Diagnostic Criteria For Diabetes Mellitus.

Diabetes Research and Clinical Practice 55 (2002) 6585
Discussion
Report of the Committee on the classication and
diagnostic criteria of diabetes mellitus
The Committee of the Japan Diabetes Society on the diagnostic criteria of

diabetes mellitus, Takeshi Kuzuya
a,
*, Shoichi Nakagawa
b
, Jo Satoh
c
,
Yasunori Kanazawa
d
, Yasuhiko Iwamoto
e
, Masashi Kobayashi
f
,
Kisihio Nanjo
g
, Akira Sasaki
h
, Yutaka Seino
i
, Chikako Ito
j
, Kenji Shima
k
,
Kyohei Nonaka
l
, Takashi Kadowaki
m
a
Aino Institute for Aging Research, Ibaraki -shi, Osaka-fu, Japan
b
Hokkaido Uni6ersity, Sapporo, Japan
c
Di6ision of Molecular Metabolism and Diabetes, Tohoku Uni6ersity School of Medicine, Sendai, Japan
d
Omiya Medical Center, Jichi Medical School, Omiya, Japan
e
Diabetes Center, Tokyo Womens medical Uni6ersity School of Medicine, Tokyo, Japan
f
Toyama Medical and Pharmaceutical Uni6ersity, Toyama, Japan
g
First Department of Medicine, Wakayama Uni6erstiy of Medical Science, Wakayama, Japan
h
Department of Epidemiology, Osaka Seijinbyo Center, Medical Institute for Noncommunicable Diseases, Osaka, Japan
i
Department of Metabolism and Clinical Nutrition, Graduate School of Medicine, Kyoto Uni6ersity, Kyoto, Japan
j
Hiroshima A-Bomb Casualty Council Health Management Center, Hiroshima, Japan
k
Kawashima Hospital, Tokushima, Japan
l
Shiroishi Joint Hospital, Shiroishi -cho, Japan
m
Department of Metabolic Diseases, Graduate School of Medicine, Uni6ersity of Tokyo, Tokyo, Japan
Accepted 31 August 2001
Abstract
In 1995, the Japan Diabetes Society (JDS) appointed the Committee for the Classication and Diagnosis of
Diabetes Mellitus. The Committee presented a nal report in May 1999 in Japanese. This is the English version with
minor modications for readers outside Japan.
Concept of diabetes mellitus: Diabetes mellitus represents a group of diseases of heterogeneous etiology, character-
ized by chronic hyperglycemia and other metabolic abnormalities, which are due to deciency of insulin effect. After
www.elsevier.com/locate/diabres
This article is the English version of the original report published in Journal of the Japan Diabetes Society 42: 385404, 1999
in Japanese, adapted for readers outside Japan. References are updated.
* Corresponding author. Present address: 9-40 Kyo-Machi, Utsunomiya, Tochigi 320-0842, Japan. Tel./fax: +81-28-634-9070.
E-mail address: kuzuya@peach.ocn.ne.jp (T. Kuzuya).
0168-8227/02/$ - see front matter 2002 Elsevier Science Ireland Ltd. All rights reserved.
PII: S0168- 8227( 01) 00365- 5
T. Kuzuya et al. / Diabetes Research and Clinical Practice 55 (2002) 6585 66
a long duration of metabolic derangement, specic complications of diabetes (retinopathy, nephropathy, and
neuropathy) may occur. Arteriosclerosis is also accelerated. Depending on the severity of the metabolic abnormality,
diabetes may be asymptomatic, or may be associated with symptoms (thirst, polyuria, and weight loss), or may
progress to ketoacidosis and coma.
Classication (cf. Tables 1 and 2 and Fig. 1): Both etiological classication and staging of pathophysiology by the
degree of deciency of insulin effect need to be considered. The etiological classication of diabetes and related
disorders of glycemia includes, (1) type 1; (2) type 2; (3) those due to specic mechanisms and diseases; and (4)
gestational diabetes mellitus. Type 1 is characterized by destructive lesions of pancreatic b cells either by an
autoimmune mechanism or of unknown cause. Type 2 diabetes is characterized by combinations of decreased insulin
secretion and decreased insulin sensitivity (insulin resistance). Category (3) includes two subgroups; subgroup A is
diabetes in which specic mutations have been identied as a cause of genetic susceptibility, while subgroup B is
diabetes associated with other pathologic conditions or diseases. The staging of glucose metabolism includes normal,
borderline and diabetic stages. The diabetic stage is further classied into three substages; non-insulin requiring,
insulin-requiring for glycemic control, and insulin-dependent (ID) for survival. In each individual, these stages may
vary according to the deterioration or the improvement of the metabolic state, either spontaneously or by treatment.
Diagnosis (cf. Tables 3 and 4): The conrmation of chronic hyperglycemia is a prerequisite for the diagnosis of
diabetes mellitus. The state of glycemia may be classied within three categories, diabetic type; borderline type; and
normal type. Diabetic type is dened when fasting plasma glucose (FPG) is 7.0 mmol/l (126 mg/dl) or higher, and/or
plasma glucose 2 h after 75 g glucose load (2hPG) is 11.1 mmol/l (200 mg/dl) or higher. A casual plasma glucose (PG)
]11.1 mmol/l (200 mg/dl) also indicates diabetic type. Normal type is dened when FPG is below 6.1 mmol/l (110
mg/dl) and 2hPG below 7.8 mmol/l (140 mg/dl). Borderline type includes those who are neither diabetic nor normal
types. These cutoff values are for venous PG measurements. The persistence of diabetic type in a subject indicates
that he or she has diabetes. For children, a dose of 1.75 g/kg (maximum, 75 g) is used for oral glucose tolerance test
(OGTT). The procedure for clinical diagnosis is as follows.
1. Diabetes mellitus is diagnosed when hyperglycemia meeting the criteria for diabetic type is shown on two or
more occasions examined on separate days.
2. Diabetes can be diagnosed by a single PG test of diabetic type if one of the following three conditions co-exists,
(1) typical symptoms of diabetes mellitus; (2) HbA
1c
]6.5% by a standardized method; or (3) unequivocal
diabetic retinopathy.
3. If the above conditions ((1) or (2)) have been present in the past and well documented, the subject is diagnosed
either to have diabetes or to be suspected of diabetes, even if the present level of glycemia does not reach that of
diabetic type.
4. If the diagnosis of diabetes cannot be established by these procedures, re-testing of PG is recommended after an
appropriate interval.
5. The physician should assess not only the presence or absence of diabetes, but also its etiology and glycemic stage,
and the presence and absence of diabetic complications or associated conditions.
Epidemiological aspects and screening: In order to determine the prevalence of diabetes in a population, diabetic
type may be regarded as diabetes. The use of 2hPG cutoff level of ]11.1 mmol/l (200 mg/dl) is recommended. If
this is difcult, the FPG cutoff level of ]7.0 mmol/l (126 mg/dl) can be used, but is likely to lead to
under-ascertainment. For screening, the most important point is not to overlook diabetes. In addition to parameters
of hyperglycemia, clinical information such as family history, obesity etc., should be regarded as indications for
further testing.
Normal type and borderline type: Only FPG and 2hPG are adopted as cutoff values, but in clinical situations, it is
recommended to measure PG also at 30 and 60 min during 75 g OGTT. Among people with normal type, those with
1hPG higher than 10.0 mmol/l (180 mg/dl) are at higher risk to develop diabetes than those with lower 1hPG. When
OGTT is performed, the borderline type corresponds to the sum of impaired fasting glycemia (IFG) plus impaired
glucose tolerance (IGT) according to the new WHO report. Subjects in this category are at higher risk of developing
diabetes than those with normal type. Those with low insulinogenic index (the ratio of increment of plasma insulin
to that of PG at 30 min during OGTT) are at particularly high risk to develop diabetes. Microvascular complications
are rare but arteriosclerotic complications are fairly frequent in this category.
Gestational diabetes mellitus (GDM): The current denition of GDM is any glucose intolerance developed or
detected during pregnancy. We adopt the proposal of the Japan Society of Gynecology and Obstetrics for the
diagnosis of GDM (1984). GDM is dened when two or more values during a 75 g OGTT are higher than the
following cutoff levels; FPG ]5.5 mmol/l (100 mg/dl), 1hPG ]10.0 mmol/l (180 mg/dl) and 2hPG ]8.3 mmol/l
(150 mg/dl). As a screening test, subjects with casual PG ]5.5 mmol/l (100 mg/dl) are recommended for further
testing. Patients who have had documented glucose intolerance before pregnancy, and who present as diabetic type
should be under closer supervision than those who develop GDM during pregnancy for the rst time.
HbA
1c
: There is a large overlap in the distribution of HbA
1c
between groups with normal type and borderline
type and mild diabetic type. Therefore, HbA
1c
is not a suitable parameter to detect mild glucose intolerance. HbA
1c
higher than 6.5% suggests diabetes, but HbA
1c
below 6.5% alone should not be taken as evidence against the
diagnosis of diabetes.
Comparison with reports of American Diabetes Association (ADA) in 1997 and WHO in 1999: The present report is
unique in the following points when compared with those of the ADA Diabetes Care 20 (1997) 1183 and WHO
Report of a WHO Consultation (1999). (1) Diabetes due to specic mechanisms and diseases is divided into two
subgroups; diabetes in which genetic susceptibility is claried at the DNA level and diabetes associated with other
diseases or conditions. (2) Cutoff PG levels are the same as those of ADA and WHO, but a term type is added to
each glycemic category, because a single coding of diabetic type hyperglycemia does not dene diabetes. Diabetes is
diagnosed when diabetic type hyperglycemia is shown on two or more occasions. (3) A single diabetic type
hyperglycemia is considered sufcient for the diagnosis of diabetes, if the patient has typical symptoms, HbA
1c
]6.5%, or diabetic retinopathy. (4) OGTT is recommended for those with mild hyperglycemia, because FPG criteria
alone would overlook many subjects with diabetic type in Japan. High 1hPG without elevation of FPG and 2hPG
is also considered to be a risk factor for future diabetes. (5) Borderline type in the present report corresponds to the
sum of IFG and IGT by WHO when OGTT is performed. (6) New criteria for GDM by OGTT are proposed.
2001 Elsevier Science Ireland Ltd. All rights reserved.
Keywords: Diabetes mellitus; JDS; Diagnosis; Classication
1. Introduction
In the past, the Japan Diabetes Society (JDS)
has presented two reports on the diagnostic crite-
ria for diabetes mellitus, in 1970 and 1982 [1,2].
Before 1970, the methods for glucose tolerance
testing and the diagnostic criteria for diabetes
were not standardized. Various criteria were used,
using different glucose load, and mutual compari-
son of results was almost impossible.
The rst Committee of JDS presented cutoff
levels of blood glucose for 50 g and 100 g glucose
tolerance tests (OGTT). In this 1970 report, a
subtitle A recommendation on the criteria of
OGTT to be used for the diagnosis of diabetes
mellitus was added [1]. The Committee took the
standpoint that OGTT is an important test to
help diagnosis but not to dene diabetes.
In 1979, the National Diabetes Data Group
(NDDG) in USA proposed a classication of
diabetes and diagnostic criteria using a 75 g
OGTT [3]. In 1980, the WHO Expert Committee
presented a report similar to that of NDDG [4].
These two reports adopted diagnostic criteria us-
ing a 75 g OGTT, and classied diabetes into
IDDM (type 1), non-insulin-dependent diabetes
(NIDDM) (type 2), and other types. They also
created the concept of impaired glucose tolerance
(IGT).
After publication of these reports, JDS orga-
nized the second Committee to examine the diag-
nosis of diabetes mellitus and to revise the 1970
JDS recommendation. This Committee regarded
the WHO report as a basis for international stan-
dardization. In addition, the Committee contin-
ued the principle of the rst JDS Committee,
namely that diabetes mellitus is not dened simply
by glycemic cutoff values but is a disease (or
diseases) which possesses other clinical character-
istics [2]. The report of the second JDS Commit-
tee in 1982 adopted the terms, diabetic type,
borderline type, and normal type to describe
the OGTT results. The cutoff plasma glucose
(PG) values for diabetic type were set as the same
as those for diabetes by WHO criteria, whereas
the cutoff values for normal type were set lower
than the lower limits of IGT. The normal type
was dened as a group which would not progress
to diabetes after follow-up of several years. The
borderline type was dened as those being neither
normal nor of diabetic type.
The borderline type of the 1982 JDS Committee
included not only IGT but also milder degrees of
glucose intolerance than IGT, thus creating two
different categories of mild glucose intolerance
(i.e. borderline type and IGT). Some researchers
complained of the inconvenience of having two
such categories. The Committee adopted the
WHO classication of diabetes without modica-
tion. In 1985, WHO made a small revision to the
1980 report [5].
Since that time, many discoveries have been
made regarding the etiology of diabetes, and epi-
demiological data have accumulated. Moves, to
seek a new classication and to revise the diagnos-
tic criteria for diabetes mellitus, have emerged in
Japan as well as internationally. In 1995, JDS
assigned a new Committee to reconsider the clas-
sication and diagnostic criteria of diabetes.
Meanwhile in 1997, the American Diabetes Asso-
ciation (ADA) proposed a new classication
based on etiology, and revised criteria for the
diagnosis of diabetes mellitus [6]. WHO also pre-
sented a provisional report in 1998 and a nal
report in 1999 [7].
The new Committee of JDS sent inquiries to
Council members of the JDS, asking about prob-
lems in the old 1982 JDS report [8]. The Commit-
tee evaluated the 1997 ADA and 1998 WHO
reports carefully after their publication, and pro-
ceeded to hold an ad-hoc symposium on the
diagnosis and classication of diabetes mellitus in
Tokyo in 28 June 1998 (Proceedings, J. Jpn. Dia-
betes Soc. 41 (Suppl. 2), 1999). The Committee
met 16 times, held intensive discussions on pub-
lished and unpublished data obtained in Japan
and produced the following nal report.
2. Concept of diabetes mellitus
Diabetes mellitus is a group of diseases charac-
terized by chronic hyperglycemia due to deciency
of insulin action. The deciency of insulin action,
a common basis of diabetes, leads to characteris-
tic abnormalities in the metabolism of carbohy-
drate, lipid, protein and so on.
The causes of diabetes are multiple. Both ge-
netic and environmental factors play roles in its
etiology. The supply of insulin may be decreased
by a decrease in pancreatic b cell mass and/or
functional disturbances of b cells. In some cases
of diabetes, the disease can be ascribed solely to
the deciency of insulin supply, but in other cases
there are both insulin resistance and relative de-
ciency of insulin. The metabolic abnormality can
be improved by various means to ameliorate the
deciency of insulin effect.
If the metabolic abnormality is mild, patients
may be asymptomatic, while in the presence of
overt hyperglycemia, characteristic symptoms
such as thirst, polydipsia, polyuria and weight loss
often occur. In severe cases, ketoacidosis or hy-
perglycemichyperosmolar states may occur and
lead to disturbances of consciousness, coma and
even death unless treated appropriately.
With long duration of diabetic metabolism, dia-
betes-specic complications, chiey involving
small vessels (retinopathy, nephropathy and neu-
ropathy), may ensue, and lead to serious out-
comes such as visual disturbance, renal failure,
and gangrene. Diabetes accelerates and exacer-
bates the occurrence of arteriosclerosis, increasing
the risks for myocardial infarction, cerebral in-
farction and occlusive artery disease of the lower
extremities. These complications constitute the
major causes of morbidity and mortality in dia-
betic patients.
3. Classication
3.1. Distinction between etiology and the
metabolic stages of diabetes mellitus
The 1980 classication by WHO consists of
clinical classes and statistical risk groups [4]. Clin-
ical classes included diabetes mellitus, IGT and
gestational diabetes. Diabetes was further
classied into IDDM (=type 1), NIDDM
( =type 2) and other types associated with specic
diseases or syndromes. Statistical risk groups in-
cluded previous abnormality of glucose tolerance
and potential abnormality of glucose tolerance. In
the 1985 WHO report, the terms type 1 and type
2 were eliminated from the classication, and
malnutrition-related diabetes mellitus (MRDM)
was added [5]. In this classication, the degree of
insulin deciency and etiology were used in com-
bination as means to classify diabetes.
The new ADA report in 1997 and the WHO
report in 1999 adopted a new classication pri-
marily based on etiology [6,7]. Etiological classi-
cation of diseases is ideal, but the methods to
identify the pathogenesis of diabetes are not yet
satisfactory, so that we cannot always identify the
etiology of diabetes in each patient.
IDDM, in the previous WHO report, was
dened as encompassing patients who need in-
sulin therapy to sustain life. NIDDM was dened
by exclusion. Those who were neither IDDM,
MRDM nor other types were labeled as NIDDM.
The terms IDDM and NIDDM imply states or
stages of diabetes representing different degrees of
insulin deciency. Evaluation of the degree of
deciency of insulin or insulin effect is usually
possible, and is still useful in clinical practice in
addition to etiological classication.
Etiology and patho-physiological states (or
stages) should be assessed separately for each
patient [9,10]. Before development of overt dia-
betes, patients will pass stages at which different
degrees of deciency of insulin effect exist. The
abnormal carbohydrate metabolism not only pro-
gresses but may regress spontaneously or in re-
sponse to treatment. For example, islet
autoantibodies are occasionally detected before
recognition of hyperglycemia, suggesting that the
autoimmune process of type 1 diabetes has al-
ready begun. Overt type 1 diabetes may some-
times be improved temporarily to a
non-insulin-requiring state, the so-called honey-
moon period. Obese diabetic patients may be
improved to borderline type or even to normal
glucose tolerance after weight reduction with diet
therapy. Considering these phenomena, the etiol-
ogy (mechanisms) and the degree of deciency of
insulin action reected by glycemic states (stages)
can be represented in two-dimensions (2-D) as
shown in Fig. 1 [6,7,10].
The horizontal axis represents the degree of
deciency of insulin effect or the degree of abnor-
mality of glucose metabolism. The patients are
judged to have diabetes when hyperglycemia has
exceeded a certain level, which is presumed to
confer risk for specic complications. The diabetic
area is divided into three stages, (1) in which
insulin treatment is not needed; (2) in which in-
sulin injections are required for glycemic control;
and (3) in which insulin treatment is indispensable
to prevent ketosis and to sustain life.
As the terms for etiological classication, type 1
and type 2 are used. The terms insulin-dependent
(ID) state (stage) and non-insulin-dependent
(NID) state (stage) can be used to describe the
degree of deciency of insulin effect. An ID state
means that the patient is at immediate risk of
developing ketosis or is unable to survive without
insulin injection.
3.2. Etiological classication
Table 1 shows the new classication, which
includes type 1, type 2, other specic types and
gestational diabetes mellitus.
Fig. 1. A scheme of the relationship between etiology (mecha-
nism) and patho-physiological states (stages) of diabetes melli-
tus The arrows towards the right indicate deterioration of
glucose metabolism, including the development of diabetes.
The lled portion of solid and broken lines represents the
states regarded as diabetes. The broken lines indicate uncom-
mon phenomena. For example, a patient with type 2 diabetes
usually does not need insulin injection for survival, but may
develop ketoacidosis in association with severe infection. The
arrows towards the left are lled for their full length, meaning
that patients who have once developed diabetes, should be
regarded to have diabetes, even if he or she improves to
resume borderline or normal glucose tolerance. NID and ID
states in the diabetic area, correspond to NIDDM and IDDM
in the previous classication, respectively (adapted from
Kuzuya and Matsuda [10], the Expert Committee of ADA [6]
and WHO Consultation [7]).
Table 1
Etiological classication of diabetes mellitus and related disorders of glucose tolerance
1. Type 1, (caused by destructive lesions A, Autoimmune
of pancreatic b cells, usually leading to B, Idiopathic
absolute insulin deciency)
2. Type 2, (ranging from predominantly
insulin secretory defect, to a
predominantly insulin resistance with
varying degree of insulin secretory
defect)
A, Those in which specic mutations (1) Genetic abnormalities of pancreatic 3. Due to other specic mechanisms or
have been identied as a cause of genetic diseases (details in Table 2) b cell function
(2) Genetic abnormalities of insulin susceptibility
action
B, Those associated with other diseases (1) Diseases of exocrine pancreas
(2) Endocrine diseases or conditions
(3) Liver diseases
(4) Drug- or chemical-induced
(5) Infections
(6) Rare forms of immune-mediated
diabetes
(7) Various genetic syndromes often
associating diabetes
4. Gestational diabetes mellitus
The occurrence of diabetes-specic complications has not been conrmed in some of these conditions. This classication differs from
those of ADA [6] and WHO [7] in two points; category 3 is subdivided into A and B, and liver diseases are added in category 3B.
3.2.1. Type 1 diabetes
This type of diabetes occurs as a result of
deciency of insulin due to destructive lesions of
pancreatic b cells, and usually progresses to the
stage of absolute insulin deciency. In the major-
ity of Japanese patients with type 1 diabetes, an
autoimmune process is thought to play a major
role in b cell destruction. Auto-antibodies to islet
cell antigens are detected in many patients (70
90%), particularly at the early period after onset
[11]. Typically, it occurs in young subjects with
acute onset, but may occur at any age, sometimes
with slow progression [12]. Occasionally, before
the occurrence of clinical symptoms or hyper-
glycemia, auto-antibodies or the loss of acute
insulin response to intravenous glucose may be
detected. In some patients who progress to an ID
state, auto-antibodies to islet antigens are never
detected. Such patients are classied as idiopathic
type 1 diabetes. Patients developing an ID state
as a result of mitochondrial mutations or other
known causes are not included as type 1 diabetes.
In the future, type 1 diabetes may be further
divided into subtypes according to the mode of
onset (i.e. acute or slowly-progressive), HLA anti-
gens, or epitopes of autoantigens [12,13].
3.2.2. Type 2 diabetes
Most patients previously called NIDDM be-
long to this category. In this type, the mass of
pancreatic b cells and their function are preserved
to some extent, and insulin injection is seldom
needed to sustain life. Ketoacidosis could occur,
however, in the presence of severe infection or
other stress. Both decreased insulin secretion and
decreased insulin sensitivity (insulin resistance) are
involved in its pathogenesis. Insulin resistance
may not always be present. The relative role of
these two factors varies between patients. With
regard to insulin secretion, the acute insulin re-
sponse to a glucose load is characteristically de-
fective. The majority of patients are obese or have
been obese in the past.
Table 2
Diabetes and related disorders of glucose tolerance due to
other specic mechanisms and diseases
A, Those in which specic (1) Genetic abnormalities of
mutations have been pancreatic b cell function
identied as a cause of Genes for insulin (abnormal
genetic susceptibility insulinemia, abnormal
proinsulinemia)
HNF 4a gene (MODY 1)
Glucokinase gene (MODY 2)
HNF 1a gene (MODY 3)
IPF-1 gene (MODY 4)
HNF 1b (MODY 5)
Mitochondria gene (MIDD)
Amylin gene
Others
(2) Genetic abnormalities of
insulin action
Insulin receptor gene
mutations (type A insulin
resistance, leprechaunism,
RabsonMendenhall
syndrome etc.)
Others
(1) Exocrine pancreatic B, Those associated with
diseases other specic diseases or
Pancreatitis conditions
Trauma/pancreatectomy
Neoplasm
Hemochromatosis
Others
(2) Endocrine diseases
Cushing syndrome
Acromegaly
Pheochromocytoma
Glucagonoma
Aldosteroinism
Hyperthyroidism
Somatostatinoma
Others
(3) Liver diseases
Chronic hepatitis
Liver cirrhosis
Others
(4) Drug- or chemical-induced
Glucocorticoids
Interferon
Others
(5) Infections
Congenital rubella
Cytomegalovirus
EpsteinBarr virus
Coxackie B virus
Mumps virus
Others
(6) Rare forms of
immune-mediated diabetes
Table 2 (Continued)
Anti-insulin receptor
antibodies
Stiffman syndrome
Insulin autoimmune
syndrome
Others
(7) Various genetic
syndromes often associating
diabetes
Down syndrome
PraderWilli syndrome
Turner syndrome
Klinefelter syndrome
Werner syndrome
Wolfram syndrome
Ceruloplasmin deciency
Lipoatrophic diabetes
Myotonic dystrophy
Others
The occurrence of diabetes-specic complications has not been
conrmed in some of these conditions.
Typically, this type of diabetes develops after
middle age, but may occur in younger people.
Screening by urinalysis of large numbers of
schoolchildren has revealed that type 2 diabetes
has been steadily increasing since the 1970s
[14,15]. The incidence of type 2 is very low under
the age of 10 years, but exceeds the incidence of
type 1 diabetes in mid-teens. About 80% of them
are obese. NID type diabetes with autosomal
dominant inheritance in young people has been
called MODY (maturity-onset diabetes of the
young) [16]. In many of these, specic DNA
abnormalities have been identied [17]. MODYs
are now classied into another category separated
from the common forms of type 2 diabetes.
Genetic abnormalities have not yet been iden-
tied in most patients with type 2 diabetes. Poly-
genic inheritance is presumed in these patients. If
future investigations reveal new genetic abnormal-
ities leading to type 2 diabetes, these would be
reclassied into other categories. Type 2 diabetes
is not a homogenous entity. There is a possibility
of subclassication according to the presence or
absence of obesity, the varying relative roles of
insulin secretory and sensitivity defects, but the
method of subclassication has not yet been
established.
3.2.3. Other types of diabetes due to specic causes
We classify these cases into two major groups
(Table 2).
3.2.3.1. Diabetes in which specic mutations ha6e
been identied as a cause of genetic susceptibility.
Many susceptibility genes for diabetes have re-
cently been identied [18]. They are divided into
(1) genetic abnormalities related to b cell function;
and (2) genetic abnormalities related to mecha-
nisms of insulin action. The rst category includes
abnormalities of the insulin gene, and MODY
cases. Mutations of genes for HNF 4a, glucoki-
nase, HNF 1a, IPF-1 (PDX-1), HNF 1b corre-
spond to MODYs 1, 2, 3, 4 and 5, respectively.
Abnormalities of mitochondrial DNA [19] and
the amylin gene [20] are also included in this
category. The second category includes a number
of insulin receptor gene abnormalities [21].
3.2.3.2. Diabetes associated with other pathologic
conditions or diseases. Diabetes and glucose intol-
erance may occur as a manifestation of various
pathologic conditions, diseases and syndromes.
Some have been previously called secondary dia-
betes. These include pancreatic diseases, en-
docrinopathies, liver diseases, exposure to certain
drugs and chemicals, viral infections, and various
genetic syndromes, as shown in Table 2. We have
added liver diseases to the corresponding tables of
ADA [6] and WHO [7], because glucose intoler-
ance is common (diabetic type, 1240%) among
subjects with hepatitis and liver cirrhosis [22,23].
They often have a normal FPG but PG is elevated
after glucose loading, presumably by decreased
hepatic uptake and increasing shunt of portal
blood to systemic circulation.
3.2.4. Gestational diabetes mellitus (GDM)
GDM is a state of glucose intolerance occurring
or detected for the rst time during pregnancy.
Pregnancy is a diabetogenic factor. Etiologically,
many GDM patients probably share common ge-
netic susceptibilities with type 1 or type 2 dia-
betes, and the deterioration of glucose tolerance is
precipitated by the metabolic effect of pregnancy.
The reason to treat GDM as an independent
category is its clinical importance which requires
special consideration. During pregnancy, glucose
intolerance milder than diabetic type may affect
the infant and mother adversely. Glucose intoler-
ance during pregnancy is often normalized after
delivery, but such cases are at higher risk of
developing diabetes in the future. Problems on the
diagnosis of GDM will be discussed later in
detail.
3.3. Information to help classify diabetes
For etiological classication of diabetes, the
following clinical information is useful.
1. Detailed information about the family history
of diabetes.
2. Age of onset and the course of diabetes.
3. Physical characteristics such as obesity, history
of weight changes in the past, hearing distur-
bance (mitochondrial DNA abnormality), and
acanthosis nigricans (severe insulin resistance).
4. Anti-GAD antibody, islet cell antibody, in-
sulin autoantibody, and anti-IA2 antibody
(the presence of any of these autoantibodies
suggests type 1 diabetes).
5. HLA antigens (DR4 and DR9, which are as-
sociated with susceptibility to type 1 diabetes,
are common among Japanese, and their ab-
sence suggests that the patient is unlikely to
have autoimmune type 1 diabetes).
6. Tests for insulin secretion and insulin sensitiv-
ity (plasma insulin and C-peptide levels, in-
sulin response to glucose loading, euglycemic
clamp, minimal model etc).
7. DNA analysis may give a denite diagnosis in
special cases belonging to A(1) and A(2) in
Table 2.
In order to assess the stage of diabetes, clinical
information (history of the disease, glycemic level
and its stability, ketosis-proneness, and response
to diet and drug therapy), plasma insulin assays
(fasting and after glucose load, and after intra-
venous glucagon), and C-peptide assays in plasma
and urine will help evaluate the degree of insulin
deciency.
4. Diagnosis of diabetes mellitus
For the diagnosis of diabetes mellitus, the
physician should evaluate whether the subject ts
to the concept of diabetes as mentioned earlier.
The conrmation of chronic hyperglycemia is a
prerequisite for diagnosis. The cut-off values of
fasting plasma glucose (FPG) and 2 h PG follow-
ing 75 g oral glucose load (2hPG) are shown in
Table 3. Persistence of hyperglycemia of diabetic
type in Table 3 indicates that the subject has
diabetes. In order to conrm persistent hyper-
glycemia, at least two PG measurements on sepa-
rate days are necessary. However, diabetes can be
diagnosed following a single PG measurement
showing diabetic type hyperglycemia, if the pa-
tient has typical diabetic symptoms, a high HbA
1c
value or denite diabetic retinopathy. If these
conditions have been present in the past and well
documented, diabetes is diagnosed or should be
suspected even though the current degree of
glycemia does not meet the criteria of diabetic
type.
PG is often elevated temporarily in cases of
severe stress (for example, infections, myocardial
infarction, cerebral hemorrhage and surgery).
Therefore, excepting the situation of a severe
metabolic disturbance necessitating immediate
treatment, the evaluation of hyperglycemia should
be made following resolution of such stressful
conditions.
We will rst describe the procedures for diagno-
sis in the clinical setting, and then proceed to
epidemiological surveys and screening.
4.1. Clinical diagnosis
4.1.1. Procedures for the diagnosis of diabetes
mellitus (Table 4)
1. Conrmation of persistent hyperglycemia.
( c1) Diabetes is diagnosed when hyper-
glycemia meeting the criteria for diabetic type
(FPG]7.0 mmol/l (126 mg/dl), 2hPG]11.1
mmol/l (200 mg/dl), and/or casual PG]11.1
mmol/l (200 mg/dl)) is recognized on two or
more occasions examined on separate days.
These cutoff plasma glucose levels are the
same as those of diabetes by ADA [6] and
WHO [7] reports.
Casual plasma glucose is the plasma glucose
value examined at any time regardless of the
interval after meals. FPG means the glucose
level in the morning before breakfast after
more than 10 h of fasting since the previous
evening. The method for performing OGTT
will be described later.
( c2) When the rst plasma glucose mea-
surement meets the criteria of diabetic type,
the subject is simply called diabetic type until
a similar degree of hyperglycemia is conrmed
by a second test.
Table 3
Criteria of fasting plasma glucose (FPG) and 2 h plasma glucose (2hPG) following 75 g glucose ingestion
Normal range Diabetic range
B6.1 (110) ]7.0 (126) FPG
2hPG after 75 g glucose ]11.1 (200) B7.8 (140)
Normal type: Evaluation of OGTT Diabetic type:
If both values belong to normal range If any of the two values falls into diabetic range
Borderline type:
Neither normal nor diabetic types
Values are venous plasma in mmol/l. Figures in the brackets are values in mg/dl. Casual plasma glucose ]11.1 mmol/l (200 mg/dl)
is also regarded as to indicate diabetic type. Subjects with 1hPG ]10.0 mmol/l (180 mg/dl) are advised to be followed similarly to
borderline type, even if they belong to normal type, because it is known that such individuals are at higher risk of developing
diabetes than those with 1hPG B10.0 mmol/l (180 mg/dl).
Table 4
The procedures of clinical diagnosis
1. Diabetes mellitus is diagnosed when hyperglycemia
meeting criteria for diabetic type in Table 3 is conrmed
on 2 or more occasions examined on separate days
2. Diabetes can be diagnosed by a single plasma glucose
test meeting criteria for diabetic type, when either one
of the following three conditions exits
(1) Typical symptoms of diabetes (i.e. thirst, polyuria,
polydipsia, weight loss)
(2) HbA
1c
]6.5% (HbA
1c
should be determined
according to the recommendation of JDS
Committee for Standardization of
Glycohemoglobin)
(3) Unequivolcal diabetic retinopathy
3. If the above conditions (1 or 2) existed in the past and
are well documented, the subject is diagnosed either as
having diabetes, or should be suspected of diabetes
regardless of the glycemic status at present
4. If the diagnosis of diabetes cannot be established by
13., re-testing of plasma glucose after some interval is
recommended
5. At clinical diagnosis, the physicians should assess not
only the presence or absence of diabetes, but also its
etiology and glycemic stage, and the diabetic
complications
The rst and second tests of plasma glucose need not be done
by the same method. When the rst test is carried out by
casual plasma glucose, the other methods are preferred as a
second test. If FPG is less than 7.8 mmol/l (140 mg/dl) at the
rst test, OGTT is recommended as the second test.
4. When the diagnosis of diabetes cannot be
made by (1)(3) as mentioned above, the pa-
tient should be followed, and re-testing is rec-
ommended after some interval, at least
annually.
5. At clinical diagnosis, the physician should
evaluate not only the presence or absence of
diabetes, but also should pay attention to its
etiology, the degree of metabolic disturbance
and the presence of complications.
The methods used for the rst and second
tests for glycemia need not be the same. When
the rst test has been casual plasma glucose,
the use of other methods is recommended as
the second test. Conrmation of the fasting
condition is particularly important when FPG
is used as a diagnostic test. If FPG is between
7.0 and 7.8 mmol/l (126 and 139 mg/dl) at the
rst test, we recommend an OGTT as the
second test.
4.1.2. Oral glucose tolerance test (OGTT) and the
criteria for OGTT
4.1.2.1. Procedure of OGTT. OGTT evaluates the
rate of glucose disposal after an oral glucose
challenge, and is the most sensitive test to detect a
mild disturbance of glucose metabolism. When
casual and FPG tests give ambiguous results,
OGTT helps to establish whether or not the sub-
ject has diabetes. In the clinical setting, OGTT is
recommended when FPG is in the borderline
range (6.16.9 mmol/l, 110125 mg/dl). In addi-
tion, when FPG exceeds 7.0 mmol/l (126 mg/dl)
but is below 7.8 mmol/l (140 mg/dl) in the dia-
betic range, OGTT is useful to clarify the
diagnosis.
In order to obtain accurate results, the follow-
ing procedures are required. Recipients should
take meals including more than 150 g carbohy-
drate for 3 days. A 250350 ml solution of 75 g
anhydrous glucose or its equivalent is adminis-
tered orally and blood is drawn before and at
certain time intervals after glucose loading. The
test should be done after an overnight fast for
1014 h. No food or drink except water nor
smoking is allowed during the test. Blood should
be centrifuged immediately to separate plasma or
2. Diabetes can be diagnosed by a single plasma
glucose measurement which meets the criteria
of diabetic type, if one of the following three
conditions exists.
( c1) The presence of typical symptoms of
diabetes (thirst, polydipsia, polyuria, and
weight loss).
( c2) HbA
1c
]6.5%. HbA
1c
should be de-
termined according to the recommendation of
the JDS Committee for the Standardization of
Glycohemoglobin Assay.
( c3) The presence of denite diabetic
retinopathy.
3. If the above conditions [(1) and (2)] existed in
the past and are well documented by the pa-
tients medical record, diabetes is diagnosed or
should be suspected, even if the present
glycemic tests do not meet the criteria of dia-
betic type.
kept cold, preferably with addition of NaF to
prevent glycolysis until centrifugation. If a timed
urine sample is taken, it can help to estimate
the threshold for glucosuria.
Starvation or low carbohydrate intake may
induce glucose intolerance. In patients who
have undergone gastrectomy, plasma glucose of-
ten reaches abnormally high levels at 3060
min.
At least, fasting and 2 h blood samples
should be taken. In clinical cases, it is recom-
mended also to measure plasma glucose also at
30 and 60 min to enhance accurate diagnosis.
The measurement of plasma insulin can help to
predict the risk for future development of dia-
betes, as discussed below.
4.1.2.2. Cutoff le6els for OGTT. Normal range
and diabetic range are set for FPG and 2hPG
(Table 3). Similarly to previous JDS recommen-
dations, we classify the OGTT results into dia-
betic, borderline and normal types according to
combinations of FPG and 2hPG.
Diabetic type. The cutoff plasma glucose val-
ues are the same as those for diabetes by 1997
ADA and 1999 WHO criteria. In comparison
with 1982 JDS criteria, the cutoff value of FPG
has been lowered from ]7.8 (140) to ]7.0
mmol/l (126 mg/dl).
Normal type. Normal type is dened as a
range of glycemia which is unlikely to develop
diabetes after several years of observation. Both
FPG and 2hPG should be within the normal
range. Even if FPG and 2hPG are in the nor-
mal range, subjects with 1hPG higher than 10.0
mmol/l (180 mg/dl) are at higher risk of devel-
oping diabetes than those whose 1hPG is lower.
Therefore, we recommend that such cases be
followed in the same way as those with border-
line type.
Borderline type. This category is dened when
the pattern of OGTT is neither diabetic nor
normal type. Borderline type includes heteroge-
neous conditions; a subject in transition to de-
velop diabetes, diabetes in remission, and
temporary deterioration of glucose tolerance due
to stress in an essentially healthy individual.
Subjects with borderline type are at little risk to
develop diabetes-specic microangiopathy but at
increased risk to progress to diabetes, and to
develop macroangiopathy.
Diabetic patients have a decreased early in-
sulin response to glucose with low insulinogenic
index, DIRI/DPG (the ratio of increment of
plasma insulin to that of glucose) at 30 min
after oral glucose load. Borderline type and nor-
mal type subjects (particularly borderline type)
with a low insulinogenic index (B7.2 mU/ml per
mmol/l, or B0.4 mU/ml per mg/dl) are at
higher risk of diabetes in the future than those
with a normal insulinogenic index.
4.2. Epidemiological study
The target of epidemiological study of dia-
betes is populations rather than individuals. In
population studies, it is usually difcult to ex-
amine plasma glucose repeatedly. The reproduci-
bility of FPG and OGTT values is not good for
individual subjects, but the mean PG values and
their distribution curve for each population are
fairly reproducible. For these reasons, diabetic
type hyperglycemia obtained by a single test is
to be regarded as diabetes for the purpose of
epidemiological study (Table 3). As it is some-
times difcult to conrm whether an examinee is
tested truly at fasting, we recommend to use the
2hPG values by OGTT as a basis to estimate
the prevalence of diabetes. In circumstances
where OGTT is difcult to perform, FPG crite-
ria of ]7.0 mmol/l (126 mg/dl) may be used
instead of 2hPG criteria. The prevalence of dia-
betes and individual grouping into glycemic cat-
egories differ depending on which criteria are
used. Subjects with FPG below 7.0 mmol/l (126
mg/dl) often have 2hPG values in the diabetic
range. Thus, the prevalence of diabetes by
OGTT may be increased by more than 50%
compared with that obtained by FPG test alone
(Table 7). Therefore, the survey report should
describe what method and criteria are used. In
addition, it is recommended that the epidemio-
logical survey report includes the data of distri-
bution of plasma glucose values, as well as the
prevalence of diabetes and other categories of
glucose intolerance.
4.3. Screening
In health screening for diabetes, the most im-
portant point is not to overlook diabetic patients
and subjects with suspect of diabetes. Not only
glycemic parameters such as plasma glucose,
HbA
1c
and urine glucose, but also information on
family history, obstetric history, obesity at present
and in the past, hypertension, and other complica-
tions should be gathered to select subjects for
further examination. The diagnosis of subjects
thus screened then follows the same procedure as
for clinical diagnosis.
4.4. Elderly people and children
4.4.1. Elderly people
The prevalence of glucose intolerance increases
with age. The criteria for OGTT in the elderly are
the same as in Table 3, but a special consideration
should be paid to treat subjects diagnosed as
diabetes. Elderly people (older than 65 years)
whose glycemic levels only slightly exceed the
cutoff values are to be treated by diet or moderate
exercise alone without using medication. In el-
derly people, 2hPG tends to be more elevated
compared with FPG.
4.4.2. Children
In children, type 1 diabetes usually presents
with overt symptoms and with marked hyper-
glycemia, leaving little problem in diagnosis. Mild
diabetes as detected by urinalysis in school poses
some problem in diagnosis. For OGTT, the
amount of glucose load is 1.75 g/kg up to a
maximum of 75 g. The same glycemic criteria are
used as in adults. In childhood diabetes, the dis-
tinction of type of diabetes is important. Those
who develop diabetes under the age of 10 years
almost always have type 1 diabetes [14]. The
incidence of type 2 diabetes exceeds that of type 1
after 15 years of age. The majority of type 2
diabetes in children is associated with obesity.
Anti-GAD antibody and other autoantibodies are
useful to identify type 1 diabetes. Detailed family
history is helpful not only to detect MODY pa-
tients, but also in type 1 and type 2 diabetes.
4.5. Gestational diabetes mellitus (GDM)
The traditional concept of GDM is mild tem-
porary glucose intolerance which appears for the
rst time during pregnancy, implying that glucose
intolerance subsides after delivery [2,24]. Recently,
the concept of GDM has undergone modication.
The denition by the Fourth International Work-
shop on GDM [25] is, carbohydrate intolerance
of varying degrees of severity with onset or rst
recognition during pregnancy. The denition ap-
plies regardless of whether insulin is used for
treatment or the condition persists after preg-
nancy. It does not exclude the possibility that
unrecognized glucose intolerance may have ante-
dated the pregnancy.
The reason to consider GDM separately from
other types of diabetes is twofold. First, mild
glucose intolerance during pregnancy, not meeting
the criteria of diabetes in general, may have
harmful effects on mother and infant, needing
special attention and treatment. Second, such sub-
jects are at higher risk to develop diabetes in the
future, even though glucose intolerance improves
after delivery.
The denition of the Fourth GDM Workshop
includes the following three different categories.
1. Diabetes, which had been present but unno-
ticed before pregnancy, detected incidentally
during pregnancy.
2. Milder degrees of glucose intolerance which
antedated pregnancy, and progress to diabetic
type during pregnancy.
3. Glucose intolerance milder than diabetic type
developing during pregnancy for the rst time.
The traditional concept of GDM seems closest
to this last case [2,24].
Deterioration of glucose tolerance usually de-
velops after the second trimester of pregnancy.
Therefore, patients who show diabetic type or
diabetic retinopathy during the rst trimester are
likely to have had diabetes before pregnancy. It is
more appropriate to regard them as pregnant
women with diabetes rather than as GDM. As
type 1 diabetes is less frequent in Japanese than in
Caucasians, type 2 diabetes is more prevalent than
type 1 diabetes in women of child-bearing age in
Japan. Due to the paucity of symptoms of mild
type 2 diabetes, it is common for diabetes to be
rst detected during pregnancy. The frequency of
anomalies and perinatal problems are more com-
mon among those in whom diabetes or glucose
intolerance antedated pregnancy than in those
who develop mild glucose intolerance during
pregnancy. The difference between these two situ-
ations should be considered during the planning
of treatment of GDM [26].
In 1984, the Committee for Nutrition and
Metabolism of the Japan Society of Gynecology
and Obstetrics proposed cutoff values for the
diagnosis of GDM by the use of 75 g OGTT.
GDM is diagnosed when any two points among
FPG, 1hPG and 2hPG exceeded 5.5, 10.0 and 8.3
mmol/l (100, 180, and 150 mg/dl) respectively
(Table 5) [27]. These cutoff values were rst se-
lected from the mean value +2 S.D. of healthy
pregnancies, and their validity was also supported
later by the study of perinatal abnormalities of
pregnant women with varying degree of glucose
intolerance. We have, therefore, decided to adopt
these criteria for the diagnosis of GDM in the
present report.
As a screening test, a casual plasma glucose test
is recommended at the rst visit. If it is 5.5
mmol/l (100 mg/dl) or higher, then a 75 g OGTT
is recommended with evaluation by the criteria
shown in Table 5, [26,28]. The frequency of casual
PG exceeding 5.5 mmol/l (100 mg/dl) during preg-
nancy was reported to be approximately 8% in
two obstetric clinics [29]. The detection of glucose
intolerance during the rst trimester suggests that
it was present before pregnancy. Normal glucose
tolerance during the rst trimester does not ex-
clude the possibility that glucose tolerance may
deteriorate after the second trimester. Therefore,
screening should be repeated at 24 to 28th weeks
of pregnancy.
Patients with GDM should be re-tested 13
months after delivery to reclassify the glucose
tolerance state. The etiological classication is
also re-evaluated if the diabetic state persists.
GDM is a group with high risk for future dia-
betes. Therefore, periodic follow-up is recom-
mended for all cases.
5. Discussion and comments
In preparation of this report, we have paid
special consideration to the following points.
First, we thought it best to adopt the recent
reports by ADA and WHO as far as possible.
Second, the report should be based on recent
clinical and epidemiological data obtained in
Japan. Third, we have continued the basic philos-
ophy on the diagnosis of diabetes used by the
1970 and 1982 JDS Committees. Fourth, we have
taken account of many opinions expressed by
Council members of JDS. Some discussion and
additional comments not mentioned in the pre-
ceding text will be presented below.
5.1. Classication of diabetes mellitus
5.1.1. Diabetes in which specic mutations ha6e
been identied as a cause of genetic susceptibility
Recently, in a number of families with diabetes,
DNA abnormalities have been identied which
explain genetic susceptibility to specic types of
diabetes [18]. They include two categories, abnor-
malities of insulin supply and abnormalities of
insulin action. These categories were placed
within other types of diabetes due to specic
causes in the ADA and WHO reports, with pan-
creatic diseases, endocrine diseases and so on. We
have separated the group with known DNA ab-
normalities (category A) from other groups of
secondary diabetes (category B).
Pancreatic diseases, endocrinopathies and oth-
ers have specic symptoms, and diabetes often
constitutes only one of the clinical features. In
contrast, diabetes is a core and sometimes the
only symptom in category A.
Table 5
Criteria for gestational diabetes mellitus by 75 g OGTT
Blood glucose mmol/l (mg/dl)
Capillary blood Venous blood Venous plasma
]5.6 (100) ]4.4 (80) FPG ]4.4 (80)
]8.9 (160) 1hPG ]10.0 (180) ]10.0 (180)
]8.3 (150) 2hPG ]8.3 (150) ]7.8 (140)
Gestational diabetes is diagnosed when two or more points
exceeded the above cutoff levels. (Sugawa et al. [27]).
At the JDS Committee Meeting, there was dis-
cussion that some causes of diabetes in category A
with DNA mutations might better be classied as
a subgroup of type 2 diabetes, because many are
indistinguishable from common type 2 diabetes
clinically, and they have features of insulin secre-
tory defect and/or insulin resistance, which are
characteristic features of type 2 diabetes. Using
such a classication, type 2 diabetes would be
separated into two categories, idiopathic type 2
diabetes and a group with known DNA abnor-
malities. We did not adopt this, however, because
some DNA abnormalities are also accompanied
specic physical features different from common
type 2 diabetes, such as deafness with mitochon-
drial DNA mutations, and the characteristic fea-
tures seen in leprechaunism.
In the future, the cause of genetic susceptibility
of common type 2 diabetes, perhaps polygenic,
will probably be gradually claried. Reconsider-
ation of the classication of diabetes will then be
necessary, when substantial data on susceptibility
genes have been accumulated.
5.1.2. Worsening and impro6ing of states of
diabetes
Each patient with diabetes is expressed in 2-D
in Fig. 1, the etiology of diabetes and the degree
of deciency of insulin effect [9,10]. In Fig. 1,
there are arrows directed to right and left. Direc-
tion to the right means worsening of the
metabolic state, and direction to the left means
improvement spontaneously or with treatment. In
similar gures in the ADA and WHO reports
[6,7], the arrows are expressed as bi-directional
lines. We separate the arrows toward right and
left, and some portions of the arrows are ex-
pressed as broken lines to indicate uncommon
phenomena. For example, it is not common for
established diabetes to revert to completely nor-
mal glucose tolerance. Nevertheless, such cases
are seen in so-called soft-drink ketosis, in which
patients presenting with ketoacidosis may be im-
proved to normoglycemia [30,31]. The left-di-
rected arrow may be regarded as indicating a goal
of treatment of diabetes.
Once a patient is diagnosed as diabetes, we
think that he or she should be regarded and
treated as diabetes even if the glycemic state
improves to a borderline type or normoglycemia.
This is the reason why the arrows toward the left
are expressed as lled lines throughout their
length. There are exceptions, however, where the
cause of diabetes can be removed and diabetes has
been regarded as cured (e.g. the surgical removal
of pheochromocytoma etc).
5.2. Diagnostic criteria and rele6ant problems
5.2.1. Rationales for use of the term diabetic
type
The most important purpose of diagnosing dia-
betes is to allow early detection and treatment, in
order to prevent complications. The occurrence
and progression of diabetes-specic complications
are closely related to the degree and duration of
hyperglycemia. The level of hyperglycemia that
can predispose to diabetic complications is an
important factor in selecting cutoff plasma glu-
cose values [8]. Any of three parameters of
glycemia, FPG, 2hPG and HbA
1c
, can serve to
predict the risk of diabetic complications [32].
In order to dene diabetic type we selected the
same plasma glucose levels as those used to dene
diabetes in the ADA and WHO reports. The
cutoff level of 2hPG is the same as the previous
JDS criteria, but that for FPG is lowered to ]7.0
mmol/l (126 mg/dl) from ]7.8 mmol/l (140 mg/
dl). The data in Japan also conrm that a mean
FPG value corresponding to 2hPG of 11.1 mmol/l
(200 mg/dl) is approximately 6.9 mmol/l (125
mg/dl) in subjects younger than 60 years (Table 6)
[33].
In the present report, the word type is added
to each glucose tolerance category classied by
OGTT, similar to earlier JDS recommendations
[1,2]. We believe that the classication of OGTT
results is conceptually different from diagnosing
diabetes mellitus. The rationale of the use of
chronic hyperglycemia for diagnosis is that it is a
most important feature of diabetes and the
strongest risk factor for specic diabetic
complications.
We have, therefore, adopted a position that
diabetes can be diagnosed by conrming persis-
tent hyperglycemia according to the criteria of
Table 6
Mutual relationships between FPG and 2hPG by 75 g OGTT
FPG mmol: mg/dl 2hPG mmol/l: mg/dl
6.7: 120 10.4 (7.812.9): 187 (140233)
10.9 (8.413.6): 197 (151244) 6.9: 125
11.6 (9.014.2): 208 (162255) 7.2: 130
12.2 (9.614.8): 219 (173266) 7.5: 135
12.8 (10.215.4): 230 (184277) 7.8: 140
8.3: 150 14.0 (11.416.6): 252 (206299)
FPG mmol: mg/dl 2hPG mmol/l: mg/dl
10.0: 180 6.6 (5.57.6): 118 (99137)
10.6: 190 6.7 (5.77.8): 121 (102140)
11.1: 200 6.9 (5.88.0): 125 (105144)
7.1 (6.18.2): 128 (109147) 11.7: 210
12.2: 220 7.3 (6.28.3): 131 (112150)
12.8: 230 7.5 (6.48.6): 135 (116154)
13.3: 240 7.7 (6.68.7): 138 (119157)
13.9: 250 7.9 (6.88.9): 142 (123160)
8.1 (7.09.1): 145 (126164) 14.4: 260
15.6: 280 8.4 (7.49.5): 152 (133171)
Data of 7454 atomic bomb survivors aged 60 years or younger
at the time of OGTT. Figures in the brackets, mean91 S.D.
(Ito et al. [33]).
the chance of misdiagnosis of diabetes on a single
plasma glucose determination would be small (B
5%).
Cross-sectional data from epidemiological sur-
veys indicate that retinopathy is concentrated in
the upper one to three deciles classied by
glycemic parameters [6]. These data show that the
frequency of retinopathy clearly increases when
FPG exceeds 7.8 mmol/l (140 mg/dl) (not 7.0
mmol/l (126 mg/dl)), when 2hPG exceeds 12.8
13.3 mmol/l (230240 mg/dl) (not 11.1 mmol/l
(200 mg/dl)), and when HbA
1c
exceeds 6.5%, re-
spectively. A clinical study in Japan indicates that
diabetic complications seldom occur when HbA
1c
is below 6.5% [36]. In view of the denite risk for
specic complications, there was a discussion in
the Committee that the cutoff levels may be better
set as ]7.8 mmol/l (140 mg/dl) for FPG and
]12.813.3 mmol/l (230240 mg/dl) for 2hPG,
namely retaining the old FPG cutoff value while
elevating that for 2hPG. However, we adopted the
present criteria for two reasons. Firstly, we were
concerned about inconvenience and confusion
with the use of the different criteria from interna-
tional standards. Secondly the above mentioned
data are derived from cross-sectional surveys.
With follow-up studies, somewhat lower glycemic
levels may also be turned out to give risk to
diabetic complications. In order to prevent com-
plications, it would be better to begin treatment of
diabetes before plasma glucose reaches denitely
risky levels.
We added casual PG higher than 11.1 mmol/l
(200 mg/dl) as indicating diabetic type. Post-
prandial PG ]11.1 mmol/l (200 mg/dl) usually
reects a more severe degree of glucose intoler-
ance than 2hPG ]11.1 mmol/l (200 mg/dl) by 75
g OGTT. Indeed, patients classied as diabetic
type by 75 g OGTT commonly have casual PG
values below 11.1 mmol/l (200 mg/dl) [37]. A
rather high cutoff level was selected for casual
PG, to ensure the specicity for abnormally
high glycemia, as the amount of meal and
time interval between the meal and blood sam-
pling are so variable. Therefore, when the rst test
has been a casual PG, we recommend the other
methods of plasma glucose testing for the second
test.
diabetic type. Repeated measurements of plasma
glucose will be necessary to conrm persistent
hyperglycemia. Nevertheless, it is desirable if the
diagnosis of diabetes can be made without
repeating the test. We have selected three condi-
tions, in the presence of which diabetes can be
diagnosed by a single diabetic type hyper-
glycemia measurement. They are (1) the presence
of typical diabetic symptoms; (2) HbA
1c
]6.5%;
and (3) denite diabetic retinopathy. High HbA
1c
indicates that hyperglycemia has continued for
some time.
Variations in plasma glucose can occur due to
uctuations of physical conditions. The standard
deviation of plasma glucose near the cutoff levels
for diabetic type is about 0.40.6 mmol/l (711
mg/dl) for FPG, and 1.42.0 mmol/l (2535 mg/
dl) for 2hPG [34,35]. Taking these variations into
account, subjects with FPG ]7.88.3 mmol/l
(140150 mg/dl), and 2hPG ]13.313.9 mmol/l
(240250 mg/dl) are likely to remain as diabetic
type on repeated tests. In such patients with
denitely higher glycemia than the cutoff levels,
5.2.2. Fasting plasma glucose 6ersus 2h plasma
glucose
Diabetic type can be judged either by FPG or
by 2hPG. The prevalence of diabetic type is
usually higher by 2hPG than by FPG in epidemi-
ological and screening data in Japan (Table 7)
[38]. In some countries FPG criteria ]7.0 mmol/l
(126 mg/dl) detected a higher prevalence for dia-
betes than 2hPG criteria ]11.1 mmol/l (200
mg/dl), or both methods resulted in similar preva-
lence of diabetes in epidemiological survey [39].
In most studies, however, there are large dis-
crepancies in the diagnosis of diabetes in individ-
ual subjects. Japanese as well as European and
Asian data show that diabetes classied by FPG
]7.0 mmol/l (126 mg/dl) and diabetes by 2hPG
]11.1 mmol/l (200 mg/dl) agree only partially in
mild diabetes (Table 7) [3841]. In Japan and
other Asian countries[38,41], the prevalence of
diabetes identied by 2hPG ]11.1 mmol/l is
1.5-fold higher than diabetes identied by FPG
]7.0 mmol/l. From a physiological viewpoint,
FPG is primarily governed by glucose output
from the liver, while 2hPG is affected by the
absorption rate of glucose from the gut, the uti-
lization rate of glucose by muscle and other pe-
ripheral tissues and changes in glucose handling
by the liver. It is conceivable that FPG and 2hPG
do not increase in parallel in some patients.
Comparison of the incidence of retinopathy
between groups with similar degree of FPG (ei-
ther 6.17.0 mmol/l (110126 mg/dl), or 7.07.8
mmol/l (126140 mg/dl)), but with different levels
of 2hPG higher or lower than 11.1 mmol/l (200
mg/dl), revealed that groups with higher 2hPG
showed 23-fold higher incidence of retinopathy
than those with 2hPG lower than 11.1 mmol/l
(200 mg/dl) [42].
For these reasons, the measurement of FPG
alone is not sufcient and OGTT is necessary to
detect diabetes and mild abnormalities of glucose
metabolism.
5.2.3. Cutoff le6els of plasma glucose for normal
type and mild glucose intolerance
In the previous JDS reports, normal type was
dened as those who would remain non-diabetic
after follow-up of several years [1,2]. In the 1982
report, normal type should meet all of the fol-
lowing criteria; FPG B6.1 mmol/l (110 mg/dl),
1hPG B8.9 mmol/l (160 mg/dl) and 2hPG B6.7
mmol/l (120 mg/dl). Subsequent studies have
conrmed that normal type by this denition
seldom deteriorates to diabetic type [43,44]. But
as the cutoff levels for normal type were set
lower than the lower limits of IGT by WHO,
claims were raised that too many subjects were
classied as borderline type at the health check
examination using OGTT [45].
We elevated the cutoff level of 2hPG for nor-
mal type from B6.7 mmol/l (120 mg/dl) to B7.8
mmol/l (140 mg/dl). By this change, the progres-
sion rate to diabetic type rises a little, but re-
mains less than 1.0% per year (Table 8). We think
that the merit of conforming with international
criteria will outweigh the demerit of a small in-
Table 7
Comparison of frequencies of diabetic type by FPG and 2hPG criteria
Caucasian* FPG Japanese** 2hPG Asian*
n=25 219 n=5384 mmol/l (mg/dl) n=16 739 mmol/l (mg/dl)
(a) B7.0 (126) ]11.1 (200) 298 (5.5%)** 473 (1.9%)* 546 (3.3%)*
(b) ]7.0 (126) B11.1 (200) 75 (1.4%)** 613 (2.4%)* 220 (1.3%)*
]11.1 (200) 346 (6.4%)** (c) ]7.0 (126) 431 (1.7%)* 449 (2.7%)*
719 (13.4%)** (a)+(b)+(c) Sum (diabetic type) 1215 (7.3%)* 1517 (6.0%)*
]7.0 mmol/l (126 mg/dl) (b)+(c) FPG 7.8%** 4.2%* 4.0%*
]11.1 mmol/l (200 mg/dl) 12.0%** 3.6%* 5.9%* (a)+(c) 2hPG
(Sasaki, A. [35]) (DECODE Study [39]) (DECODA Study [41])
Data of Japanese were taken from results of health check examinees. *, Excludes known diabetes; **, includes known diabetes.
Table 8
Deterioration rate to diabetic type of health check examinees by the baseline results of 75 g OGTT
(B) Deterioration rate 2hPG (A) Deterioration rate 1hPG FPG
mmol/l (mg/dl) mmol/l (mg/dl) Number of cases (%)/5.1 years Number of cases (%)/4 years
Normal type
B6.7 (120) 7/536 (1.3) B6.1 (110) 14/1088 (1.3)
B7.8 (140) 25/778 (3.2) 27/1441 (1.9) B6.1 (110)
B6.1 (110) B8.9 (160) B7.8 (140) 4/501 (0.8) 5/1137 (0.4)
B7.8 (140) 2/125 (1.6) 8.99.9 (160179) 6/146 (4.1) B6.1 (110)
10.011.0 (180199) B6.1 (110) B7.8 (140) 8/74 (10.8) 8/92 (8.7)
B7.8 (140) 5/51 (9.8) B6.1 (110) 2/40 (5.0) 11.112.1 (200219)
B7.8 (140) 6/27 (22.2) ]12.2 (220) 7/27 (25.9) B6.1 (110)
B6.1 (110) ]10.0 (180) B7.8 (140) 19/152 (12.5) 17/159 (10.7)
B7.8 (140) B6.1 (110) 11/78 (14.1) ]11.1 (200) 9/67 (13.4)
Borderline type* 98/424 (23.1) 64/281 (22.8)
B7.0 (126)** 7.811.0 87/333 (25.8) 47/217 (21.7)
7.811.0 (140199)
B7.8 (140) 11/91 (12.1) 17/64 (26.6) 6.16.9***
(110125)
Mean follow-up periods, A, 4 years, B, 5.1 years. *, Borderline type, as dened by Table 3, corresponds to the sum of IFG and IGT
by WHO, when OGTT is performed; **, corresponding to IGT by ADA and WHO. ***, corresponding to IFG by WHO when
OGTT is performed (A: Sasaki, A., 1998; B: Hara, H. 1999, unpublished data).
crease in the rate of progression to diabetic
type.
The ADA report recommended the use of FPG
alone to diagnose diabetes, and dened impaired
fasting glucose (IFG) for those with FPG between
6.1 and 7.0 mmol/l (110 and 126 mg/dl). This
range of FPG corresponds to the intermediate
range between normal and the diabetic ranges in
the present report. Subjects with IFG could be
classied as diabetic type or IGT if they are
tested by OGTT. According to WHO report,
when tested by OGTT, the use of term impaired
fasting glycemia (IFG) is restricted to those with
2hPG less than 7.8 mmol/l (140 mg/dl). Both
ADA and WHO reports dened IGT as those
with FPG less than 7.0 mmol/l (126 mg/dl) and
2hPG between 7.8 and 11.1 mmol/l (140 and 200
mg/dl). The borderline type in the present report
exactly corresponds to the sum of IGT and IFG
in the narrow sense by WHO. On an individual
basis, IFG and IGT are highly discordant [38,46].
We combined IFG and IGT together as border-
line type, because we think there is little need to
handle IFG and IGT separately.
We eliminated the cutoff values of 1hPG to
dene normal type, which was set as B8.9
mmol/l (160 mg/dl) in the 1982 JDS report. Data
showed, however, that the progression to diabetic
type from normal type increased with the eleva-
tion of 1hPG, even with normal FPG and 2hPG.
When 1hPG exceeded 12.2 mmol/l (220 mg/dl),
the progression rate was equal to that of IGT
(Table 8). Therefore, we recommend that 1hPG
be measured during an OGTT whenever possible,
and that subjects with high 1hPG be followed
even though they belong to normal type by FPG
and 2hPG criteria. One study from USA indicates
that a high 3090 min plasma glucose is associ-
ated with increased cardiovascular risk factors,
even in groups with normal FPG and 2hPG [47].
The low insulin secretory response in the early
phase after glucose challenge is a characteristic
feature of diabetes mellitus. Among subjects with
borderline type, those with a low insulin response
are at higher risk of developing diabetes than
those with a normal insulin response [48]. A ratio
of increment of insulin to that of PG at 30 min
after glucose load lower than 7.2 mU/ml per
mmol/l (0.4 mU/ml per mg/dl) is a useful parame-
ter to predict the future risk of development of
diabetes. A high fasting insulin level, suggesting
the presence of insulin resistance, is also a risk
factor for type 2 diabetes.
5.2.4. HbA
1c
HbA
1c
is an important and useful parameter for
the treatment of diabetes, but there are several
problems relating to its use for diagnosis. It varies
not only according to the level of glycemia but
also to the turnover rate of hemoglobin. There is
a large overlap of distribution between groups
with normal type and borderline type, making
it difcult to distinguish between these two groups
(Fig. 2) [37].
Various methods are now being used to mea-
sure HbA
1c
, yielding somewhat different values of
glycohemoglobins. High performance liquid chro-
matography, a standard method of assay, may
not be sufciently specic for HbA
1c
. Inter-labo-
ratory variation and day-to-day assay errors are
still unsatisfactory. No chemical standard for
HbA
1c
is yet available.
In Japan, thanks to the effort of the Committee
for Standardization of Glycohemoglobin, inter-
laboratory variation has been decreased, by mea-
suring only the stable fraction of HbA
1c
and by
inclusion of standard samples in each run to
adjust assay values [49,50].
The use of HbA
1c
should be limited as a supple-
ment to plasma glucose tests for the diagnosis of
diabetes. If HbA
1c
is denitely high in a hyper-
glycemic patient, diabetes can be diagnosed with-
out repeating PG. Namely, when FPG, 2hPG or
casual PG is in the diabetic range and HbA
1c
exceeds 6.5%, the patient is judged to have dia-
betes. To select this value, we put emphasis on
specicity for the diagnosis of diabetes, while
ignoring sensitivity. As seen from Fig. 2, subjects
with HbA
1c
]6.5% are unlikely to be classied as
normal type or borderline type by OGTT.
However, HbA
1c
values less than 6.5% should not
be taken as evidence against the diagnosis of
diabetes, because a signicant portion of subjects
of diabetic type have HbA
1c
lower than 6.5%.
In subjects younger than 60 years, the mean
HbA
1c
value, which corresponds to FPG of 7.0
mmol/l (126 mg/dl) and 2hPG of 11.1 mmol/l
(200 mg/dl), is about 6.1% using the assay method
recommended by the JDS Committee for Stan-
dardization of Glycohemoglobin [33]. This value
could be used to estimate the prevalence of dia-
betes in an epidemiological survey.
The use of HbA
1c
assay in combination with
plasma glucose tests is expected to improve the
efciency of screening for glucose intolerance [51
54]. In Japan, this has already been introduced
into the health check program for the elderly
people [51]. There is a need for further study to
select the most appropriate criteria for this
purpose.
6. Conclusions: Comparison of this report with
those of American Diabetes Association [6] and
WHO [7]
The present report resembles those of ADA and
WHO but differs in the following points.
6.1. Classication
1. Diabetes and related disorders of glucose tol-
erance, due to specic mechanisms and dis-
eases, are divided into two subgroups; 3A, in
Fig. 2. Distribution of HbA
1c
in groups with varying degree of
glucose intolerance (number of cases in each group of glucose
tolerance: Normal type, n=6720; borderline type, n=6296;
and diabetic type, n=5040). Diabetic type in which both
FPG]7.0 mmol/l (126 mg/dl) and 2hPG]11.1 mmol/l (200
mg/dl), n=2950; (Ito, C. unpublished data).
which genetic susceptibility is claried at the
DNA level, and 3B, which is associated with
other diseases or conditions.
2. Liver diseases are added into category 3B.
3. The gure showing the relationship of etiology
and stage of diabetes is expressed in a more
sophisticated way.
6.2. Diagnosis
1. Cutoff plasma glucose levels for each category
are the same, but a term type is added to
each category.
2. Borderline type is dened as neither diabetic
nor normal type, including both IFG and IGT
by WHO when OGTT is performed.
3. Diabetes is generally diagnosed when diabetic
type hyperglycemia is conrmed on two or
more occasions.
4. Diabetes can be diagnosed on a single diabetic
type hyperglycemia if the patient has typical
symptoms of diabetes, HbA
1c
higher than
6.5%, or diabetic retinopathy.
5. OGTT is recommended for those with mild
hyperglycemia, because FPG criteria alone
would overlook many subjects with diabetic
type in Japan. High 1hPG with normal FPG
and 2hPG is also a risk factor for future
diabetes.
6. New criteria for gestational diabetes are
proposed.
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