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METHOD
s55
HOLT
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
s57
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H I AT R I S T S
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
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.
s59
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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)
Diabetes secondary to endocrine disease diabetes in children and adolescents. Diabetes Care,
Care, 23,
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Lancet, 359,
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Cushings syndrome
American Diabetes Association (2001) Diabetes 2001 Colditz, G. A., Willett, W. C., Rotnitzky, A., et al
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