1

The Definition and Classification of

Diabetes Mellitus

H. KEEN
S. N G T A N G F U I

Diabetes earned its name from an uncommon combination of dramatic

symptoms and lethal outcome, distinctive enough to have made it one of the
earliest 'clinical syndromes' to be recognized and recorded by ancient
observers of human disease (Frank, 1957; Papaspyros, 1964). Recognition
of the central importance of surfeit of glucose in the urine and, later, in the
blood have led to a progressive expansion of the concept of diabetes
mellitus to the point where it is now considered a common and widespread
biochemical disorder of which the original descriptive, clinical entity
occupies only a small part. The concept of diabetes broadened first to
include patients with marked glycosuria and lesser symptoms and then, with
the application of automated biochemistry to population groups, large
numbers of totally asymptomatic persons found to transgress arbitrary
blood glucose norms. It is this conceptual expansion that has led to current
re-evaluations of diagnostic criteria and classification for the disease. The
search for satisfactory diagnostic blood glucose values recapitulates the
history of this conceptual expansion; the clinical origins of diabetes remain
indelibly stamped upon the terminology of classification. In essence, recent
reviews have set boundaries to the diagnostic expansion, resulting in some
withdrawal from the limits which biochemical 'diagnosis' had reached. This
is signified by the upward revision of diagnostic blood glucose criteria for
'diabetes mellitus' (DM) and the introduction of the new intermediate class
of 'impaired glucose tolerance' (IGT).
Recognition of the variety of genetic and environmental factors that may
give rise to the diabetic state and its sequelae (Fajans, Cloutier and
Crowther, 1978) has prompted attempts to introduce aetiological mech-
anisms into an essentially clinical classification. This creates problems,for
individual aetiological mechanisms may express themselves in several
clinical forms, and a given clinical form may owe its origin to a number of
pathogenic mechanisms. Thus, although the diabetogenic process
associated with particular histocompatibility (HLA) types and certain
autoimmune phenomena (Madsbad et al, 1980; Nerup and Lernmark, 1981)
usually expresses itself as the severely symptomatic 'classical' syndrome, it
Clinics in E n d o c r i n o l o g y a n d M e t a b o l i s m - - Vol. 11, No. 2, JuIy 1982. 279
0300-595X/82/11.02/279 $03.00 © 1982 W. B. Saunders Company Ltd.
280 H. KEEN AND S. NG TANG FUI

may also be associated, for varying periods of time, with less urgent
manifestations, with asymptomatic impairment of glucose tolerance or even
with normal metabolism (Irvine, Gray and Steel, 1980; Gorsuch et al, 1981).
It also appears probable that similar clinical types of diabetes will, on some
occasions or in some populations, be generated by quite different
mechanisms. Unless this is understood, the effort to incorporate both
clinical manifestations and causal mechanisms in the same classification
scheme is likely to be misleading and to lead to fruitless argument.

DEFINITION OF DIABETES AND ITS EVOLUTION

A clear definition of DM is an essential prerequisite for its diagnosis and
classification into subtypes.
The historical description and naming of diabetes is usually attributed to
Aretaeus of Cappadocia who, in the first century AD, described 'a
wonderful but not very frequent affection among men, being a melting
down of the flesh and limbs into urine . . . life is short, disgusting and
painful, thirst unquenchable, death is inevitable'. Derived exclusively from
the clinical phenomena of thirst, polyuria and weight loss, the classical
account describes manifestations now known to arise from severe,
ultimately lethal insulinopenia, only the tip of the 'diabetic iceberg'.
A great expansion in numbers and a substantial shift in the diagnostic
concept followed the inclusion of the much more abundant, non-lethal
variant, characterized by symptoms of variable kind and degree, often
including thirst and polyuria, sometimes including features of accom-
panying vascular disease, but always associated with marked glycosuria.
Initially, the glycosuria was crudely recognized by the sweetness and
stickiness of the urine or its attractiveness to insects, properties mentioned
in ancient writings (Papaspyros, 1964). The importance of glycosuria in the
recognition of diabetes was clearly implanted in European medicine by
Thomas Willis (1679) in his account of the 'pissing evil'. The term 'mellitus'
(honeyed) was added by Cullen after Matthew Dobson (1776), a century
later, identified the sweetness of the urine as due to a yeast-fermentable
sugar, subsequently characterized as glucose.
By 1835, Ambrosiani (cited by Renold, Stauffacher and Cahill, 1976) had
established that the glycosuria and polyuria of diabetes were the
consequence not of abnormality of the kidneys, but of the greatly elevated
circulating concentration of glucose, a discovery which was followed by the
experimental studies of Claude Bernard and ushered in the modern era of
understanding.

GLYCOSURIA AND HYPERGLYCAEMIA

By the mid nineteenth century, diabetes was no longer diagnosed exclusively
on clinical grounds, but needed chemical confirmation to establish glyco-
suria and, later, elevated blood glucose concentrations. This differentiated
DM from other polyuric conditions such as diabetes insil~idus and also from
other melliturias such as that due to low renal threshold or sugars other than
glucose in the urine. As simpler tests developed, the chemical abnormalities
D E F I N I T I O N AND CLASSIFICATION 281

of diabetes were increasingly frequently detected in older patients, often

with inconspicuous clinical symptoms, and in many cases with a history of
obesity rather than of wasting. When urine testing became a routine part of
medical examination, glycosuria was detected in the absence of significant
polyuria or polydipsia. Sometimes it was found with significant associations
such as gangrene or cataract, and also came to light in apparently healthy
subjects undergoing routine medical examination for employment or
insurance and, more recently, in diagnostic screening in population surveys.
Though marked glycosuria with symptoms of osmotic diuresis is almost
always indicative of underlying diabetes, simple glycosuria is frequently a
falsely positive indicator, especially in young people, during pregnancy,
after a heavy carbohydrate meal or among groups with 'low renal threshold'
for glucose (Butterfield, Keen and Whichelow, 1967) or recognized clinical
associations. Furthermore, in older people, particularly older women,
negative urine tests for glucose may accompany diagnostic degrees of
hyperglycaemia, masked by the rising renal threshold with age. The
demonstration of glycosuria thus came to be seen as an indirect diagnostic
marker for diabetes, an important if somewhat unreliable and occasionally
misleading guide to underlying hyperglycaemia.
The vulnerability of the diabetic to eye, kidney, nerve and arterial disease
had long been recognized clinically, but was much magnified in frequency
and importance when insulin greatly prolonged the life-span of the
'classical' diabetic. Microvascular disease and, ultimately, abnormalities of
function affecting the retina and kidney, the various types of neuropathy
and the increased liability to major obstruction of leg, coronary and
cerebral circulations were so frequently seen that they became regarded as
inherent parts of the diabetic syndrome. These delayed complications, of
which retinopathy is probably the most characteristic and clinically the most
readily identified, coupled with chronic hyperglycaemia, have come to
underlie and to unify the modern concept of the diabetic syndrome.

TESTS OF GLUCOSE TOLERANCE

The need to make a chemical diagnosis in the absence of symptoms, and the
drive towards earlier diagnosis in the hope of preventing long-term
complications, reinforced the search for standardized conditions under
which glucose metabolism could reliably be evaluated. Blood glucose
concentration rises promptly after the intake of readily absorbed carbo-
hydrate foods, long known to aggravate the glycosuria, hyperglycaemia and
symptoms of the diabetic. The 'provocation' of hyperglycaemia with a
carbohydrate load, the glucose tolerance test (GTT), was introduced early
in this century (Jacobsen, 1913) as a sensitized diagnostic probe for
abnormal glucose metabolism. In its commonly practised form, it assesses
the ability of the individual to maintain blood glucose homeostasis
following a single substantial oral glucose challenge. Intravenous adminis-
tration of glucose (IVGTT) has also been explored as a provocative test
(Amatuzio et al, 1953; Lundbaek, 1962; Ganda, Day and Soeldner, 1978)
but is rarely used as a routine diagnostic procedure. The oral glucose
282 H. KEEN AND S. NG TANG FUI

tolerance test (OGTT) has become established as the diagnostic yardstick

and many variants have been applied to healthy subjects and diabetics to
define normal and abnormal ranges of blood glucose responses. The earliest
studies were reviewed by Goldberg and Luft (1948) and the subject of the
diagnostic use of the O G T T was widely surveyed by West (1978a). The size
of the oral glucose load, the timing and source of the blood samples, the
analytical methods employed and the criteria by which results were judged
normal or abnormal have all varied widely. This has hindered comparison
of results between groups and led to major differences, even among diabetes
experts, in the diagnostic criteria for diabetes used clinically (West, 1975).
In 1950 Mosenthal and Barry, on the basis of O G T T after 100 g glucose
in 50 healthy young subjects, recommended that diabetes should be
diagnosed when the peak venous plasma glucose concentration exceeded
150 mg/dl and the two-hour value (2 H P G ) exceeded 100 mg/dl, criteria
subsequently quite widely adopted for the diagnosis of diabetes in the USA.
A contemporary report by Moyer and Womack (1950), based on O G T T
data from 103 healthy young soldiers, proposed marginally higher
diagnostic values (i.e., a one-hour value (1 H P G ) of 168 mg/dl and a 2 H P G
of 106 mg/dl). The later criteria of Fajans and Conn (1959) were also
derived from studies on selected healthy young individuals. Their glucose
load was 1.75 g/kg ideal body weight and they recommended as diagnostic
combination a 1 H P G of 160 mg/dl or more and a 2 H P G of 120 mg/dl or
more. Another widely used set of criteria was proposed by Wilkerson
(Remein and Wilkerson, 1961) and adopted by the US Public Health
Service. They used a different approach to the interpretation of the O G T T
(100 g), recommending rather higher diagnostic values for the one- and two-
hour samples. Blood glucose limits in the fasting state and at one, two and
three hours after the load were set at 130, 195, 140 and 130 mg/dl respec-
tively. Attaining or exceeding the fasting or three-hour values scored one
point each, breaching the other ratings scored half a point. A total score of
2 points or more diagnosed diabetes; 1 or 1 ½ were considered borderline
cases.
The British Diabetic Association (Fitzgerald and Keen, 1964) recom-
mended a 50 g oral glucose load and based the diagnosis of diabetes on a
2 H P G of 110 mg/dl or more with a preceding peak value of 160 mg/dl or
more, values similar to Fajans and Conn's (1959). The British methodology
and criteria were officially endorsed in the First Report of the W H O Expert
Committee on Diabetes Mellitus (1965): but never widely applied. After
comprehensive review the OGTT, its methods and interpretation by the
American Diabetes Association (Klimt et al, 1969) the society's recom-
mendations were widely accepted in and outside the US.
West (1978a) lists at least 17 different tests and sets of diagnostic criteria
recommended throughout the world between 1959 and 1976, and comments
on the widely differing estimates of diabetes prevalence, depending on
which were employed. Glucose loads of 100 g and 50 g were used by most,
75 g by some and a variable load, proportional to ideal body weight or
surface area, by others. Glucose was measured in capillary or venous blood
samples, in whole blood, or in serum or plasma (with or without arbitrary
DEFINITION AND CLASSIFICATION 283

'corrections' for source). Some analytical techniques measured total blood

reducing activity, some 'true glucose'. The fasting and two-hour time points
were usually included as diagnostically important sampling times, but some
required one or more intervening samples and some a three-hour value.
Allowance for age was made in some, but not in all, sets of criteria.
West found the two-hour value considered diagnostic of diabetes to vary
from 130 mg/dl to 260 mg/dl. Reporting on a postal enquiry into the
diagnostic values used by an American and an international group of
diabetes experts (West, 1975) he found as much variation in actual practice
within the US as between countries. The lowest two-hour concentration
considered clearly abnormal ranged from 120 to 200 mg/dl (mean 160
mg/dl). The highest value considered normal ranged between 110 and
180 mg/100 ml (mean 140 mg/dl). This wide overlap meant that the same
test results could be interpreted by one expert as unquestionably diabetic
and by another as definitely normal, disconcerting for the patient if not for
the doctor and highly unsatisfactory for epidemiological comparisons
(Valleron et al, 1975). Jarrett and Keen's (1976) estimated prevalence of
diabetes in a random sample of the Bedford population (see below) varied
from 6.6 per cent to 35 per cent, depending upon which of a series of
glycaemic criteria were applied. Population studies which based estimates
of the prevalence of diabetes on O G T T results applying commonly used
criteria gave far higher figures than those generally accepted, calling the
O G T T into question as an epidemiological diagnostic tool.
These problems were pungently summarized by Siperstein (1975) when he
was moved to term the glucose tolerance test 'a pitfall in the diagnosis of
diabetes mellitus'. The subject of methodology and diagnostic criteria was,
therefore, ripe for reconsideration. The recent reviews discussed below,
culminating in new recommendations, go a long way towards meeting the
problems. Unlike earlier recommendations, they have the advantage of
being based upon larger, epidemiologically sounder population samples and
planned observation of natural history across time.
Epidemiological and long-term follow-up studies
A major dilemma which has always beset diagnosis of diabetes is the
absence of any glucose-independent marker of the diabetic state against
which selected values of glycaemia can be validated in respect of their
diagnostic sensitivity, specificity, accuracy and reproducibility. In cases
with severe glycaemic abnormality accompanied by symptoms, there is no
diagnostic difficulty. It is in asymptomatic individuals, coming under
diagnostic suspicion indirectly or brought to light in population surveys,
that the difficulties multiply. Using population data to select diagnostic
criteria raises questions of its own. A statistical approach to diagnosis can
be adopted: with this, values of blood glucose exceeding the mean plus twice
(or, if one wishes to be more rigorous, thrice) the standard deviation may be
classified as abnormal. The biological justification for such an approach is
insecure. Values so selected will vary from population to population and be
influenced by the degree of skewing or the existence of bimodality in blood
glucose distributions. Alternatively, one may elect to nominate as diabetic
284 H. KEEN AND S. NG TANG FUI

the top one, two or five (or whatever) per cent of the population of
glycaemic responses. However, there must be reservations in the use of a
method which enables one to make diabetes as rare, or as common, as one
decides; variability in blood glucose ranges between populations would lead
to great variation in 'cut-off' values. Diagnostic values may be based on the
opinion of clinical experts, but West's (1975) findings show the lack of
unanimity which excludes such a strategy. A rational, though by no means
convenient, approach to validation is the empirical one, namely to ask the
question 'what degree of glucose intolerance is associated with increased
risk of adverse outcome?' rather than 'what glucose values define DM?'.
The answer to this question requires adequate observation of the evolution
and natural history in people with those degrees of hyperglycaemia or
glucose intolerance which span the region of diagnostic contention. Even
this empirical approach has the drawback that given degrees of glucose
intolerance may have variable effects in different people, determined by a
variety of secondary genetic and environmental factors. These and other
epidemiological aspects of diagnosis were considered at length at a Kroc
Foundation International Conference (1979).
Age and diabetes diagnosis
The diagnosis of diabetes by glucose tolerance test is most often made in
older adults, but early criteria were based on small samples o f selected
healthy young subjects. Variation with age occurs in the case of many
biological variables such as body weight, blood pressure, plasma lipids and
thyroid function, and this extends to oral glucose tolerance responses
(Andres, 1971; Davidson, 1979). Cross-sectional population studies all
agree that glucose tolerance 'deteriorates' with increasing age, particularly
after 50 years. The average 2 H P G rises approximately 10 mg/dl (0.5
mmol/1) each decade after the fifth and some recommend a correction to
'allow' for this. However, it is not clear whether the loss o f glucose
tolerance in the elderly should be regarded as benign or pathological, a
physiological consequence of ageing or the emergence of diabetes with time.
A recent review (Keen and Fuller, 1980) concluded that, particularly in
respect of risk of arterial disease, glucose intolerance was a hazard at all
ages. However, Davidson (1979) recommended that diabetes should be
diagnosed in the elderly only if fasting hyperglycaemia were present.

The Bedford and Whitehall studies

The Bedford survey, carried out in 1962 (Sharp, Butterfield and Keen,
1964), was designed to discover the prevalence of undiagnosed diabetes in
an English country town, to assess screening techniques and to estimate the
prophylactic value of early diagnosis. Of 38 400 registered voters aged 21
years or more, 25 701 provided a screening postprandial urine sample for
glucose analysis. Of these, four per cent (1046) were positive to Clinistix
(Ames Co. Ltd) and 986 accepted the invitation to submit to a simplified
OGTT, a single, capillary whole blood glucose measurement two hours
after a 50 g oral glucose load (2 HBG) taken after ar~ overnight fast
(glycosuric sample). In addition, 600 subjects (whether glycosuric or not,
D E F I N I T I O N AND CLASSIFICATION 285

but excluding known diabetics) were randomly sampled from the whole
cooperating population, stratifying for age and sex. A full, standard 50 g
glucose O G T T was performed on the 572 of those who agreed (random
sample).
The 2 HBG concentrations in both glycosuric and random samples were
unimodally and 'continuously' distributed, positively skewed towards the
higher values and lacking any natural division which would differentiate a
normal from a diabetic subpopulation. Mean values in the random sample
rose steadily with age, due to progressive spreading of values to the right.
There was no justification in these distributions for the then prevailing
diagnostic 2 HBG values, nor did they clearly suggest any other.
Application of the 1964 British Diabetic Association diagnostic criteria
(Fitzgerald and Keen, 1964) (a peak response >/180 mg/dl and a two-hour
value of >i 120 mg/dl) to the random sample responses gave an overall
prevalence of diabetes of 12 to 14 per cent (predominantly from those aged
50 years or more), a dramatically higher estimate than the widely quoted
figure of one to two per cent. As a basis for a prospective diagnostic and
therapeutic evaluation, a three-tier classification of the blood glucose
responses was, therefore, proposed.
1. Diabetes mellitus. A two-hour capillary blood glucose >/ 200 mg/dl
(11.1 mmol/1) was taken as diagnostic o f DM, being acceptable as such by
virtually all authorities.
2. Non-diabetic. A two-hour value < 120 mg/dl (6.7 mmol/1) was
designated as non-diabetic since this too was very widely acceptable as
normal, even by the most inclusive sets of criteria.
3. Borderline diabetes. The range of two-hour blood glucose values
between 120 and 200 mg/dl (6.7 and 11.1 mmol/1) was designated
'borderline diabetes'. This demarcated a zone of diagnostic uncertainty
where authoritative sources differed in their interpretation and which was,
therefore, ideally suited for planned, long-term evaluation of pathological
significance.
The prevalence of retinal and renal abnormalities and of clinical/electro-
cardiographic evidences of arterial disease was studied systematically using
standardized methods in the borderline diabetic and the newly diagnosed
diabetic groups, and also in a matched proved normoglycaemic group
selected without bias from the random sample.
At inception, the key 'borderline diabetic' group showed very little
evidence of retinal abnormality, the 1.3 per cent affected having at most
two microaneurysms in one eye, in contrast with the six to seven per cent
affected diabetics, in whom lesions were considerably more numerous
(Jarrett and Keen, 1976). Arterial disease was, by comparison, distinctly
more abundant in borderline diabetics than in normoglycaemic subjects,
and intermediate in frequency between normoglycaemic and diabetic
subjects (Keen et al, 1965).
The borderline diabetics were submitted (with their fully informed
consent) to a double-blind, randomly allocated clinical trial of tolbutamide
286 H. KEEN AND S. NG TANG FUI

a n d / o r diet a n d w e r e f o l l o w e d up for 10 y e a r s ( J a r r e t t et al, 1982; K e e n ,

J a r r e t t a n d M c C a r t n e y , 1982). M e t a b o l i c w o r s e n i n g to d i a b e t e s (a s u s t a i n e d
o r s e v e r e e l e v a t i o n o f 2 H B G >i 200 m g / d l ) o c c u r r e d in 36 o f 221 e v a l u a t e d
s u b j e c t s , a n a v e r a g e r a t e o f 1.2 p e r c e n t p e r y e a r ( T a b l e 1). A h i g h
p r o p o r t i o n o f t h e g r o u p f a i l e d to s u s t a i n t h e i r b o r d e r l i n e status a n d r e v e r t e d
to n o r m a l t o l e r a n c e . M e t a b o l i c f a t e in this g r o u p was n o t s i g n i f i c a n t l y
i n f l u e n c e d by a s s i g n m e n t t o e i t h e r t o l b u t a m i d e o r diet t r e a t m e n t g r o u p s .
T h o s e b o r d e r l i n e d i a b e t i c s w h o n e i t h e r r e m i t t e d n o r d e t e r i o r a t e d failed to
d e v e l o p r e t i n a l o r r e n a l a b n o r m a l i t i e s . T h e b o r d e r l i n e g r o u p as a w h o l e
s h o w e d i n c r e a s e d m o r b i d i t y a n d m o r t a l i t y ( K e e n et al, 1981) w h i c h was
a t t r i b u t e d to c a r d i o v a s c u l a r disease ( T a b l e 2). I n t h e n e w l y f o u n d d i a b e t i c
g r o u p , b y c o n t r a s t , t h e r e was a s p e c t a c u l a r rise in r e t i n o p a t h y rates to o v e r
30 p e r c e n t a f t e r f i v e y e a r s o f f o l l o w - u p .

Table 1. Baseline characteristics of Bedford "borderline diabetic" subjects by metabolic fate at

lO-year follow-up
Worsened Stable Reverted
to diabetes borderline to normal
Number a 36 55 128
Age in years 56 _+2 ** 68 _+ 1 ** 52 _+2 *
BMI weight (kg)/height (m 2) 27.6 _+ 0.8 ** 24.9 _+ 0.6 ** 27.0 _+0.5
Triceps skinfold (mm) 15.8 _+ 1.8 13.6 _+ 1.2 * 16.8 _+ 1.2
Systolic BP (mmHg) 167 -+ 5 165 _+ 4 167 _+ 5
Blood glucose (mg/dl) 164 _+ 2 ** 146 _+ 3 * 140 -+ 3 **
Two-hour plasma insulin (mu/1) 24.4 _+ 7.4 29.3 -+ 3.9 * 17.8 _+ 2.7
Urine albumin (mg/2 hour) 1.4 _+0.6 2.4 _+ 0.8 * 0.7 _+ 0.2
% Cigarette smokers 61 62 62
% Female 48 49 51
% 1st degree family history of DM 19 2 12
aTwenty-two of the total of 241 subjects qualifying to enter this analysis had fewer-than the six
two-hour blood glucose estimations necessary for allocating a metabolic fate with certainty. A
subject was considered 'worsened to diabetes' when two consecutive or three non-consecutive
blood glucose values two hours after 50 g glucose were >/200 mg/dl (as in 28 of the 36), when a
single value was /> 200 mg/dl with diabetic symptoms (three subjects) or when, at a final
10-year full OGTT, 2 HBG >/200 mg/dl regardless of prior values (five subjects). Two grades
of 'reverted to normal' were recognized (pooled here, but treated separately elsewhere), a
'minor' grade when at least two consecutive or three non-consecutive two-hour values were <
120 mg/dl (74 subjects) and a 'major' grade when no more than two such values were > 120
mg/dl (54 subjects). Neither in simple tabular analyses nor in multivariate analysis did the
randomized 'treatment' with tolbutamide and/or diet significantly influence metabolic fate.
*P < 0.05; ** P < 0.01 (for adjacent groups or between end columns).

C o m p a r a b l e results w e r e o b t a i n e d in t h e p r o s p e c t i v e W h i t e h a l l s t u d y o f
204 s u b j e c t s w i t h ' b o r d e r l i n e d i a b e t e s ' d e t e c t e d in a s y s t e m a t i c s c r e e n i n g
s t u d y o f 2 0 0 0 0 m a l e civil s e r v a n t s a g e d 40 y e a r s o r m o r e ( R e i d et al, 1974).
A f t e r f i v e y e a r s , 27 m e n h a d ' w o r s e n e d to d i a b e t e s ' , a r a t e o f less t h a n t w o
p e r c e n t p e r y e a r ( J a r r e t t et al, 1979) a n d o f t h e s a m e o r d e r as f o r t h e
B e d f o r d b o r d e r l i n e g r o u p . M o r t a l i t y a s c r i b e d to c a r d i o v a s c u l a r d i s e a s e w a s
d o u b l e d b y c o m p a r i s o n w i t h n o r m o g l y c a e m i c m e n ( F u l l e r et al, 1980) b u t
n o d i a b e t i c r e t i n o p a t h y was o b s e r v e d in t h e b o r d e r l i n e g r o u p ( J a r r e t t a n d
A1 S a y e g h , 1978; A1 S a y e g h a n d J a r r e t t , 1979).
D E F I N I T I O N AND CLASSIFICATION 287

Table 2. Mortality at lO-yearfollow-up in Bedford study in the three glycaemic groups defined
in 1962
Normoglycaemic Borderline Newly found
control diabetic diabetic
Men Women Men Women Men Women
Number 104 85 130 119 51 63
All causes of mortality °/0 15.4 9.4 18.7 20.9 25.9 25.5
Cardiovascular death % 10.0 4.0 13.5 14.8 19.9 20.0

Mortality data ascertained on 10th anniversary of recruitment to trial by intensive enquiry.

Cause of death from certificate. Rates age standardized.

It may be concluded from the Bedford and Whitehall studies that

'worsening to diabetes' in borderline diabetic subjects will occur at a rate of
two per cent or less per year, that a substantial proportion will revert to
normal or near-normal glucose tolerance and about one-third will remain in
the borderline range. This may not be true for borderline groups initially
selected in a different way (e.g., from among relatives of diabetics, from the
obese or the pregnant) but is probably applicable to broad population
samples. Similar rates were seen in a Swedish borderline group (Sartor,
Schersten and Carlstrom, 1980) where it appeared that tolbutamide
treatment may have reduced rates of metabolic deterioration. In the
Birmingham Diabetes Survey Working Party (1976) follow-up of subjects
submitted to O G T T 10 years before, deterioration rates were somewhat
higher, but were based on different criteria and on the results of a single
repeat test. Though at higher risk for arterial disease than normoglycaemic
subjects, neither the Bedford nor the Whitehall borderline groups
developed significant specific diabetic retinopathy over the observation
period, unlike those groups with 2 HBG i> 200 mg/dl (11.1 mmol/1), in
whom increased prevalence and incidence of retinopathy were seen.
Studies in special population groups
Further justification for upward revision of glycaemic criteria for diabetes
has come from observations upon two carefully studied ethnic subgroups,
the Pima Amerindians (Bennett et al, 1976) and the Micronesian people
inhabiting the Pacific island of Nauru (Zimmet and Whitehouse, 1978).
These groups differ from each other and from Caucasian populations in
their ethnic origins and cultural patterns, but they nevertheless share certain
important characteristics. They are both isolated, highly inbred small
communities, comparatively recently exposed, though for different reasons,
to nutritional adequacy and surfeit. Both are remarkable for the frequency
of comparatively recently acquired obesity and, perhaps as a consequence, a
uniquely high prevalence of diabetes. Both populations differ from others
in showing distinctly bimodal distributions of both fasting plasma glucose
(FPG) and 2 H P G . The point of intersection of the two subdistributions of
FPG is at approximately 140 mg/dl (7.8 mmol/1) and of 2 H P G at or above
200 mg/dl (11.1 mmol/1). Diabetic symptoms, microvascular disease of the
retina and proteinuria indicative of diabetic kidney disease in the Pima
288 H. KEENAND S. NG TANG FUI

Indians where they have been systematically ascertained are largely

restricted to subjects in the upper, 'diabetic' glycaemic distribution. These
observations do not distinguish between the alternative hypotheses that
specific delayed complications of diabetes occur above a 'threshold' degree
of glucose intolerance, however occasioned, or that they are an integral part
of a qualitatively, probably genetically, differing diabetic subset. They do,
however, support the argument for upward revision of glycaemic criteria
for diabetes.
These long-term observations and others detailed elsewhere (National
Diabetes Data Group, 1979) gave force and support to the recommend-
ations, now widely accepted, that the diagnosis of DM should be restricted
to subjects with two-hour capillary blood glucose /> 200 mg/dl (11.1
mmol/1). This protects people with the lesser degrees of glucose intolerance
from the social, psychological and economic disadvantages of being
labelled diabetic, even though qualifying terms such as 'borderline',
'chemical' or 'latent' are used. However, degrees of glucose intolerance
intermediate between the clearly normal and the newly recommended higher
levels for diabetes cannot be disregarded because of the increased risk of
arterial disease and of subsequent 'worsening to diabetes'. This range has
been incorporated into the new at-risk category of 'impaired glucose
tolerance'.

NEW DIAGNOSTIC CRITERIA

Origins
Against the background described above, several authoritative bodies have,
over the last few years, reviewed diagnostic methodology and criteria with
the objective of rationalizing, standardizing and, if possible, achieving
international agreement. An early review originated from the medical and
scientific section of the British Diabetic Association. It was put to the
European Association for the Study of Diabetes (EASD) through an
editorial in Diabetologia (Keen, Jarrett and Alberti, 1979) 'to promote
discussion and wide consultation' preparatory to the reconvening of the
WHO Expert Committee on Diabetes. Virtually concurrently, the US
National Diabetes Data Group (NDDG) of the National Institutes of Health
convened a working group (including four European members) which
reported its deliberations and conclusions (National Diabetes Data Group,
1979) after seeking the general concurrence of American professionals. Like
EASD, the NDDG report concerned itself with diagnostic criteria, but, in
addition, it formulated a new classification. When the WHO Expert
Committee met and prepared its Second Report (World Health Organisa-
tion, 1980) both of these widely discussed documents were available to it.
It provisionally accepted the NDDG classification 'en bloc', drawing
attention to some need for review.
Criteria
The three sets of recommendations (EASD, NDDG, WHO) are not
identical, but have many important features in common (see Table 3).
DEFINITION AND CLASSIFICATION 289

Table 3. Glycaemica'b criteria for diagnosis of diabetes mellitus (DM) and impaired glucose
tolerance (IGT) from the 75G OGTT
Fasting Two-hour Inter
DM:
WHO c /> 8.0 (140) >/ 11.0 (200) n.r. d
NDDG e i> 140 (7.8) /> 200 (11.1) >~ 200 (11.1)
EASDf >--8.0 (140) >~ 11.0 (200) ~> 11.0 (200)
IGTg:
WHO < 8.0 (140) 8-11 (140-200)
NDDG < 140 (7.8) 140-200 (7.8-11.1) /> 2O0 (11.1)
EASD < 8.0 (140) 8-11 (140-200)
aValues for venous plasma; for venous whole blood subtract 1.0 or 20; for capillary whole
blood, fasting as for VWB, post-load add 1.0 or 20.
bSmaller values mmol/l; larger mg/dl. WHO and EASD 'rounded up' to nearest mmol/1;
NDDG gave precise equivalence.
CWHO permits diagnosis of DM on one of these if symptoms of diabetes are present. In their
absence, an additional abnormal confirmatory value is required in the same or a further test.
aRaised intervening value not required by WHO for diagnosis, though it can be used for
'confirmatory' purposes.
eNDDG accepts as diagnostic FBG elevated on more than one occasion without further GTT;
or an elevated 2 HBG plus an elevated intermediate value on more than one occasion. For
children, FBG, IBG and 2 HBG must all be abnormal. (Special requirements for pregnancy,
see below.)
ZEASD proposed that FBG and 2 HBG and intermediate BG exceed limits for diagnosis.
gWHO requires only a qualifying 2 HBG for IGT; NDDG requires elevated IBG also; EASD
also accepts abnormal values failing to meet DM.
NDDG criteria for gestational diabetes (O'Sullivan and M ahan, 1964): 100 g oral glucose load.
BG at 0, 60, 120 and 180 rains. Two or more values to exceed 105, 190, 165, 145 mg/dl
respectively. Gestational 'IGT' suggested when 2 HBG 120 to 164 mg/dl. WHO and EASD
suggest use of normal criteria.
WHO - - World Health Organisation Expert Committee on Diabetes Mellitus. 2rid Report,
1980; NDDG - - National Diabetes Data Group, 1979; EASD - - Keen, Jarrett and Alberti,
1979.

. T h e r e is a g r e e m e n t t h a t t h e O G T T is o f t e n u n n e c e s s a r y to e s t a b l i s h t h e
d i a g n o s i s o f d i a b e t e s . I n p a t i e n t s w i t h c h a r a c t e r i s t i c s y m p t o m s s u c h as
p o l y u r i a a n d p o l y d i p s i a , d i a g n o s i s is u s u a l l y e s t a b l i s h e d b y a single
u n e q u i v o c a l l y e l e v a t e d b l o o d g l u c o s e c o n c e n t r a t i o n , t h a t is, a r a n d o m
p l a s m a g l u c o s e / > 11.1 m m o l / 1 (200 m g / d l ) a n d / o r a f a s t i n g v a l u e >/7.8
m m o l / 1 (140 m g / d l ) . T w o studies ( W a t k i n s , 1979; B a r k e r , G a r d n e r a n d
P o w e r , 1982) s u g g e s t t h a t this is a d e q u a t e in 80 p e r c e n t o r m o r e o f
d i a b e t i c s p r e s e n t i n g c l i n i c a l l y f o r m e d i c a l care.
2. W h e n O G T T is p e r f o r m e d , t h e t h r e e g r o u p s r e c o m m e n d a n o r a l g l u c o s e
l o a d o f 75 g (in c h i l d r e n 1.75 g / k g i d e a l b o d y w e i g h t t o a m a x i m u m o f
75 g; in p r e g n a n c y N D D G c o n t i n u e s t o r e c o m m e n d t h e 100 g l o a d ,
a p p r o p r i a t e t o t h e O ' S u l l i v a n a n d M a h a n (1964) d i a g n o s t i c c r i t e r i a f o r
g e s t a t i o n a l d i a b e t e s (see b e l o w ) ) . T h i s n e w s t a n d a r d l o a d has b o t h
s c i e n t i f i c a n d p r a c t i c a l j u s t i f i c a t i o n . T h e 100 g test w i d e l y u s e d in N o r t h
A m e r i c a s o m e t i m e s c a u s e s n a u s e a a n d t h e 50 g l o a d u s e d in E u r o p e ,
p a r t i c u l a r l y in t h e U K , is a s u b m a x i m a l s t i m u l u s . T h e 75 g l o a d has b e e n
w i d e l y u s e d in e p i d e m i o l o g i c a l studies a n d w o u l d b e a c c e p t a b l e i n t e r -
n a t i o n a l l y . It w a s n o t m a d e clear w h e t h e r t h e w e i g h t r e c o m m e n d e d
290 H. KEEN AND S. NG TA N G FUI

referred to anhydrous glucose or glucose monohydrate, the difference

amounting to 10 per cent (mol.wt. 180 vs 198) (Garcia-Webb and
Bonser, 1981); glucose monohydrate is cheaper and most often used.
Dietary carbohydrate should be unrestricted for three days before the
test which should be performed in the morning, after a 10- to 14-hour
overnight fast, with the subject seated and not smoking.
3. The pretest fasting blood glucose (FBG) and the 2 HBG are of prime
diagnostic importance. In the case of NDDG, BG is also required at an
intermediate time point (e.g., at 30, 60, or 90 minutes after the load) and
this may be useful for confirmatory purposes for W H O and EASD.
Venous plasma is preferred, but venous whole blood, capillary whole
blood and plasma are acceptable, with appropriate adjustments of
values. Glucose-specific enzymatic methods of estimation are favoured
but 'true-glucose' chemical methods may also be used (Cooper, 1974).
4. Similar upward revision for responses classified as indicating DM are
recommended and all interpose the new class o f 'impaired glucose
tolerance' (corresponding to the zone of diagnostic uncertainty des-
cribed earlier). There are, however, minor differences and some residual
ambiguities. Significant points of difference are pinpointed in Table 3,
which also demonstrates the anomalies introduced by having two
methods of expressing glucose concentration. The decision of W H O and
EASD to 'round-up' SI values was ill advised and precise equivalents are
preferable.
Although all groups insist upon the importance of confirmatory tests in
asymptomatic individuals qualifying for diagnosis on the basis of OGTT,
none of them recommend what action should ensue if a second test is
normal or equivocal, an outcome which is not unlikely if the initial result
lay close to the cut-off values for the diagnostic categories. Such subjects,
and those with 'unclassifiable' tests, are probably best classed as IGT, with
maintained observation until the issue becomes clarified.
In general, the revised criteria have met with approval (Reitsma, 1981; Ad
Hoc Committee, 1982) and they have been formally endorsed and adopted
by a number of national diabetes associations. Sasaki (1981) applied them
to a group of diabetics followed up for 10 years and found the FBG more
predictive of mortality than the 2 HBG, in contrast to the apparently
superior predictive power of the 2 H P G in respect of retinopathy and
nephropathy in Pima Indians (Pettitt et al, 1980), a view supported by
Taylor and Zimmet (1980). It should be noted that NDDG recommend
slightly more stringent diagnostic criteria for children than for adults
(Rosenbloom, Kohrman and Sperling, 1981).
Other diagnostic indices
Glycosylated haemoglobin (GHb). Circulating glucose reacts with red cell
haemoglobin to form glycosylated compounds (Bunn et al, 1976). This
slow, non-enzymatic process is essentially irreversible and continues
throughout the lifespan of the red cells at rates varying directly with
prevailing blood glucose concentrations. This integrating and rectifying
property would, therefore, appear to commend itself as a stable record o f
D E F I N I T I O N AND CLASSIFICATION 291

glycaemic status, and perhaps a diagnostic indicator, that is less subject to

unpredictable variations than the O G T T (Koenig, Peterson and Jones,
1976; Gonen et al, 1977). Several glycosylated haemoglobins separated and
quantitated by various techniques (Bunn, 1981) have been identified, of
which HbAlc is the most abundant (Gonen and Rubenstein, 1978). For
quantitative assessment, either HbAlc or total HbAla+b+c have been
estimated. However, in diabetics with widely fluctuating blood glucose
concentrations, total G H b concentration is disproportionately influenced
by the degree of glycaemia in the days or even hours immediately preceding
its measurement, probably owing to the existence of a labile reversible
aldimine precursor included with the stable ketoamine in the measurement
(Svendsen et al, 1980).
G H b estimation has been used mainly to monitor metabolic control in
established diabetics (Gabbay et al, 1977; Gonen et al, 1977; Paisey et al,
1980). Its potential as a diagnostic tool for DM and IGT has as yet been
comparatively little explored. The theoretical advantages of its diagnostic
use are numerous. A small blood sample is adequate. Prior dietary prep-
aration and pretest fasting are unnecessary, no glucose loading is needed,
the test can be done at any time of the day and does not require the two
hours of the standard OGTT. Confirmatory repetition of the test, as
required for OGTT, would appear unnecessary. However, measurement of
G H b is still beset with problems. Samples are unstable on storage and
reproducibility of some assay methods is less good than for blood glucose.
Because of the variety of methods used, the absolute values of normal and
abnormal ranges (usually expressed as percentage of total Hb glycosylated)
differ considerably and so cannot be directly compared. As the following
brief review suggests, the technique usually detects well-marked hyper-
glycaemia, but its sensitivity to lesser degrees is questionable.
Dunn et al (1979) found significant deviations from their normal GHb
range (4.0 to 6.0 per cent) in diet-treated (7.5 per cent), oral agent-treated
(8.1 per cent) and insulin-treated (11.1 per cent) diabetics, but out of 63
newly diagnosed diabetics (USPHS criteria) 23 (37 per cent) failed to exceed
the normal GHb range. Dods and Bolmey (1979) selected a value of 9.5 per
cent or more as abnormal; of 44 OGTTs classed as diabetic by various sets
of glycaemic criteria, between 16.7 per cent and 64.3 per cent were classed
as normal by GHb. A similar lack of sensitivity of GHb was shown in the
study of Santiago, Davis and Fisher (1978) in which GHb was found to be
supranormal only when the O G T T 2 HBG exceeded 228 mg/dl. Lev-Ran and
VanderLan (1979) assessed 167 OGTTs using three sets of criteria. In 124
OGTTs classed normal by all criteria, G H b ranged from 4.4 per cent to 10.3
per cent (mean 8.1 per cent); in 26 abnormal OGTTs with FBG < 120 mg/dl,
G H b ranged from 7.2 to 10.2 per cent (mean 8.4 per cent) and in 17 with FBG
~>120 mg/dl or known diabetics, it ranged from 7.7 per cent to 18.2 per cent
(mean 10.5 per cent). This overlap and insensitivity of GHb to lesser degrees
of glucose intolerance were supported by the reports of Bolli et al (1980) and
Dix et al (1979); in the latter study of 32 patients with O G T T in (their)
borderline diabetic range only 11 had GHb values exceeding their normal
range (3 per cent to 4.7 per cent). Though mean blood glucose values of the
292 H. KEEN A N D S. NG TA N G FUI

borderline group clearly exceeded those of the normal subjects - - indeed

fell just short of DM by current criteria, the overlap of GHb values was so
great as to give them little power to predict OGTT individually. Boucher,
Welch and Beer (1981) also found that GHb fell above their normal range
only when OGTT 2 HBG exceeded 10 mmol/1; their study group was small.
These preliminary reports suggest that, although GHb is often raised in
established diabetics, it is not as sensitive as the OGTT in detecting new DM
and is insensitive to the presence of IGT. An improved standard
methodology and further exploration of the diagnostic potential of GHb
estimation in the population setting is necessary. GHb may prove to offer a
useful rapid confirmation of an abnormal OGTT, obviating the need for
further tests, but is unlikely to replace the dynamic glucose challenge
procedure (McFarland, 1981).

Insulinaemia in diagnos&. Since the diabetic syndrome has been described

elsewhere as a state of absolute or relative insulin deficiency, it might be
argued that, by analogy with a number of endocrine disorders, measures of
plasma insulin ought to be introduced into the diagnostic equation.
However, apart from shortcomings in the standardization of insulin
measurements and the technical difficulties of performing them rapidly on a
wide scale, there is reason to doubt whether knowledge of them would add
to diagnosis (as distinct from providing valuable explanatory information).
In the first place, there is extremely wide variation in basal and post-glucose
insulinaemia in the normal general population (Boyns et al, 1969) which
overlaps the range found in people who are undoubtedly diabetic. Insulin
secretion in diabetes may be low, normal or high (Pfeifer, Halter and Porte,
1981), the levels probably denoting underlying differences in the mechanism
of diabetogenesis. Cerasi and Luft (1967) have suggested that diabetics may
be recruited from normals who betray their susceptibility with a low insulin
response to intravenous glucose infusion, perhaps an inherited character-
istic. However, long-term study has yet to define the proportion of low
insulin responders who do not become diabetic and of normal responders
who do. Jackson, Van Meghern and Keller (1972) claimed thatqnsulin
excess was the 'initial lesion' of diabetes. No predictive power was found in
the insulinaemic response to an oral glucose load in respect of the later
development of diabetes in Pima Amerindians (Savage, Bennett and
Gordon, 1975) and no relationship could be demonstrated between a
baseline standardized fasting or two-hour post-load plasma insulin
concentration and risk of worsening to diabetes over the subsequent 10
years in the Bedford study (Table 1). However, Kosaka, Hagura and
Kuzuya (1977) did find some predictive power of insulin measurements in
Japanese subjects with IGT and Fajans et al (1974), in a small group of
glucose-intolerant relatives of known diabetics closely observed over
decades, found that metabolic deterioration is much more likely in those
with lower than those with higher GTT insulin responses. Even in grossly
hyperglycaemic symptomatic patients, Turkington and Weindling (1978)
argued that the diagnosis of DM should be restricted to those with low post-
glucose peak insulin (under 60 mu/1) for it was only in these 'true diabetics'
DEFINITION AND CLASSIFICATION 293

that they found evidence of specific retinal, renal and neurological

abnormalities of diabetes. These important assertions are in need of confir-
mation; (Soeldner and Christlieb, 1979); and the notion of 'true diabetes'
with its diagnostic implications has been considered elsewhere (Keen and
Jarrett, 1979).
There is no question of the importance of further study of insulinaemia.
On an epidemiological scale, it may cast new light on the mechanisms of
arterial disease and diabetic microangiopathy in diabetic and normal
subjects (Py0rala, 1979; Welborn and Wearne, 1979; Ducimeti6re et al,
1980). However, at present it has no place in establishing the diagnosis of
DM or IGT.

Other diagnostic tests

Apart from OGTT and IVGTT, a number of variant tests have appeared in
the literature as possible diagnostic tests for diabetes. These include the
effects of priming with adrenal glucocorticoids, the use of sulphonylureas,
glucagon and amino acid infusions with measures of glucose or of insulin
response. These tests have been reviewed and evaluated by West (1978b).
None have established themselves as useful diagnostic procedures, though
they have contributed to knowledge of mechanisms of diabetogenesis.

THE NEW CLASSIFICATION OF DM AND ALLIED CONDITIONS

The classification of DM and associated states, proposed by NDDG (1979)
and provisionally endorsed by WHO (1980), is show.n in condensed form in
Tables 4 and 5. Much of the older ambiguous, overlapping and ill-defined
terminology has been replaced and efforts have been made to meet the
following requirements in the classification:
1. It should accommodate all cases;
2. No case should occupy more than one class (though cases may move
between classes);
3. Allocation to class should be on the basis of simple, readily available
information;
4. As far as possible, each class should be aetiologically homogeneous;
5. Class terminology should be clinically descriptive;
6. The classification should be modifiable in the light of new knowledge.
It is noteworthy that the classification includes some non-diabetic
categories such as IGT and statistical risk classes, but that the term
'diabetes' is no longer used in their titles, a restriction based upon sound
scientific and social logic.
Much has been written by the NDDG (1979) and others in commentary
upon this classification, and comment here will be restricted to a few major
considerations and problems.
Insulin-dependent diabetes mellitus (IDDM)
An individual diabetic can be assigned to this diagnostic category only on
the basis of clinical considerations. IDDM describes the classical form of
294 H. KEEN AND S. NG TANG FUI

Table 4. Classification o f diabetes mellitus and related conditions (from NDDG, 1979)
Clinical classes
Diabetes mellitus (DM):
Meets glycaemic criteria in Table 3.
Insulin-dependent type (IDDM; 'type 1'): 'classical' type, formerly known as juvenile-
onset, ketosis-prone, HLA-D/DR and autoimmune associations. Virus infection(s) may
be directly or indirectly involved. Commoner in youth, abrupt onset with ketosis, insulin
treatment mandatory.
Non-insulin-dependent type (NIDDM; 'type 2'): subdivided into
(i) non-obese NIDDM (BMI males < 25 females< 27)
(ii) obese NIDDM (BMImales >i 25 females~<27)
Formerly known as maturity-onset, ketosis-resistant. Probably multiple causation, strong
association with obesity in some. Familial pattern common. Insidious onset, often in later
life, rarely ketosis associated, insulin treatment optional.
Other types: DM associated with or due to other distinctive disorders, drugs, etc.
Comprehensive listing of named syndromes, primary disorders, drugs, etc. in NDDG
(1969). Subdivided into (i) pancreatic (ii) hormonal (iii) drug-induced (iv) insulin/receptor
abnormalities (v) genetic syndromes (vi) other associations.
Gestational diabetes (GDM): onset or detection in pregnancy. Reclassify postpartum.
Fetal morbidity/mortality and fetomegaly risk enhanced. Increased risk of later maternal
DM. WHO and NDDG criteria differ (q.v.)
Impaired glucose tolerance (IGT):
Determined only by GTT, see criteria Table 3
Subdivided into (i) non-obese IGT (ii) obese IGT (obesity criteria for NIDDM) (iii)
secondary IGT (see Other types DM for subclasses). Formerly known as chemical, latent,
borderline diabetes. Highly heterogeneous, associated with age. Increased risk of
worsening to DM and arterial disease.
Statistical risk classes
Previous abnormality of glucose tolerance (PrevAGT):
Formerly known as latent or prediabetes. OGTT normal,, hut past IGT or DM. Includes
remitted DM, GDM or IGT whether spontaneous or after treatment.
Potential abnormality of glucose tolerance (PotAGT):
Formerly known as potential diabetes or prediabetes. No history or presence of glucose
intolerance. Characterized by increased statistical risk of later DM of varying degree/
specificity. Risk indicator(s) should be stated.

the diabetic s y n d r o m e , florid with s y m p t o m s , rapidly progressive in course

a n d lethal in the absence of i n s u l i n t r e a t m e n t . The mere use o f i n s u l i n in the
t r e a t m e n t of a diabetic is n o t a d e q u a t e in itself to fulfill the classification
r e q u i r e m e n t . F u r t h e r s u p p o r t can usually only come f r o m the clinical
record. A history of clinical onset with ketoacidosis is the strongest
s u p p o r t i n g evidence, b u t it m a y n o t always be d o c u m e n t e d . Also very
suggestive is a n u n b r o k e n history of daily i n s u l i n injections, its start dating
back to the hours or days following diagnosis, especially if onset was a b r u p t
a n d clinically severe. Classification becomes increasingly difficult as these
c o n d i t i o n s are n o t met. Onset in c h i l d h o o d or y o u t h per se, t h o u g h
suggestive, is n o t conclusive for I D D M . A well-defined s u b g r o u p of
y o u t h f u l - o n s e t diabetics, sometimes k n o w n as M O D Y ( m a t u r i t y - o n s e t
diabetes of y o u t h , perhaps n o w N I D D Y ) , m a y be diagnosed in their teens.
T h o u g h these patients are usually treated with insulin, they are able to
survive w i t h o u t it (Tattersall, 1974; F a j a n s , Cloutier a n d Crowther, 1978).
A large p r o p o r t i o n o f the y o u t h f u l - o n s e t diabetics reported in the c o h o r t
study by W a d s w o r t h a n d Jarrett (1974) were n o t receiving i n s u l i n injections.
DEFINITION AND CLASSIFICATION 295

Table 5. Classification data base for diabetes

1. Requirements for classification:

Degree of hyperglycaemia or OGTT value
History of presence or absence of ketosis
History of insulin injection
Obstetric history
Drug history
Associated disorders
Body mass index [weight (kg)/height 2 (m2)]
History of glucose intolerance
2. Additional personal data:
Date of birth and age at DM diagnosis
Sex
Family history of DM (type) and/or endocrinopathy
Ethnic/geographical origin
Special exposure risks (toxins, infection, etc.)
History of metabolic 'control'
Presence and type of complications
3. Laboratory data:
HLA type (especially D/DR)
Islet cell (and ? pituitary cell) antibodies-complement fixing or not
Insulin receptor antibodies
Insulin antibodies
Immune complexes
Insulin secretory status (C peptide responsiveness)
Other genetic markers (e.g., acetylator, ? CPAFa, ABO/MN blood groups, etc.)
Data base for diabetes classification:
Items in Section 1 are required for assignment to the current NDDG classification.
Sections 2 and 3 contain additional information, often unavailable or available only in
part, much of it as yet unstandardized and some of incompletely established relevance
to DM and IGT which may be used to specify subclasses further.
aChlorpropamide alcohol flushing.

In contrast, clinical onset in later life by n o m e a n s excludes (though it makes

statistically less likely) a truly i n s u l i n - d e p e n d e n t state. Clinical onset a n d
progression to severe ketosis can be j u s t as d r a m a t i c in a 70-year-old p e r s o n
as in a child. P r o b l e m s o f classification m a y arise in diabetics o f later onset,
with the disease diagnosed d u r i n g or after the f o u r t h or fifth decades, who
lack a clear history or record, b u t who are receiving i n s u l i n injections. This
is p a r t i c u l a r l y true n o w , when a n increasing p r o p o r t i o n o f later-onset
diabetics j u d g e d to have failed to r e s p o n d a d e q u a t e l y to dietary restriction
or oral a n t i d i a b e t i c agents are p.rescribed i n s u l i n to achieve i m p r o v e d
control. This sometimes appears to be due to n a t u r a l e v o l u t i o n o f the
m e t a b o l i c disorder. The m e t a b o l i c w o r s e n i n g o f i n a d e q u a t e c o m p l i a n c e
with t r e a t m e n t can sometimes be identified by its reversal by i n t e n s i f i c a t i o n
o f therapy. Progressive m e t a b o l i c d e t e r i o r a t i o n in a lean diabetic in w h o m
i n s t i t u t i o n of i n s u l i n t h e r a p y is followed by p r o m p t relief o f s y m p t o m s m a y
be extremely difficult to classify with confidence. W i t h d r a w a l o f i n s u l i n a n d
o b s e r v a t i o n o f the m e t a b o l i c c o n s e q u e n c e s m i g h t answer the question, b u t
it is q u e s t i o n a b l e whether a need to classify could ever j u s t i f y such a
manoeuvre.
296 H. KEEN AND S. NG TANG FUI

Under conditions of infective, traumatic or other stress, adequately diet-

or tablet-treated diabetics may lose control, become temporarily keto-
acidotic and require insulin as a life-preserVing measure, an episode of
unquestionable insulin-dependency occurring during the course of non-
insulin-dependent diabetes. The proposed classification allows for
movement of an individual between classes, but the transition here is
clinical (NIDDM to IDDM) and not aetiological (type 2 to type 1). The
same dilemma, if such it is, may occur when vigorous initial treatment of a
ketoacidotic young diabetic (IDDM, type 1) provokes the so-called
honeymoon remission, and allows the suspension of insulin injections and
perhaps all antidiabetic therapy, sometimes for protracted periods of time
(NIDDM, but not type 2). A protracted period of non-insulin-dependent
diabetes may precede the transition to insulin dependency in subjects
genetically likely to be classed as 'type 1' (Gorsuch et al, 1981). Irvine et al
(1979) suggested that those apparently typical non-insulin-dependent
patients of late onset who after many years are judged to require insulin are
genetically and immunologically constituted as 'type 1' diabetics. A further
class of diabetic may be identified in which dependence upon insulin is very
difficult to determine clinically. Such diabetics appear to be true
'intermediate' types, are commonly met with in tropical areas - - see
'Tropical Diabetes' below - - and are not rare among Caucasian populations.

Non-clinical markers of insulin-dependency. It would clearly be helpful if

there were some measure or marker to distinguish truly insulin-dependent
diabetics. Selected as clinical groups, diabetics demonstrating dependency
on insulin differ sharply in respect of certain genetic and immunological
characteristics from non-insulin-dependent diabetics. Certain histocompati-
bility specificities (HLA types) first detected at the B locus but now
considered to be best represented by D3 and D4 (or DR3 and DR4) haplo-
types and their heterozygous combination (Cudworth, 1980; Nerup and
Lernmark, 1981) are greatly overrepresented in IDDM compared with
NIDDM and non-diabetics, between whom frequencies do not differ
significantly. However, a significant proportion of unquestionably insulin-
dependent diabetics lack these genetic markers and a substantial proportion
of the non-diabetic population possess them. Thus, for an individual
diabetic the presence of D3, D4 or D3/D4 does not,certainly establish them
as IDDM or type 1, nor does their absence conclusively exclude it. Whether
this is an indication that the genetic component of IDDM is not actually the
D3 or D4 allele itself, but some other closely associated diabetes suscepti-
bility gene, or whether it is evidence for true genetic heterogeneity (or
perhaps some non-genetic form) of IDDM, is not yet clear. However, it
does mean that IDDM cannot be independently established from H L A
constitution.
Another clearly established characteristic of the IDDM group is the
demonstration of circulating antibodies directed against surface antigens in
the islet cells - - islet cell antibody (ICAb) (Bottazzo, Florin-Christensen and
Doniach, 1974). These antibodies are heterogeneous with a less common,
though perhaps more specifically IDDM-related, complement-fixing sub-
DEFINITION AND CLASSIFICATION 297

type (Bottazzo et al, 1980). They cannot be demonstrated in 10 to 15 per

cent of IDDM patients and fall to levels below detection threshold in the
great majority a year or two after clinical onset (Lendrum, Walker and
Cudworth, 1976). Furthermore, ICAb may be demonstrated in some
clinically NIDDM patients (see above) and may, indeed, exist in some non-
diabetics. Few laboratories possess the skills to determine them and results
differ even among those that do.
At present, the use of these valuable investigations is restricted to
research centres, and they cannot be used in the individual case to establish
insulin dependency status with certainty. Their potential value may be to
distinguish aetiological subclasses within clinical classes.
The basis of insulin dependency is likely to be a greatly diminished insulin
secretory capacity of the pancreatic B cells; some test of islet function
might, therefore, seem to be a suitable objective classifying variable for
insulin dependency. There are technical problems in measuring plasma
insulin reproducibly, particularly in insulin-treated patients when
antibodies to the hormone may be present. The measurement of C peptide
(Bloch et al, 1972) released in parallel with insulin (Horwitz et al, 1975) as
an index of B-cell function (Faber and Binder, 1977; Madsbad et al, 1978;
Heding, 1978) might meet some of these problems, and has been used to
estimate insulin secretion rates (Waldh~iusl et al, 1979). Responsiveness of
plasma C peptide to food intake, glucose, glucagon, tolbutamide or
betamimetics can be measured (Faber and Binder, 1977; Mirel et al, 1980)
and urinary C peptide assay may also be of value (Horwitz, Rubenstein and
Katz, 1977). Absent C peptide responsiveness must be treated as strong
presumptive evidence of insulinopenia and IDDM status, though avail-
ability of this investigation is necessarily restricted.
Non-insulin-dependent diabetes meilitus (NIDDM)
The great majority of diabetics in all ethnic groups fall into this major class.
The central distinguishing feature, as the name suggests, is that life (though
not necessarily good health) can be sustained without injected insulin.
Although in paradigm it occurs in older, fatter persons and is characterized
by the absence of persistent ketosis, substantial exceptions to each of these
features are familiar. A distinct subgroup with strong familial tendency is
diagnosed in youth, the 'maturity-onset diabetes of youth' (MODY),
described by Tattersall (1974), Tattersall and Fajans (1975) and Pyke (1979).
Although obesity is a frequent accompaniment or forerunner of NIDDM it
is by no means always so and the classification makes allowance for this by
proposing 'obese' and 'non-obese' subtypes. Reference has already been
made to episodic and sometimes sustained ketosis that may occur in the
course of NIDDM and the problems this may raise in class assignment. This
variability points to underlying variations in the mechanism responsible for
hyperglycaemia, for example, impaired islet function, tissue resistance to
the effects of insulin or both of these (Olefsky and Kolterman, 1981;
Pfeifer, Halter and Porte, 1981). It also indicates the aetiological hetero-
geneity of this class. It seems probable that it contains slowly evolving or
incomplete examples of the mechanisms (HLA-associated) which usually
298 H. KEEN AND S. NG TANG FU

express themselves as IDDM. Those few diabetics shown to have abnormal

insulin structure (see below) were classed as NIDDM until the underlying
fault was identified. The process of separating out aetiologically distinct
subgroups from both NIDDM and IDDM is certain to continue.
Reference has already been made to difficulties in classification when
NIDDM patients receive insulin and, to meet this, a subgroup of 'indeter-
minate dependency' may be required when epidemiological-type com-
parisons of diabetics are made. This points to the probability that the
distinction between IDDM and NIDDM is not as sharp as the classification
suggests. That true intermediate clinical types exist in Caucasian
populations would be accepted by many experienced observers. In some
tropical countries (q.v.) they may be a predominant group.
Other types of diabetes mellitus
This class, which contains those diabetics in whom a presumptive cause or a
close genetic association has been established, is also causally highly
heterogeneous. Its variety illustrates the many points at which disturbance
of glucose homeostasis may give rise to the diabetic syndrome. This class
may be expected to increase in size as causes of diabetes are discerned. To it
have been added a small but growing number of diabetics with abnormal
structure of insulin (Kanazawa et al, 1978; Gabbay et al, 1979; Given et al,
1980; Robbins, Blix and Rubenstein, 1981) or its receptor (Flier, Kahn and
Roth, 1979; Roth et al, 1979). A listing of genetic syndromes, primary
diseases, drugs, toxins, etc., associated with (and sometimes causal of)
glucose intolerance is given by the NDDG (1979) and reviewed at some
length by Rotter and Rimoin (1981).

Tropical diabetes. Included in 'other types' but numerically by far the

greater part of it on a global scale, this form of diabetes greatly outnumbers
IDDM and may equal the prevalence of NIDDM in some parts of the world
(Tripathy and Kar, 1965; Ahuja, 1973). Probably similar to the J type
diabetes described by Hugh-Jones (1955) in the West Indies, this wasting
form of diabetes, usually seen in young people with a background of severe
past undernutrition, illustrates well the indeterminate region between
dependence and non-dependence on injected insulin. Though characteristi-
cally unaccompanied by severe ketosis, insulin is required for metabolic
recovery and then, for variable periods, may be dispensed with. It probably
contains several subtypes (West, 1978c) and requires fuller clinical
epidemiological study. As a gesture to its importance, Morrison (198!) has
suggested that it deserves ranking as type 3 diabetes or P I D D M (phasic
insulin-dependent diabetes mellitus).
Gestationai diabetes mellitus (GDM)
The difference between the NDDG and W H O approach to this class
emphasizes the current uncertainties about its nature. There is general
agreement that-women developing glucose intolerance qualifying for W H O
(or non-pregnant NDDG) criteria of DM require antidiabetic treatment and
special management during pregnancy and labour. In the case of those with
DEFINITION AND CLASSIFICATION 299

lesser degrees of glucose intolerance (e.g., IGT) there is less unanimity of

view. The fetal risk is very small, though birthweight may be increased, and
there is little data on the future risk of diabetes in the mother. The issue has
been clouded in the past by the selective inclusion of women with bad
obstetric histories in addition to (and in some even without) glucose
intolerance in this group. This difficult subject has been well reviewed
recently (Symposium on Gestational Diabetes, 1980; Jarrett, 1981).
Analysis of risk and outcome would be aided by maintaining the W H O
distinction between IGT and DM in pregnancy without prejudice to
management decisions, though NDDG goes part way towards this in its
recommendation for a pregnancy IGT when 2 H P G is between 120 mg/dl
(6.7 mmol/1) and 165 mg/dl (9.2 mmol/1).
Statistical risk classes
These classes are restricted to individuals who, at the time of ascertainment,
have neither DM nor IGT. The use of the term 'diabetes' has therefore been
excluded from the nomenclature in view of the ill-deserved stigma that such
individuals might bear.
Previous abnormality of glucose tolerance (infelicitously PrevAGT)
accommodates those individuals who have been classed as DM, GDM or
IGT in the past and have, with the recession of some diabetogenic stress or
as a result of treatment, reverted to normal glucose tolerance. Potential
abnormality of glucose tolerance (PotAGT) describes those persons
considered t o be at 'substantially increased risk for the development of
diabetes'. As with PrevAGT, there are many and varying subcategories for
people entering these classes - - relationship with a diabetic, H L A consti-
tution, ethnic origin, etc. - - and these should be specified when possible.

Table 6. Identifying features o f various stages in the evolution o f diabetes mellitus

(IDDM and NIDDM) a
Marker of stage in
Stage IDDM NIDDM
1. Unchallenged susceptibility HLA D3/D4 ? DNA polymorphism CHR 11
2. Challenged susceptibility ICAb ? CMI Changed insulin glucose
association
3. Concealed dysfunction Low Insulin release IGT
4. Minimal disease Stress glycaemia, IGT Labile DM
5. Clinical disease -Ketoacidosis DM symptoms +
6. 'Early' complications Retinal/renal microvascular abnormality, neuropathy
7. Organ failure Blindness, renal failure, tissue breakdown
aThe interaction with classification of DM is evident. Individuals may stay for variable periods
(perhaps indefinitely) at any stage or move rapidly from stage to stage, in some cases in either
direction.
The intensity of the diabetic state (degree of hyperglycaemia or insulinopenia) will influence
movement between stages, as may currently poorly defined inherent susceptibility factors (e.g.,
HLA, acetylator status) or indirect factors (e.g., arterial pressure, smoking, obesity). Special
procedures, many currently poorly standardized, are required to ascertain individuals in stages
1-4.
300 H. KEEN AND S. NG TANG FUI

CONCLUSION
Criteria a n d classification of disease are b o t h attractive a n d repellent
subjects. They s h a r p e n the critical a n d logical faculties, b u t they are
d o o m e d f r o m the start to failure because they always represent a n a t t e m p t
based o n i n a d e q u a t e i n f o r m a t i o n to impose d i v i s i o n s u p o n N a t u r e , which
k n o w s n o n e . They are essential as a structure for t h o u g h t , research a n d , to
a n extent, clinical practice. F o r this reason, N D D G stated that classification
'will need to be a m e n d e d a n d revised'; W H O c o n c l u d e d that ' a new
a p p r o a c h to classification is r e q u i r e d ' . Neither of t h e m , for example,
considered at length the p r o b l e m o f i n t r o d u c i n g a ' s t a g i n g ' d i m e n s i o n into
classification, as suggested b y T a b l e 6. T h a t is for the future. F o r the
present, there can be little d o u b t that, despite m a n y imperfections, the
revised views described here represent a n a d v a n c e o n what went before a n d
should be systematically applied to the diabetic s y n d r o m e a n d allied
conditions.

REFERENCES

Ad Hoc Committee on Diagnostic Criteria for Diabetes Mellitus. Clinical and Scientific
Section, Canadian Diabetes Association (1982) Acceptance of new criteria for diagnosis of
diabetes mellitus and related conditions by the Canadian Diabetes Association. Canadian
Medical Association Journal, 126, 473-476.
Ahuja, M. M. S. (1973) Profile of young Indian diabetics - - biochemical studies. Journal of
the Association of Physicians of India, 21, 87-99.
A1 Sayegh, H. A. & Jarrett, R. J. (1979) Oral glucose tolerance tests and the diagnosis of
diabetes: results of a prospective study based on the Whitehall survey. Lancet, ii, 431-435.
Amatuzio, D. S., Stutzman, F. L., Vanderbilt, M. J. & Nesbitt, S. (1953) Interpretation of the
rapid intravenous glucose tolerance test in normal individuals and in mild diabetes
mellitus. Journal of Clinical Investigation, 32, 428-435.
Andres, K. (1971) Aging and diabetes. Medical Clinics of North America, 55, 835-845.
Barker, D. J. P., Gardner, M. J. & Power, C. (1982) Incidence of diabetes in nine British
towns: a collaborative study. Diabetologia (in press).
Bennett, P. H., Rushforth, H. B., Miller, M. & LeCompte, P. M. (1976)Epidemiologic studies
of diabetes in the Pima Indians. Recent Progress in Hormone Research, 32, 333-376.
Birmingham Diabetes Survey Working Party (1976) Ten-year follow-up report on the
Birmingham diabetes survey of 1961. British Medical Journal, ii, 35-37.
Bloch, M. B., Mako, M. E., Steiner, D. F. & Rubenstein, A. H. (1972) Circulating C peptide
immunoreactivity. Studies in normal and diabetic patients. Diabetes, 21, 1013-1026.
Bolli, G., Compagnucci, P., Cartechini, M. C., Santeusanio, F., Cirotto, C., Scionti, L. &
Brunetti, P. (1980) HbA in subjects with abnormal glucose tolerance but normal fasting
plasma glucose. Diabetes, 29, 272-277.
Bottazzo, G. F., Florin-Christensen, A. & Doniach, D. (1974) Islet cell antibodies in diabetes
mellitus with autoimmune polyendocrine deficiencies. Lancet, ii, 1279-1283.
Bottazzo, G. F., Dean, B. M., Gorsuch, A. N., Cudworth, A. G. & Doniach, D. (1980)
Complement fixing islet-cellantibodies in type 1 diabetes: possible monitoring of active B
cell damage. Lancet, i, 668-672.
Boucher, B. J., Welch, S. G. & Beer, M. S. (1981) Glycosylated haemoglobins in the diagnosis
of diabetes mellitus and for the assessment of chronic hyperglycaemia. Diabetologia, 21,
34-36.
Boyns, D. R., Crossley, J. N., Abrams, M. E., Jarrett, R. J. & Keen, H. (1969) Oral glucose
tolerance and related factors in a normal population sample. I. Blood sugar, plasma
insulin, glyceride and cholesterol measurements and the effects of age and sex. British
Medical Journal, i, 595-598.
Bunn, H. F. (1981) Evaluation of glycosylated hemoglobin in diabetic patients. Diabetes, 30,
613-617.
DEFINITION AND CLASSIFICATION 301

Bunn, H. F., Hanney, D. N., Kamin, S., Gabbay, K. H. & Gallop, P. M. (1976) The
biosynthesis of human hemoglobin Alc: slow glycosylation of hemoglobin in vivo.
Journal of Clinical Investigation, 57, 1652-1659.
Butterfield, W. J. H., Keen, H. & Whichelow, M. J. (1967) Renal glucose threshold variations
with age. British Medical Journal, iv, 505-507.
Cerasi, E. & Luft, R. (1967) 'What is inherited - - what is added' hypothesis for the
pathogenesis of diabetes mellitus. Diabetes, 16, 615-627.
Cooper, G, R. (1974) Methods for determining the amount of glucose in blood. CRC Critical
Reviews of Clinical and Laboratory Science, 4, 101-145.
Cudworth, A. G. (1980) Current concepts in theaetiology of type 1 (insulin-dependent)
diabetes mellitus. In Advanced Medicine 16, (Ed.) Bellingham, A. J. pp. 123-135.
London: Pitman Medical.
Davidson, M. B. (1979) The effect of aging on carbohydrate metabolism: a review of the
English literature and a practical approach to the diagnosis of diabetes mellitus in the
elderly. Metabolism, 28, 688-705.
Dix, D., Cohen, P., Kingsley, S., Senkbeil, J. & Sexton, K. (1979) Glycohemoglobin and
glucose tolerance tests compared as indicators of borderline diabetes. Clinical Chemistry,
25, 877-879.
Dobson, M. (1776) Experiments and observations on the urine in diabetes. Medical
Observations and Investigations, 5, 298-303.
Dods, R. F. & Bolmey, C. (1979) Glycosylated hemoglobin assay and oral glucose tolerance
test compared for detection of diabetes mellitus. Clinical Chemistry, 25, 764-768.
Ducimeti6re, P., Eschwege, E., Papoz, J. L., Richard, J. L., Claude, J. R. & Rosselin, G.
(1980) Relationship of plasma insulin levels to the incidence of myocardial infarction and
coronary heart disease mortality in a middle-aged population. Diabetologia, 19, 205-209.
Dunn, P. J., Cole, R. A., Soeldner, J. S. & Gleason, R. E. (1979) Reproducibility of
hemoglobin Alc and sensitivity to various degrees of glucose intolerance. Annals of
Internal Medicine, 91, 390-396.
Faber, O. K. & Binder, C. (1977) C peptide response to glucagon. A test for the residual beta
cell function in diabetes mellitus. Diabetes, 26, 605-610.
Fajans, S. S. & Conn, J. W. (1959) Early recognition of diabetes mellitus. Academy of
Sciences, 82, 208-218.
Fajans, S. S., Cloutier, M. C. & Crowther, R. L. (1978) Clinical and etiologic heterogeneity of
idiopathic diabetes mellitus. Diabetes, 27, 1112-1125.
Fajans, S. S., Floyd, J. C., Taylor, C. I. & Pek, S. (1974) Heterogeneity of insulin responses in
latent diabetes. Transactions of the Association of American Physicians, 87, 83-94.
Fitzgerald, M. G. & Keen, H. (1964) Diagnostic classification of diabetes. British Medical
Journal, ii, 1567-1568.
Flier, J. S., Kahn, C. R. & Roth, J. (1979) Receptors, antireceptor antibodies and mechanisms
of insulin resistance. New England Journal of Medicine, 300, 413-419.
Frank, L. L. (1957) Diabetes mellitus in the texts of old Hindu medicine (Charaka, Snaruta,
Vagbhata). American Journal of Gastroenterology, 27, 76.
Fuller, J. H., Shipley, M. J., Rose, G. A., Jarrett, R. J. & Keen, H. (1980) Coronary heart
disease risk and impaired glucose tolerance. The Whitehall study. Lancet, i, 1373-1376.
Gabbay, K. H., Harty, K., Breslow, J. L., Ellison, R. C., Bunn, H. F. & Gallop, P. M. (1977)
Glycosylated hemoglobins and long-term blood glucose control in diabetes mellitus.
Journal of Clinical Endocrinology and Metabolism, 44, 859-864.
Gabbay, K. H., Bergenstal, R. M., Wolff, J., Mako, M. E. & Rubenstein, A. H. (1979)
Familial hyperproinsulinaemia: partial characterisation of circulating proinsulin-like
material. Proceedings of the National Academy of Science, USA, 76, 2881-2885.
Ganda, O. P., Day, J. L., Soeldner, J. S. (1978) Reproducibility and comparative analysis of
repeated intravenous and oral glucose tolerance tests. Diabetes, 27, 715-725.
Garcia-Webb, P. & Bonser, A. M. (1981) Glucose or glucose monohydrate for glucose
tolerance tests? Diabetologia, 21, 580.
Given, B. D., Mako, M. E., Tager, H. S., Baldwin, D., Markese, J., Rubenstein, A. H.,
Olefsky, J., Kobayashi, M., Kolterman, O. & Poucher, R. (1980) Diabetes due to
secretion of an abnormal insulin. New England Journal of Medicine, 302, 129-135.
Goldberg, L. & Luft, R. (1948) A comparison of oral and intravenous dextrose tolerance tests
in healthy subjects. Acta Medica Scandinavica, 132, 201-222.
302 H. KEEN AND S. NG TANG FUI

Gonen, B. & Rubenstein, A. H. (1978) Haemoglobin A1 and diabetes mellitus. Diabetologia,

15, 1-8.
Gonen, B., Rubenstein, A. H., Rochman, H., Tanega, S. & Horwitz, D. L. (1977)
Haemoglobin Al: an indicator of the metabolic control of diabetic patients. Lancet, ii,
734-736.
Gorsuch, A. N., Spencer, K. M., Lister, J., McNally, J. M., Dean, B. M., Bottazzo, G. F. &
Cudworth, A. G. (1981) Evidence for a long prediabetic period in type 1 (insulin-
dependent) diabetes mellitus. Lancet, ii, 1363-1365.
Heding, L. G. (1978) Insulin, C peptide and proinsulin in non-diabetics and insulin treated
diabetics. Diabetes, 27 (Supplement 1), 178-183.
Hugh-Jones, P. (1955) Diabetes in Jamaica. Lancet, ii, 891-897.
Horwitz, D. L., Rubenstein, A. H. & Katz, A. J. (1977) Quantitation of human pancreatic
beta cell function by immunoassay of C peptide in urine. Diabetes, 26, 30-35.
Horwitz, D. L., Starr, J. I., Mako, M. E., Blackbaird, W. E. & Robenstein, A. H. (1975)
Proinsulin, insulin and C peptide concentrations in human portal and peripheral blood.
Journal of Clinical Investigation, 55, 1278-1283.
Irvine, W. J., Gray, R. S. & Steel, J. M. (1980) Islet cell antibody as a marker for early stage
type 1 diabetes mellitus. In Immunology of Diabetes (Ed.) Irvine, W. J. pp. 117-154.
Edinburgh: Teviot Scientific Publications.
Irvine, W. J., Sawers, J. S. A., Feek, C. M., Prescott, R. J. & Duncan, L. J. P. (1979) The
value of islet cell antibody in predicting secondary failure of oral hyperglycaemic
treatment. Journal of Laboratory and Clinical Immunology, 2, 23-26.
Jackson, W. P. U., van Meghern, W. & Keller, P. (1972) Insulin excess as the initial lesion in
diabetes. Lancet, i, 1040-1044.
Jacobsen, A. (1913) Untersuchunger fiber den Einfluss des Kohlenhydrates auf experimentelle
Hyperglykemieformen. Biochemische Zeitschrift, 51, 443.
Jarrett, R. J. (1981) Reflections on gestational diabetes mellitus. Lancet, ii, 12-20.
Jarrett, R. J. & A1 Sayegh, H. (1978) Impaired glucose tolerance - - defining those at risk of
diabetic complications. Diabetologia, 15, 243.
Jarrett, R. J. & Keen, H. (1976) Hyperglycaemia and diabetes mellitus. Lancet, ii, 1009-1012.
Jarrett, R. J., McCartney, P. & Keen, H. (1982) The Bedford survey: ten-year mortality rates
in newly diagnosed diabetics, borderline diabetics and normoglycaemic control and risk
for coronary heart disease in borderline diabetics. Diabetologia, 22, 79-84.
Jarrett, R. J., Keen, H., Fuller, J. H. & McCartney, M. (1979) Worsening to diabetes in men
with impaired glucose tolerance ('borderline diabetes'). Diabetologia, 15, 25-30.
Kanazawa, Y., Hayashi, M., Ikeuchi, M., Hiramatsu, K. & Kosaka, K. (1978) Familial
proinsulinaemia: a possible cause of abnormal glucose tolerance. European Journal of
Clinical In vestigation, 8,327.
Keen, H. & Fuller, J. H. (1980) The epidemiology of diabetes. In Metabolic and Nutritional
Disorders in the Elderly (Ed.) Exton-Smith, N. & Caird, F. I. pp. 146-160. Bristol:
John Wright.
Keen, H. & Jarrett, R. J. (1979) Hyperglycaemia, microvascular disease and 'true diabetes'.
Diabete et Metabolisme, 5, 89-91.
Keen, H., Jarrett, R. J. & Alberti, K. G. M. M. (1979) Diabetes mellitus: a new look at
diagnostic criteria. Diabetologia, 16, 283-285.
Keen, H., Jarrett, R. J. & McCartney, P. (1982) The ten-year follow-up at the Bedford survey
(1962-1972). Glucose tolerance and diabetes. Diabetologia, 22, 73-78.
Keen, H., Rose, G. A., Pyke, D. A., Boyns, D., Chlouverakis, C. & Mistry, S. (1965) Blood
sugar and arterial disease. Lancet, ii, 505-508.
Keen, H., Jarrett, R. J., Fuller, J. H. & McCartney, P. (1981) Hyperglycaemia and arterial
disease. Diabetes, 30 (Supplement 2), 49-53.
Klimt, C. R., Prout, T. E., Bradley, R. F. et al (1969) Standardisation of the oral glucose
tolerance test. Report of the Committee on Statistics of the American Diabetes
Association. Diabetes, 18, 299-307.
Koenig, R. J., Peterson, C. M. & Jones, R. L. (1976) Correlation of glucose regulation and
hemoglobin Alc in diabetes mellitus. New England Journal of Medicine, 295, 417-420.
Kosaka, K., Hagura, R. & Kuzuya, T. (1977) Insulin responses in equivocal and definite
diabetes, with special reference to subjects who had mild glucose intolerance but later
developed definite diabetes. Diabetes, 26, 944-952.
DEFINITION AND CLASSIFICATION 303

Kroc Foundation International Conference on Epidemiology of Diabetes and its Macro-

vascular Complications (1979) Diabetes Care, 2, 63-226.
Lendrum, R., Walker, G. & Cudworth, A. G. (1976) Islet cell antibodies in diabetes mellitus.
Lancet, ii, 1273-1276.
Lev-Ran, A. & VanderLan, W. P. (1979) Glycohemoglobins and glucose tolerance. Journal of
the American Medical Association, 241, 912-914.
Lundbaek, K. (1962) Intravenous glucose tolerance as a tool in definition and diagnosis of
diabetes mellitus. British Medical Journal, ii, 1507-1509.
Madsbad, S., Faber, O. K., Binder, C., McNair, P., Christiansen, C. & Transbol, I. (1978)
Prevalence of residual beta cell function in ~nsulin-dependent diabetics in relation to age at
onset and duration of diabetes. Diabetes, 27 (Supplement 1), 262-264.
Madsbad, S., Bottazzo, G. C., Cudworth, A. G., Dean, B., Faber, O. K. & Binder, C. (1980)
Islet cell antibodies and beta cell function in insulin-dependent diabetics. Diabetologia,
18, 45-47.
McFarland, K. F. (1981) Glycosylated hemoglobin. What is its value? Archives of Internal
Medicine, 141,712.
Mirel, R. D., Ginsberg-Fellner, F., Horwitz, D. L. & Rayfield, E. J. (1980) C peptide reserve in
insulin-dependent diabetes. Comparative responses to glucose, glucagon and tolbutamide.
Diabetologia, 19, 183-188.
Morrison, E. (1981) Diabetes mellitus - - a third syndrome. Phasic insulin dependence (PID).
International Diabetes Federation Bulletin, 26, 6-8.
Mosenthal, H. O. & Barry, E. (1950) Criteria for interpretation of normal glucose tolerance
test. Annals of lnternal Medicine, 33, 1175-1194.
Moyer, J. H. & Womack, C. R. (1950) Glucose tolerance. 1. A comparison of four types of
diagnostic tests in 103 control subjects and 26 patients with diabetes. American Journal of
Medical Science, 219, 161-173.
National Diabetes Data Group (1979) Classification and diagnosis of diabetes mellitus and
other categories of glucose intolerance. Diabetes, 28, 1039-1057.
Nerup, J. & Lernmark, A. (1981) Autoimmunity in insulin-dependent diabetes mellitus.
American Journal of Medicine, 70, 135-141.
Olefsky, J. M. & Kolterman, O. G. (1981)Mechanisms of insulin resistance in obesity and non-
insulin-dependent (type II) diabetes. American Journal of Medicine, 70, 151-168.
O'Sullivan, J. M. & Mahan, C. M. (1964) Criteria for the oral glucose tolerance test in
pregnancy. Diabetes, 13, 278-285.
Papaspyros, N. S. (1964) The history of diabetes mellitus. Stuttgart: Georg Thieme Verlag.
Paisey, R. B., Macfarlane, D. G., Sherriff, R. J., Hartog, M., Slade, R. R. & White, D. A. J.
(1980) The relationship between glycosylated haemoglobin and home capillary blood
glucose levels in diabetics. Diabetologia, 19, 31-34.
Pettitt, D. J., Knowler, W. C., Lisse, J. R. & Bennett, P. M. (1980) Development of
retinopathy and proteinuria in relation to plasma glucose concentrations in Pima Indians.
Lancet, ii, 1050-1052.
Pfeifer, M. A., Halter, J. B. & Porte, D. Jr (1981) Insulin secretion in diabetes mellitus.
American Journal of Medicine, 70, 579-588.
Pyke, D. A. (1979) Diabetes: the genetic connections. Diabetologia, 17, 333-343.
Py6rala, K. (1979) Relation of glucose tolerance and plasma insulin to the incidence of
coronary heart disease: results from two population studies in Finland. Diabetes Care, 2,
131-136.
Reid, D. D., Brett, G. Z., Hamilton, P. J. S., Jarrett, R. J., Keen, H. & Rose, G. (1974)
Cardiorespiratory disease and diabetes among middle-aged male civil servants; a study of
screening and intervention. Lancet, i, 469-473.
Reitsma, W. D. (1981) Adaptation of the classification and diagnostic criteria of diabetes to
present knowledge. Netherland Journal of Medicine, 24, 97-98.
Remein, Q. K. & Wilkerson, H. L. C. (1961) The efficiency of screening methods for diabetes.
Journal of Chronic Diseases, 13, 6-21.
Renold, A. E., Stauffacher, W. & Cahill, G. F. (1976) Diabetes mellitus. In The Metabolic
Basis of lnherited Disease (Ed.)Stanbury, J. H., Wyngaarden, J. B. & Frederickson, D. S.
p. 83. New York: McGraw-Hill.
Robbins, D. C., Blix, P. M. & Rubenstein, A. H. (1981) A human proinsulin variant at
arginine 65. Nature, 291, 679-681.
304 H. KEEN AND S. NG TANG FUI

Rosenbloom, A. L., Kohrman, A. & Sperling, M. (1981) Classification and diagnosis of

diabetes mellitus in children and adolescents. Journal of Pediatrics, 98, 320-323.
Roth, J., Lesniak, M. A., Bar, R. S., Muggeo, M., Megyesi, K., Harrison, L. C., Flier, J. S.,
Wachslicht-Rodboard, H. & Gorden, P. (1979) An introduction to receptors and receptor
defects. Proceedings of the Society for Experimental Biology and Medicine, 162, 3-12.
Rotter, J. I. & Rimoin, D. L. (1981) The genetics of the glucose intolerant disorders. American
Journal of Medicin e, 70, 116-126.
Santiago, J. V., Davis, J. E. & Fisher, F. (1978) Hemoglobin Alc levels in a diabetes detection
program. Journal of Clinical Endocrinology and Metabolism, 47, 578-580.
Sartor, G., Schersten, B. & Carlstrom, S. (1980) Ten-year follow-up of subjects with impaired
glucose tolerance. Prevention of diabetes by tolbutamide and diet regulation. Diabetes,
29, 41-49.
Sasaki, A. (1981) Assessment of the new criteria for diabetes meUitus according to 10-year
relative survival rates. Diabetologia, 20, 195-198.
Savage, P. J., Bennett, P. H. & Gordon, P. (1975) Insulin responses to oral carbohydrate in the
prediabetics and matched controls. Lancet, i, 300-302.
Sharp, C. L., Butterfield, W. J. H. & Keen, H. (1964) Diabetes survey in Bedford. Proceedings
of the Royal Society of Medicine, 57, 193-202.
Siperstein, M. D. (1975) The glucose tolerance test: a pitfall in the diagnosis of diabetes
mellitus. Advances in Internal Medicine, 20, 297-323.
Soeldner, J. S. & Christlieb, A. R. (1979) Diagnosis of diabetes mellitus. Journal of the
American Medical Association, 241, 1462.
Svendsen, P. A., Christiansen, J. S., Soegaard, B., Welinder, B. S. & Nerup, J. (1980) Rapid
changes in chromatographically determined haemoglobin Ale induced by short-term
changes in glucose concentration. Diabetologia, 19, 130-136.
Symposium on Gestational Diabetes (1980) Diabetes Care, 3, 399.
Tattersall, R. B. (1974) Mild familial diabetes with dominant inheritance. Quarterly Journal of
Medicine, 43, 339-357.
Tattersall, R. B. & Fajans, S. S. (1975) A difference between the inheritance of classical
juvenile-onset and maturity-onset types of diabetes of young people. Diabetes, 24, 44-53.
Taylor, R. & Zimmet, P. (1980) Limitation of fasting plasma glucose for the diagnosis of
diabetes mellitus. Diabetes Care, 4, 556.
Tripathy, B. B. & Kar, B. C. (1965) Observations on clinical patterns of diabetes mellitus in
India. Diabetes, 14, 404-412.
Turkington, R. W. & Weindling, H. K. (1978) Insulin secretion in the diagnosis of adult-onset
diabetes mellitus. Journal of the American Medical Association, 240, 833-836.
Valleron, A. J., Eschwege, E., Papoz, L. & Rosselin, G. E. (1975) Agreement and discrepancy
in the evaluation of normal and diabetic oral glucose tolerance tests. Diabetes, 24, 585-593.
Wadsworth, M. E. F. & Jarrett, R. J. (1974) Incidence of diabetes in the first 26 years of life.
Lancet, ii, 1172-1174.
Waldhausl, W., Bratusch-Marrain, P., Gasic, S., Korn, A. & Nowotny, P. (1979) Insulin
production rate following glucose ingestion estimated by splanchnic C peptide output in
normal man. Diabetologia, 17, 221-227.
Watkins, P. J. (1979) A new look at diagnostic criteria. Diabetologia, 17, 127.
Welborn, T. A. & Wearne, K. (1979) Coronary heart disease incidence and cerebrovascular
mortality in Bussalton with reference to glucose and insulin concentrations. Diabetes
Care, 2, 154-159.
West, K. M. (1975) Substantial differences in the diagnostic criteria used by diabetes experts.
Diabetes, 24, 641-644.
West, K. M. (1978a) Screening, detection and diagnosis. Epidemiology of Diabetes and its
Vascular Lesions. pp. 74-112. New York: Elsevier.
West, K. M. (1978b) Screening, detection and diagnosis. Epidemiology of Diabetes and its
Vascular Lesions. pp. 115-126. New York: Elsevier.
West, K. M. (1978c) Special types of diabetes. Epidemiology of Diabetes and its Vascular
Lesions. pp. 321-324. New York: Elsevier.
Willis, T. (1679) Of the diabetes or pissing evil. Pharmaceutica Rationalis, London.
World Health Organisation Expert Committee on Diabetes Mellitus. First Report, 1965. WHO
Technical Report Series No. 310. Geneva: WHO.
DEFINITION AND CLASSIFICATION 305

World Health Organisation Expert Committee on Diabetes Mellitus. Second Report, 1980.
WHO Technical Report Series No. 646. Geneva: WHO.
Zimmet, P. & Whitehouse, S. (1978) Bimodality of fasting and two-hour glucose tolerance
distributions in a Micronesian population. Diabetes, 27, 793-799.