.7 88
Diagnosis and Classification of Diabetes Type 2 diabetes is a heterogeneous disorder Middle East 18.2 35.9 97
Mellitus, 1997; World Health Organiza- that results from an interaction between a
Africa 13.6 26.9 98
tion, 1999). The terms IDDM and NIDDM genetic predisposition and environmental
Australasia 1.1 1.7 59
were considered to be confusing, with factors. It accounts for around 90% of all
many clinicians categorising insulin-treated cases of diabetes. There are approximately Total cases 189 324 72
patients with NIDDM as having IDDM. 1.4 million people with diagnosed type 2 worldwide
The preferred terminology is now type 1 diabetes in the UK, with a further 1 million
Data from Zimmet et al (2003).
diabetes, which is equivalent to IDDM, having undiagnosed type 2 diabetes
and type 2 diabetes, which is equivalent to (Bennett et al,
al, 1995). The incidence of
NIDDM. Malnutrition-related diabetes diabetes increases with age, with most cases twin studies show a high concordance rate
was omitted from the new classification being diagnosed after the age of 40 years. (6090%) in monozygotic twins (Barnett
because its aetiology is uncertain, and it is This equates to a lifetime risk of developing et al,
al, 1981). A maternal history of diabetes
unclear whether it is a separate type of diabetes of 1 in 10 (Neil et al,
al, 1987). confers a higher risk of type 2 diabetes in
diabetes. The prevalence of diabetes is increasing the offspring than a paternal history of
rapidly. The World Health Organization diabetes (Thomas et al, al, 1994), possibly
(2003) has predicted that by 2030 the through an effect of maternal hyperglycae-
Type 1 diabetes number of adults with diabetes will have mia during pregnancy (Pettitt et al,
al, 1993).
Epidemiology almost doubled worldwide, from 177 Type 2 diabetes is a polygenic disorder,
million in 2000 to 370 million. Using the and it is clear that no single major locus
Type 1 diabetes is caused by an absolute
WHOs data, Zimmet et al (2003) have explains its inheritance. There appear to
deficiency of insulin, and it represents
compared current and predicted prevalence be many candidate genes involved in con-
around 10% of all cases of diabetes, affect-
for certain regions for the years 2003 and trolling insulin secretion and action, and
ing approximately 20 million people world-
2025 (Table 2). A marked geographical these are all likely to play a part in the
wide (American Diabetes Association,
variation in the prevalence of type 2 development of type 2 diabetes.
2001). Although type 1 diabetes affects all
age groups, the majority of individuals diabetes exists (Zimmet, 1982). The highest
are diagnosed either at around the age of rates are found in the Pima Native factors. The most important
Environmental factors.
45 years, or in their teens and early Americans of Arizona and in the inhabitants environmental risk factors for diabetes are
adulthood (Bloom et al,
al, 1975). of the South Pacific island of Nauru, where obesity and physical inactivity. The massive
The incidence of type 1 diabetes is approximately half the adult population explosion in obesity rates worldwide has
rising. Across Europe, the average annual have diabetes. In contrast, in the rural com- largely been responsible for the increase in
increase in the incidence in children under munities of China and Chile, the prevalence diabetes, and it is estimated that up to
15 years old is 3.4% (EURODIAB ACE is less than 1%. In general, rates of type 2 80% of all new cases of diabetes can be at-
Study Group, 2000), with the steepest rise diabetes are higher in urban populations tributed to obesity (Lean, 2000). In the UK,
in those under 5 years old (Karvonen et than in rural communities (Zimmet, 1982). the average body mass index (BMI) of a
al,
al, 1999). Regional and ethnic differences in the person with type 2 diabetes is 30.0 kg/m2
prevalence of type 2 diabetes reflect not (Jonsson, 2002); in the USA, 67% of those
only differences in environment, but also with type 2 diabetes have a BMI of more
Aetiology differences in genetic susceptibility. For ex- than 27 kg/m2 and 46% have a BMI of
The aetiology of type 1 diabetes remains ample, in the UK people from the Indian more than 30 kg/m2 (National Task Force
poorly understood, but it is likely that an subcontinent living in Southall have a rate on the Prevention and Treatment of Obe-
environmental factor triggers an auto- of diabetes four times higher than the local sity, 2000). The risk of developing type 2
immune process in a predisposed individ- White population (Mather & Keen, 1985). diabetes increases across the normal range
ual. Although the genetic susceptibility to of BMI, such that the risk in a middle-aged
type 1 diabetes is inherited, only 1215% predisposition. The heritability of
Genetic predisposition. woman whose BMI is over 35 kg/m2 is 93.2
of type 1 diabetes occurs in families. Twin type 2 diabetes is greater than for type 1 times greater than in a woman whose BMI
studies have shown that the concordance diabetes, and is estimated to account for is below 22.5 kg/m2 (Fig. 2; Colditz et al, al,
rate for type 1 diabetes in monozygotic 4080% of total disease susceptibility. 1995).
twins is around 2030% (Barnett et al, al, Many patients will have a family history In addition to total adiposity, the distri-
1981). of diabetes (Thomas et al, al, 1994), and bution of fat is important. For any given

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response (Kahn, 1978). The main advan-


tage of the latter definition is that it does
not restrict consideration of insulin action
to a solitary aspect of intermediary metabo-
lism.
The importance of insulin actions on
other aspects of intermediary metabolism,
including lipid and protein metabolism,
has now been appreciated. In 1988, Rea-
ven described syndrome X (now commonly
known as the metabolic syndrome or insu-
lin resistance syndrome) as the association
between several cardiovascular risk factors,
including hypertension, dyslipidaemia and
glucose tolerance, and he proposed that
insulin resistance was the underlying cause
(Reaven, 1988). Since his original descrip-
tion, it has been recognised that a signifi-
cant proportion of patients with the
metabolic syndrome do not have insulin re-
sistance (Ford et al,
al, 2002). The definition
of the metabolic syndrome has therefore
been modified: most notably, central obe-
sity has been added as a core feature. This
is important, as it is increasingly recog-
nised that central obesity is fundamental
to the origin of this disorder (Maison et
Fig. 2 Risk of developing diabetes according to body mass index (BMI) in 114 281 women participants in the
al,
al, 2001).
US Nurses Health Study. Data from Colditz et al (1995).
The metabolic syndrome is thought to
affect just under a quarter of American
level of obesity, the more visceral fat an assessed by the birth ponderal index adults (Ford et al,
al, 2002), and it is known
individual has, the greater the risk of (weight/length3) (Phillips et al,
al, 1994). to be a significant risk factor for type 2 dia-
developing diabetes (Carey et al, al, 1997). betes and cardiovascular disease. However,
Physical inactivity is also associated with one major problem with the concept of the
Pathogenesis
an increased risk of diabetes (Hu et al, al, metabolic syndrome has been the lack of
1999). In the US Nurses Health Study, Under normal physiological conditions, specific diagnostic criteria or an easy mea-
those in the top quintile for exercise plasma glucose concentrations are main- sure of insulin resistance. Fortunately, the
(equivalent to more than 200 min of tained within a narrow range, despite wide publication of diagnostic criteria, by the
exercise per week) had a 46% lower risk fluctuations in supply and demand, through National Cholesterol Education Program
of diabetes compared with those in the a tightly regulated and dynamic interaction and the WHO (Table 3), has largely recti-
lowest quintile (less than 20 min of exer- between tissue sensitivity to insulin (espe- fied this problem (Alberti & Zimmet,
cise). Although some of the difference can cially in the liver) and insulin secretion 1998; Expert Panel on Detection, Evalua-
be explained by differences in adiposity, (DeFronzo, 1988). In type 2 diabetes these tion, and Treatment of High Cholesterol
after adjusting for BMI those in the most mechanisms break down, with the conse- in Adults, 2001). These criteria have facili-
active quintile still had a 26% reduction quence that the two main pathophysio- tated epidemiological research as well as
in risk of diabetes. logical defects in type 2 diabetes are improving identification of individuals at
The intrauterine environment is also impaired insulin secretion through a risk of diabetes and cardiovascular disease.
considered to be important in the develop- dysfunction of the pancreatic b-cell, and
ment of type 2 diabetes. There are now over impaired insulin action through insulin
48 reports linking poor foetal growth with resistance. dysfunction. In response to glu-
Beta-cell dysfunction.
impaired glucose metabolism in later life cose, insulin is secreted in a characteristic
(Newsome et al,al, 2003). In most of these resistance. Insulin resistance is now
Insulin resistance. biphasic pattern: an acute first phase lasting
studies, birth weight has an inverse regarded as being synonymous with a re- a few minutes, followed by a sustained sec-
relationship with plasma glucose and insu- duced rate of whole-body insulin-mediated ond phase. The major b-cell abnormalities
lin concentrations, the prevalence of type 2 glucose disposal in insulin-sensitive tissues in type 2 diabetes are a marked reduction
diabetes and measures of insulin resistance (DeFronzo & Ferrannini, 1991; Moller & in first-phase insulin secretion and, in estab-
and secretion. Birth weight is a crude mea- Flier, 1991). This definition is too narrow, lished diabetes, an attenuated second phase.
sure of foetal growth, and it appears that and insulin resistance may be better defined Abnormalities in b-cell function are
adult glucose intolerance is more closely as existing when normal insulin concentra- found early in the natural history of type 2
associated with thinness at birth, as tions fail to produce a normal biological diabetes and in first-degree relatives of

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T
Table
able 3 Metabolic syndrome: National Cholesterol Education Program (NCEP) Adult Treatment Program III and World Health Organization (WHO) diagnostic
criteria

NCEP1 WHO2

Three or more of the following: Insulin resistance in the top quartile of the population
Abdominal obesity (waist 4102 cm in men, 488 cm in women) Impaired glucose tolerance or type 2 diabetes
Fasting triglyceride concentration 51.69 mmol/l (150 mg/dl) At least two of the following:
HDL cholesterol level 51.04 mmol/l (40 mg/dl) in men or Abdominal obesity (waist:hip ratio 4 0.90 or body mass index 530 kg/m2)
51.29 mmol/l (50 mg/dl) in women Dyslipidaemia
Hypertension 5130/85 mmHg (serum triglyceride concentration 51.70 mmol/l or HDL cholesterol 50.9 mmol/l)
Fasting blood glucose concentration 56.1mmol/l (110 mg/dl) (5160/90 mmHg)
Hypertension (5
Microalbuminuria

HDL, high-density lipoprotein.


1. From Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (2001).
2. From Alberti & Zimmet (1998).

people with type 2 diabetes (Pratley & As insulin sensitivity falls, the b-cell Drug-induced diabetes
Weyer, 2001), suggesting that they are an responds by increasing insulin secretion to Many drugs can worsen or precipitate
integral component of the pathogenesis of compensate and to maintain glucose con- hyperglycaemia through a number of
type 2 diabetes. centrations within the normal range. The mechanisms. These include drugs that are
In the UK Prospective Diabetes Study, maximal insulin secretory capacity is directly toxic to the b-cell, such as cyclo-
which was a large epidemiological study eventually reached and, beyond that point, sporin and pentamidine, or drugs that
of newly diagnosed patients with type 2 insulin secretion declines. The blood worsen insulin resistance, such as glucocor-
diabetes, long-term increases in fasting glucose concentrations rise, initially in the ticoids and high-dose thiazide diuretics.
plasma glucose levels were accompanied postprandial period, as the individual These effects are often reversible, but other
by a progressive decline in b-cell function develops impaired glucose tolerance before treatments should be used whenever poss-
of around 4% per year (UK Prospective the onset of frank diabetes. ible. Where no alternative exists, careful
Diabetes Study Group, 1995). By the time This process may, however, be reversi- monitoring of glycaemic control and treat-
of diagnosis, mean b-cell function was ble. Although around 25% of individuals ment of the diabetes can mitigate the effect
already less than 50%, and further with impaired glucose tolerance will of these drugs.
deterioration of b-cell function was not progress to diabetes each year, many revert Hyperglycaemia has been reported with
prevented by any of the diabetic therapies to normal (Saad et al,al, 1988), and since both conventional and atypical anti-
used in the study. there is good evidence to show that lifestyle psychotic drugs. These drugs are not
Extrapolation of the observed rate of b- intervention at this stage can reduce directly toxic to the b-cells (Sowell et al,
al,
cell decline suggests that the loss of b-cell incident diabetes, people falling into these 2002) but are associated with significant
function begins around 12 years prior to categories should be managed actively with weight gain (Allison & Casey, 2001), so
diagnosis (Holman, 1998; Fig. 3). This advice about their diet and exercise (Pan et the underlying mechanism has been as-
progressive loss of b-cell function explains al,
al, 1997; Tuomilehto et al,
al, 2001; Knowler sumed to be through an increase in insulin
why patients require escalations in the et al,
al, 2002). resistance (Sowell et al,
al, 2002). However,
number and dosage of oral hypoglycaemic
agents with time, and why eventually they
become refractory to the oral treatments
and require insulin.
Although the mechanisms underlying
the b-cell dysfunction remain unclear, they
are likely to be multifactorial. As well as
genetic factors (Pratley & Weyer, 2001), a
number of environmental factors (including
early-life malnutrition and obesity) and
hyperglycaemia and hyperlipidaemia per se
may all accelerate the decline in b-cell func-
tion (Hales et al,
al, 1991; Prentki et al,
al, 2002).
There has been much discussion about
the relative roles of insulin resistance and
b-cell function in the natural history of dia-
betes, since both components occur early in
the disease process. One model for the Fig. 3 Extrapolation of the time of deterioration of b-cell dysfunction. From Holman (1998) with permission
development of diabetes is shown in Fig. 4. from Elsevier.

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HOLT

randomised to receive a dietary inter-


vention, an exercise intervention, or a com-
bination of both, had a nearly 50%
reduction in risk of diabetes over 6 years
compared with a control group.
More recently, the results of the Finnish
Diabetes Prevention Study (Tuomilehto et
al,
al, 2001) and the US Diabetes Prevention
Program (Knowler et al, al, 2002) have been
published. In the Finnish study, 523 over-
weight individuals aged 4065 years with
impaired glucose tolerance were randomly
assigned to a control or lifestyle inter-
vention group and were followed for a
mean of 3.2 years. The control group was
given general verbal and written infor-
mation about a healthy diet and exercise;
the intervention group received individual-
ised dietary counselling, aimed at reducing
weight by 5%, reducing total fat and
saturated fat intake (to less than 30% and
10% of total energy intake, respectively)
and increasing intake of fibre, given in
Fig. 4 Natural history of insulin resistance and insulin secretion in type 2 diabetes.
frequent face-to-face sessions with a diet-
since there is no direct relationship between tolerance. This high prevalence of undiag- ician. The intervention group members
weight gain and the development of dia- nosed diabetes in the general population were encouraged to undertake 30 min of
betes, other mechanisms are thought to be should be borne in mind when interpreting aerobic exercise and resistance training
involved (Jin et al,
al, 2002). This is discussed epidemiological data assessing the effects of per day through individually designed
in greater detail by Haddad (2004, this antipsychotic medications on the develop- programmes. The proportion of individuals
supplement) and Bushe & Leonard (2004, ment of diabetes. who progressed to diabetes was reduced
this supplement). Around half of patients with type 2 dia- from 7.8% per annum in the control group
betes are diagnosed as a result of the typical to 3.2% per annum in the intervention
diabetic symptoms of polyuria, nocturia, group a substantial risk reduction of
Clinical features of type 2 diabetes 58%. The rate of diabetes was found to
thirst, tiredness and blurred vision; a further
Type 2 diabetes usually affects overweight 16% of patients are diagnosed after pre- be related to the number of targets
individuals, and most cases are diagnosed senting with an infection (UK Prospective achieved; there were no cases of diabetes
in those over 40 years old (Jonsson, 2002). Diabetes Study Group, 1988). Microvascu- during the study in those who achieved four
However, the demographics of this disease lar diabetic complications are frequently or five of the targets.
are changing, and it is now becoming present at the time of diagnosis, but account The Diabetes Prevention Program com-
increasingly common in children and young for only 2% of all presentations. pared the effectiveness of intensive lifestyle
adults (American Diabetes Association, modifications similar to those used in the
2000). Finnish study with metformin (850 mg
Type 2 diabetes has a gradual and Prevention of diabetes twice daily) treatment in preventing type 2
insidious onset, with nearly a third of cases One of the most exciting areas in diabetes diabetes (Knowler et al,al, 2002). Originally,
being identified as an incidental finding at present is a focus on the possibility that a third group received the thiazolidinedione
(1988) or in the coronary care unit type 2 diabetes can be prevented, or at least troglitazone, but this arm of the study was
(Malmberg et al,al, 1995). The diagnosis is its onset delayed. Interest in this area has stopped after the drug was withdrawn from
often delayed, and some degree of hyper- been rekindled by the publication of studies the market. A major strength of the
glycaemia may have been present for more showing that both lifestyle and pharmaco- Diabetes Prevention Program was its size
than 20 years before the diagnosis is logical interventions can reduce incident and diversity: 3234 people with impaired
confirmed (Liu et al,
al, 2002). This accounts diabetes. glucose tolerance took part, of whom 45%
for the so-called missing million people had non-White European backgrounds and
with undiagnosed diabetes in the UK. The 68% were women. After an average
Isle of Ely Diabetes Project was undertaken Lifestyle studies follow-up period of 2.8 years, the incidence
to determine the prevalence of undiagnosed The first randomised study to show that of diabetes in the lifestyle intervention
glucose intolerance in this community lifestyle interventions could reduce diabetes group was reduced by 58%; metformin re-
(Williams et al,al, 1995). Of the 1122 was the Da Qing Impaired Glucose Toler- duced incident diabetes by 31%. Since none
participants in the study, 4.5% were found ance and Diabetes Study published in of the trial participants received both the
to have undiagnosed diabetes, and 16.8% 1997 (Pan et al, al, 1997). Individuals with lifestyle intervention and metformin, it is
were found to have impaired glucose impaired glucose tolerance who were interesting to speculate whether further

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benefits might accrue from combining these blood pressure and lipid profile, were also microalbuminuria a higher than normal
interventions. A remarkable observation in achieved. albumin excretion that cannot be detected
both the Finnish and the American studies by standard urine reagent strips and a sign
was that the impressive reductions in dia- of early diabetic nephropathy is around
Screening for diabetes
betes were achieved with only moderate 2530%. Approximately 513% of pa-
reductions in weight. The high prevalence of undiagnosed dia- tients with type 2 diabetes have frank
Unfortunately, it is unlikely that the betes and the proportion of patients with proteinuria (American Diabetes Associa-
lifestyle intervention used in these studies evidence of complications at diagnosis tion, 2001). Although the individual risk
could ever be replicated outside a research undoubtedly create a strong imperative for of developing end-stage renal failure is
setting. Public health policies are therefore screening. Many possible screening meth- lower in type 2 diabetes, patients with this
urgently required that will encourage ods have been shown to be feasible, accep- form of diabetes requiring renal replace-
people to adopt a healthy lifestyle and table and accurate (Wareham & Griffin, ment therapy outnumber patients with
prevent the development of impaired 2001), but there is still debate about whom type 1 diabetes because of the much greater
glucose tolerance and diabetes. Primary to screen. Universal screening for diabetes prevalence of type 2 diabetes.
prevention strategies should target individ- is currently impractical because of the bur- Neuropathy affects 2050% of patients
uals at especially high risk of developing den that would be placed upon general with type 2 diabetes, and its sequelae, such
type 2 diabetes, including those with pre- practitioners (Wylie et al,al, 2002). There is as foot ulceration and amputation, cause
diabetes, first-degree relatives of people justification, however, for screening high- considerable morbidity and mortality (Boul-
with type 2 diabetes, women with a history risk groups in whom undiagnosed diabetes ton & Malik, 1998). Fifteen per cent of peo-
of gestational diabetes, individuals with is especially prevalent. Patients with schizo- ple with type 2 diabetes develop foot ulcers,
other features of the metabolic syndrome phrenia fall within this high-risk category, of whom 515% require foot amputations.
(Zimmet et al,al, 2003) and, I suggest, those and therefore should be considered for
with severe mental illness. screening for diabetes. This is discussed in
greater detail by Gough & Peveler (2004,
Pharmacological intervention this supplement). Macrovascular disease
In addition to the Diabetes Prevention Diabetes confers a two-fold to four-fold in-
Program, there have been several other Complications of type 2 diabetes creased risk of myocardial infarction and
pharmacological intervention studies. The Since the introduction of effective treat- stroke in men, and up to a ten-fold in-
STOP-NIDDM trial was designed to evalu- ment that allows patients with diabetes creased risk in pre-menopausal women
ate the effect of acarbose, an a-glucosidase to live through the acute metabolic conse- (2001). Mortality following a myocardial
inhibitor, in reducing the risk of type 2 quences of the illness, it has become ap- infarction is far greater in people with dia-
diabetes (Chiasson et al, al, 2002). After a parent that diabetes is associated with a betes. Furthermore, 6075% of all people
mean follow-up of 3.3 years, a 25% number of chronic microvascular compli- with diabetes die from cardiovascular dis-
relative risk reduction in progression to cations, which affect the eyes, kidneys ease (Stamler et al,
al, 1993). These statistics,
diabetes was observed in the acarbose- and nervous system, and macrovascular coupled with the observation that people
treated group compared with the placebo complications, which lead to an increased with diabetes who have not had a previous
group, with an absolute risk reduction in risk of myocardial infarction, stroke and myocardial infarction share the same risk
the acarbose-treated group of 9%. peripheral vascular disease. of having a myocardial infarction as non-
In the TRIPOD study (Buchanan et al, al, diabetic patients who have had a myo-
2002), 236 Hispanic women with previous cardial infarction (Haffner et al, al, 1998),
gestational diabetes were randomized to Microvascular complications have begun to shift the focus of manage-
receive either placebo or troglitazone. After Microvascular complications are frequently ment of diabetes from glucose control to a
a median follow-up of 30 months, troglita- present at diagnosis in patients with type 2 greater emphasis on arterial risk-factor
zone treatment was associated with a 56% diabetes. Retinopathy and cataracts each management.
relative reduction in incident diabetes. affect around 15% of individuals with Hyperglycaemia per se is insufficient to
Furthermore, a beneficial effect of the drug type 2 diabetes and are frequently present explain the increased prevalence of cardio-
was seen during the 8-month wash-out at diagnosis (UK Prospective Diabetes vascular disease in diabetes, and it is my
period immediately after the end of the Study Group, 1988; American Diabetes belief that increased prevalence of meta-
trial, suggesting that troglitazone might Association, 2001). Maculopathy a reti- bolic syndrome features in people with
affect the natural history of glucose intoler- nopathy affecting the macula and therefore diabetes largely explains the excess cardio-
ance, thereby preventing diabetes in some the central vision is the most common vascular disease in these patients (Stratton
people. cause of sight-threatening retinopathy in et al,
al, 2000). In the Prospective Cardio-
The results of the XENDOS study type 2 diabetes; proliferative retinopathy vascular MuMunster
nster Study, for example,
have recently been published (Torgerson the most common cause of sight-threatening 49% of individuals with diabetes had hyper-
et al,
al, 2004). In this study, the use of retinopathy in type 1 diabetes is less tension, 24% had a low level of high-density
orlistat plus lifestyle interventions reduced common. lipoprotein cholesterol and 37% had hyper-
the risk of developing type 2 diabetes by The risk of developing nephropathy is trigylceridaemia, compared with values of
37% compared with lifestyle interventions lower in type 2 diabetes than in type 1 dia- 31%, 16% and 21%, respectively, in people
alone. Furthermore, improvements in betes because of the generally later onset of without diabetes (Assmann & Schulte,
other cardiovascular risk factors, including the former disorder. The prevalence of 1988).

s 61
HOLT

DISCUSSION
CLINICAL IMPLICATIONS
Diabetes is already a costly disease in
individual, social and economic terms, and & Diabetes is associated with significant morbidity and premature mortality.
the global burden of diabetes is increasing.
Diabetes is associated with premature mor- & The prevalence of undiagnosed impaired glucose tolerance and diabetes is high,
bidity and mortality, and it should never be suggesting that active screening in high-risk groups would be advantageous.
considered to be a mild condition. Many
people with diabetes have asymptomatic
& Lifestyle modification and pharmacotherapy can prevent or delay the development
disease, and it is hoped that, with improved of type 2 diabetes.
screening procedures and better treatments,
LIMITATIONS
the long-term outlook for these individuals
will be greatly improved. & Most of the studies described in this article are in people without mental illness.

APPENDIX & An holistic approach, which is not solely focused on blood glucose, is needed to
prevent cardiovascular disease in people with diabetes.
The 1999 World Health Organization classifi-
cation of diabetes & A greater understanding of the molecular mechanisms that cause insulin resistance
Type 1 diabetes and pancreatic b-cell failure is needed.
Immune-mediated
Idiopathic
Type 2 diabetes
Equivalent to non-insulin-dependent
RICHARD I.G. HOLT, MA, MB, BChir, PhD, MRCP(UK), Endocrinology and Metabolism Sub-Division, Fetal
diabetes
Origins of Adult Disease Division, University of Southampton, Level F (MP113) Centre Block, Southampton
Type 3 diabetes (other specific types) General Hospital, Tremona
Tremona Road, Southampton SO16 6YD, UK. Tel: (0) 23 8079 4665; fax: (0) 23 8079 4154;
Diabetes secondary to pancreatic disease
righ@soton.ac.uk
e-mail: righ@
chronic pancreatitis
haemochromatosis
pancreatic surgery
American Diabetes Association (2000) Type 2 Chiasson, J. L., Josse, R. G., Gomis, R., et al (2002)
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