PAPER

WHO and ADA criteria for the diagnosis of diabetes

mellitus in relation to body mass index. Insulin
sensitivity and secretion in resulting subcategories of
glucose tolerance
N Melchionda
1
, G Forlani
1
*, G Marchesini
1
, L Baraldi
1
and S Natale
1
1
Unit of Metabolic Diseases, Department of Internal Medicine and Gastroenterology, University of Bologna, Policlinico S Orsola,
Bologna, Italy
OBJECTIVE: To determine the inuence of body mass index (BMI) on agreement between the American Diabetes Association
(ADA) and the new World Health Organization diagnostic criteria for the diagnosis of diabetes mellitus and to investigate the
metabolic prole of the resulting subcategories.
DESIGN: Cross-sectional study
SUBJECTS: A total of 3018 subjects with no previous history of diabetes and fasting glucose <7.8mmol=l, with a wide range of
BMIs.
MEASUREMENTS: (1) Prevalence of impaired glucose regulation (IGR) and diabetes (DM) according to ADA and WHO
diagnostic criteria; (2) basal and post-load insulin sensitivity and secretion, calculated on the basis of data derived from an oral
glucose tolerance test (OGTT).
RESULTS: The diagnosis according to the two classications was concordant in 2490 subjects, discordant in 528 (452 were
identied as impaired glucose tolerance (IGT) and 76 as DM only by means of OGTT). The disagreement increased with
increasing BMI, being as high as 25.3% in subjects with BMI 35kg=m
2
. Subjects with isolated fasting hyperglycaemia were
mainly characterised by reduced insulin sensitivity and secretion in the basal state, but normal rst-phase insulin secretion and
moderately reduced insulin sensitivity after glucose challenge. Subjects with isolated 2h hyperglycaemia were mainly
characterised by normal basal insulin secretion and by a marked insulin resistance associated with a blunted rst-phase insulin
secretion after the glucose load.
CONCLUSIONS: The disagreement between ADA and WHO classications is particularly relevant in obesity, making OGTT
mandatory in these subjects. Different pathogenic mechanisms are involved in isolated fasting or post-load hyperglycaemia,
possibly related to a different site of insulin resistance (hepatic vs peripheral), and=or to a different disregulation of insulin
secretion (basal vs post-load). A correct identication of the underlying mechanism(s) is the rationale for future studies to detect
the effectiveness of different pharmacological or behavioural approaches.
International Journal of Obesity (2002) 26, 90 96. DOI: 10.1038=sj=ijo=0801847
Keywords: diabetes; glucose tolerance; insulin sensitivity; insulin secretion
Introduction
In 1997 the American Diabetes Association (ADA) proposed a
new classication of diabetes mellitus (DM) and other cate-
gories of glucose regulation, simply based on fasting blood
glucose (BG).
1
The threshold for DM was lowered to
7.0mmol=l from the value of 7.8 mmol=l, set almost 20y
earlier by the World Health Organization (WHO).
2
A new
category (impaired fasting glucose IFG) was introduced, to
include patients with a fasting BG in the range between 6.1
and 7.0 mmol=l.
1
Patients with IFG were supposed to be at
the same risk of progression as patients with impaired
glucose tolerance (IGT) according to WHO criteria (a 2h
BG during an oral glucose tolerance test (OGTT) in the range
between 7.8 and 11.1mmol=l).
Epidemiological studies proved that ADA and WHO diag-
nostic criteria do not completely overlap. A few patients,
*Correspondence: G Forlani, Unita` di Malattie del Metabolismo, Azienda
Ospedale S. Orsola-Malpighi, Via Massarenti 9, I-40138 Bologna, Italy.
E-mail: forlani@orsola-malpighi.med.unibo.it
Received 18 October 2000; revised 16 February 2001;
accepted 6 July 2001
International Journal of Obesity (2002) 26, 9096
2002 Nature Publishing Group All rights reserved 03070565/02 $25.00
www.nature.com/ijo
identied by WHOcriteria as IGTor DMon the basis of OGTT,
are not recognised as IFG or DM by ADA criteria, based on the
sole fasting BG. The disagreement was reported to be mainly
present in groups at high risk of DM, and an increased body
mass index(BMI) was a relevant source of disagreement.
3 5
On
this basis, in 1998 the WHO
6
accepted the ADA proposal to
lower the cut-off of fasting BG for the diagnosis of DM to
7.0mmol=l, and the new category of IFG, but supported the
need of OGTT to diagnose IGT and DM with post-load hyper-
glycaemia. IFGandIGTwere joinedinthecategoryof impaired
glucose regulation (IGR). This policy obviously reduces the
disagreement between the two classications.
At present, patients with IGR may be stratied into three
subcategories, according to fasting and post-load glucose
concentrations: (a) isolated IFG (fasting BG between 6.1
and 7.0 mmol=l and 2h BG<7.8mmol=l); (b) isolated IGT
(fasting BG<6.1 and 2h BG between 7.8 and 11.1); (c)
combined IFG=IGT. The same applies to the diagnosis of
DM. These patients are now stratied into three subcate-
gories: (a) isolated fasting DM (fasting BG7.0 and 2h
BG<11.1); (b) isolated 2h DM (fasting BG<7.0 and 2h
BG11.1mmol=l); (c) combined fasting and post-load DM.
Subjects with isolated IGT or isolated post-load DM are only
identied by WHO criteria (discordant diagnoses). These
subcategories probably identify populations at different risk
to progress from IGR to overt DM,
7
with peculiar metabolic
features,
8,9
cardiovascular risk prole
9,10
and death risk.
11
In
particular, differences in hepatic and peripheral insulin sen-
sitivity and rst-phase and total insulin secretion might play
a primary role.
12
Fasting and glucose-stimulated insulin and glucose con-
centrations may be used to compute several indices of
insulin sensitivity and secretion,
13
which proved to correlate
with parameters derived from quantitative, dynamic meth-
ods (namely, the glucose clamp technique).
13 17
They may
be relevant for a better denition of the metabolic features of
individual patients, identifying the mechanism(s) responsi-
ble for IGR and DM and giving clues to pharmacological
therapy, also in relation to overweight and obesity.
We report the retrospective analysis of data derived from
3018 consecutive OGTTs, performed in our department in
subjects withnoprevious diagnosis of DM, inorder toidentify:
(a) the prevalence of subcategories of IGRandDMinrelationto
classes of BMI; (b) the differences in insulin release and insulin
resistance in the subcategories of IGR and DM.
Materials and methods
Subjects
Between 1992 and 1999, 3046 Caucasian subjects, with no
previous history or symptoms of DM and no previous fasting
BG levels 7.8mmol=l, underwent an OGTT in our Depart-
ment of Metabolic Diseases. Twenty-eight cases (young
females with anorexia nervosa, with a BMI below 16kg=m
2
)
were excluded from the nal analysis. The remaining 3018
subjects, mainly subjects with overweight or obesity
screened for DM at the time of rst visit, were 1314 males
and 1704 females, aged 38s.d. 11y (range, 18 78y). In
particular, 450 subjects had a BMI <25.0kg=m
2
(males, 194;
females, 256; aged 3712y), 1140 were overweight (BMI,
25.0 29.9; males, 550; females, 589; aged 3811), 856 were
obese (BMI, 30.0 34.9; males, 384; females, 472; aged
3811), and the remaining 572 were severely obese
(BMI 35; males, 186; females, 386; aged 3911). The
OGTT was performed after a 10h overnight fast, according
to standard methodology. All subjects were given a 200ml
solution containing 75g of glucose; venous blood samples
were obtained at 0, 30, 60, 90 and 120 min for determination
of plasma glucose and insulin concentrations.
Glucose was measured by glucose-oxidase reaction; insu-
lin was measured by an immuno-enzymometric assay (AIA-
PACK IRI, AIA-1200 system, Tosoh Co., Tokyo, Japan). The
protocol of this retrospective analysis was approved by the
senior staff committee of the Department.
Parameters of insulin sensitivity and secretion
Data from the OGTTs were used to calculate the following
indices of insulin sensitivity:
1. Homeostasis model assessment insulin resistance
(HOMA IR):
14
fasting insulin (mU=l) multiplied by fasting
glucose (mmol=l), divided by 22.5.
2. Insulin sensitivity index (ISI composite), according to
Matsuda et al:
15
10.000=square root (fasting glucose
(mg=dl)fasting insulin (mU=l) mean OGTT glucose
(mg=dl)mean OGTT insulin (mU=l)).
3. Sensitivity index (SI), according to Cederholm et al:
16
75000 (fasting glucose (mg=l) 72h OGTT glucose
(mg=l)0.19body weight (kg)=120log (mean OGTT
insulin (mU=l)mean OGTT glucose (mmol=l)).
HOMA IR,
14
an index of insulin sensitivity derived simply
from basal glucose and insulin concentrations, has been
shown to correlate with the index of insulin sensitivity
derived from the euglycaemic glucose clamp,
17
universally
considered the gold standard for quantifying insulin
sensitivity.
18
It reects hepatic insulin sensitivity and
basal hepatic glucose production, due to the role of
endogenous glucose output in the determination of fasting
hyperglycaemia.
19,20
The sensitivity index (SI), proposed by Cederholm,
16
explores the disposal of the glucose load and is mainly
related to peripheral insulin sensitivity and muscular glucose
uptake, due to the major role of peripheral muscle tissue in
the handling of an oral glucose load.
21
The insulin sensitivity
index, proposed by Matsuda
15
(ISI composite), explores both
liver and muscle insulin sensitivity.
The following indices of insulin release were considered:
(1) Homeostasis model assessment insulin secretion
(HOMA IS)
14
(20fasting insulin (mU=l)=(fasting glucose
International Journal of Obesity
WHO=ADA criteria and BMI
N Melchionda et al
91
(mmol=l) 73.5); it reects insulin secretion in basal con-
ditions.
(2) Insulin response to glucose (IRG):
16
D Ins 0 30 (mU=l)=
Dglucose 0 30 (mmol=l); it explores the rst phase of
post-load insulin secretion.
(3) Area under 0 120 min insulin curve=area under 0
120 min glucose curve (AUC insulin (pmol=l)=AUC
glucose (mmol=l)); it explores total insulin secretion in
response to glucose ingestion.
HOMA IS
14
is an index of insulin secretion derived from
basal glucose and insulin concentrations, exclusively explor-
ing basal insulin secretion. IRG (insulin response to
glucose)
16
and the ratio AUC insulin=AUC glucose explore
the rst phase and total insulin secretion in response
to glucose ingestion, respectively. In conclusion, each test
provides a different piece of information.
Statistical analysis
All data were implemented on a personal computer and the
statistical analysis was carried out by means of StatView 5.0
2
program (SAS Institute Inc., Cary, NC.). Results were
expressed as meanss.d. for each subject group and each
variable. Statistical comparison between group means was
carried out by means of ANOVA and Students t-test for
unpaired data. The chi-square test was used for comparison
of prevalence among groups. Since six sets of variables were
simultaneously tested, the limit of signicance was calcu-
lated according to Duncans multiple range
22
to
P
0
1
n1

1 P
p
, where P0.05 and n6. The nal critical
value of signicance was therefore set at 0.01.
Results
Prevalence of IGR and DM according to ADA and WHO
criteria
When analysed according to ADA (fasting BG) and WHO
criteria (fasting BG plus 2h BG), 2490 out of our 3018 cases
(82%) had a concordant diagnosis in terms of glucose reg-
ulation (Table 1). In all 2264 subjects had normal fasting
glucose and normal glucose tolerance, 68 had isolated IFG,
72 had combined IFG and IGT, 86 had DM (24 isolated
fasting DM and 62 combined fasting and 2h DM).
In 528 cases (18%) the two criteria led to discordant
diagnoses (Table 1). A total of 452 subjects with isolated
IGT and 76 2h DM would have been misclassied on the
basis of fasting BG (according to ADA criteria).
The total prevalence of IGR and DM obviously increased
when fasting BG was combined with 2h BG. IGR increased
four-fold (from 4.6 to 19.6%; chi-square, 317.6; P<0.0001)
and DM doubled (from 2.8 to 5.4%; chi-square, 24.3;
P<0.0001).
Distribution of IGR and DM according to BMI
The distribution of IGR and DM was not similar in the
various groups of BMI (Table 1), with the expected larger
prevalence with increasing BMI (chi-square; RC96.4;
P<0.0001).
Also the disagreement between ADA and WHO classica-
tion increased with increasing BMI: discordant diagnoses
ranged from 13.1% in normal-weight subjects to 14.8% in
overweight, to 18.1% in obese and nally to 25.3% in
severely obese subjects (chi-square RC36.3; P< 0.0001).
This was due to an increasing prevalence both of isolated IGT
with increasing BMI (from 11.8% to 12.7, 16.2 and to 20.1
respectively; chi-square 21.1; P<0.0001) and of 2h DM
(from 1.3% in normal weight, to 2.1, 1.9 and to 5.2%,
respectively; chi-square, 22.2; P<0.0001). On the contrary
the prevalence of isolated IFG and isolated fasting DM was
not inuenced by BMI.
Insulin sensitivity
The indices of insulin sensitivity were altered in all categories
of overweight and obesity. Insulin sensitivity progressively
declined from normal subjects to the category of overweight,
obese and severely obese patients (Table 2).
Table 1 Distribution of subjects among the subcategories of impaired glucose regulation and diabetes, in relation to
the class of BMI (number of cases (%))
Class of body mass index
Normal weight Overweight Obese Severely obese Total
Class of glucose tolerance (n450) (n1140) (n856) (n572) (n3018)
Normal 368 (81.8%) 904 (79.3%) 626 (73.1%) 366 (64.0%) 2264
Isolated IFG 10 (2.2%) 27 (2.3%) 24 (2.8%) 7 (1.2%) 68
Isolated IGT 53 (11.8%) 145 (12.7%) 139 (16.2%) 115 (20.1%) 452
Combined IFGIGT 6 (1.3%) 14 (1.2%) 23 (2.7%) 29 (5.1%) 72
Isolated fasting DM 1 (0.2%) 8 (0.7%) 10 (1.2%) 5 (0.8%) 24
Isolated 2 h DM 6 (1.3%) 24 (2.1%) 16 (1.9%) 30 (5.2%) 76
Combined fasting and 2 h DM 6 (1.3%) 18 (1.6%) 18 (2.1%) 20 (3.5%) 62
International Journal of Obesity
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When related to the categories of glucose regulation, the
indices of insulin sensitivity had a different behaviour
(Figure 1). HOMA-IR, expressing basal insulin resistance,
was signicantly higher in isolated IFG (4.783.47%), in
comparison to isolated IGT (3.922.37; P<0.01), while the
SI showed a lower resistance in response to glucose in
isolated IFG (43.010.1) in comparison to isolated IGT
(35.18.8; P<0.001). Similarly, post-load insulin resistance
was lower isolated fasting DM compared with isolated 2h
DM (SI, 22.55.9 and 32.06.9; P<0.001). The ISI, a
measure of overall insulin sensitivity, did not show any
signicant differences between discordant IGR and between
discordant DM. These differences in insulin sensitivity
among the various categories of IGR and DM were main-
tained in all BMI classes. As an example, in obese subjects
(obese plus severely obese subjects, n1428) HOMA-IR was
higher in isolated IFG (n31; 5.864.48) than in isolated
IGT (n254; 4.482.55; P<0.003), and the SI was lower in
isolated IFG (42.610.9) in comparison to isolated IGT
(32.67.9; P<0.0001), and in isolated 2h DM (n46;
20.04.5) when compared to isolated fasting DM (n15,
30.07.8, P<0.003).
Insulin secretion
Also the indices of insulin secretion increased with increas-
ing BMI (Table 2), and for each class of BMI signicant
differences were observed in comparison to the lower class.
In relation to glucose regulation (Figure 2), HOMA-IS,
exploring basal insulin secretion, was signicantly reduced
in all categories with fasting hyperglycaemia: isolated IFG
(112.172.3), combined IFG-IGT (111.862.5), isolated
fasting DM (87.645.1), combined fasting and 2h DM
(89.763.1). In contrast, HOMA-IS was normal in subjects
with isolated post-load hyperglycaemia: isolated IGT
(198.7131.27) and isolated 2h DM (173.6136.3). IRG,
exploring the rst-phase insulin response to glucose, was
reduced only in subjects with post-load hyperglycaemia: IGT
either isolated or combined with IFG, and 2h DM (both
isolated and associated with fasting hyperglycaemia). This
last subgroup was the sole category characterised by a
decreased insulin-to-glucose area (25.514.5 vs 52.733.3
in controls; P<0.001).
The differences in the indices of insulin secretion were
maintained in various classes of BMI, although not always in
the statistical range because of the low number of cases. As
an example in the whole group of obese subjects HOMA-IS
was lower in isolated IFG (13788) than in isolated IGT
(219140), and IRG was higher (33.422.1 vs 24.315.6).
When diabetic patients were compared with subjects with
IGR, isolated fasting DM was mainly associated with a
further worsening of all indices of insulin sensitivity, a fall
in basal insulin secretion and maintenance of insulin
response to glucose. The presence of isolated 2h DM was
mainly associated with a worsening of all indices of insulin
sensitivity, a blunted insulin response to glucose and
maintenance of basal insulin secretion. DM with both
fasting and 2h hyperglycaemia was accompanied by a
marked deterioration of all indices of insulin sensitivity
and secretion.
Discussion
Prevalence of IGR and DM according to ADA and WHO
criteria and in relation to BMI
Several studies proved that the new ADA criteria, based on
the sole fasting BG, lead to underestimate the prevalence of
disease.
3,5,7,10
ADA proposal was mainly based on data
derived from selected populations, that cannot be extrapo-
lated to all groups of subjects. In our series, based on data
mainly derived from overweight and obese subjects, we
would have missed 76% of patients with IGR and
Table 2 Indices of insulin sensitivity and insulin secretion in relation to classes of BMI (for acronyms and units: see
Methods)
Class of body mass index
Normal-weight Overweight Obese Severely obese ANOVA
Insulin sensitivity
HOMA IR 2.481.46 2.991.71* 3.702.33*
{
4.623.12*
{
P <0.0001
ISI (composite) 5.983.43 4.612.57* 3.672.02*
{
3.011.99*
{
P <0.0001
SI 56.517.1 50.014.4* 44.914.2*
{
39.113.7*
{
P <0.0001
Insulin secretion
HOMA IS 161117 189168
{
209182*
{
250358*
{
P <0.0001
IRG 15.511.6 20.616.9* 27.828.6*
{
31.032.2*
{
P <0.0001
AUC insulin=AUC glucose 34.818.1 46.626.7* 59.936.1*
{
68.840.6*
{
P <0.0001
For acronyms and units, see Methods.
*P <0.001 vs normal weight.
{
P <0.001 vs the corresponding lower category of BMI.
{
P <0.005 vs normal weight.
International Journal of Obesity
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N Melchionda et al
93
misclassied 47% of patients with DM, by not considering
OGTT values. Similar data were published by Mannucci et
al
23
in a smaller series of obese patients.
We showed that the disagreement between ADA and
WHO criteria, which is 13% in normal-weight subjects,
increases with the degree of overweight and obesity, being
as high as 25% in severely obese subjects. The risk of under-
estimate the prevalence of IGR and DM on the basis of the
sole fasting BG is therefore very high and the OGTT is more
and more recommended with increasing BMI.
Insulin resistance and secretion in IGR and DM
categories, and in relation to BMI classes
The combined use of WHO and ADA diagnostic criteria
highlighted the existence of different subgroups with pecu-
liar metabolic characteristics, probably reecting different
genetic abnormalities, inside the categories of impaired
glucose regulation and DM. Patients with isolated fasting
hyperglycaemia have decreased hepatic insulin sensitivity
Figure 1 Indices of insulin sensitivity according to the classes of glucose
regulation identied by ADA and WHO criteria. Open bars are subjects
with normal glucose regulation; dashed bars are subjects with isolated
fasting hyperglycaemia (either IFG or DM); dotted bars are subjects with
isolated 2h hyperglycaemia (either IGT or DM); closed bars are subjects
with IGR or DM with combined fasting and post-load hyperglycaemia.
Data are presented as means and 95% condence intervals. Note that
HOMA-IR is a measure of insulin resistance. In IGR and DM, all indices are
signicantly different from values measured in normal subjects. The P-
value of differences between discordant categories of IGR or DM are
reported, whenever signicant.
Figure 2 Indices of insulin secretion according to the classes of glucose
regulation identied by ADA and WHO criteria. For classes, see legend to
Figure 1. The P-value of differences between discordant categories of IGR
or DM are reported, whenever signicant. *Signicantly different from
normal values.
International Journal of Obesity
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N Melchionda et al
94
and increased basal hepatic glucose output, whereas subjects
with isolated post-load hyperglycaemia have decreased per-
ipheral insulin sensitivity.
8,12,15
There is evidence that such
metabolic differences may be relevant from a clinical stand-
point: patients with post-load hyperglycaemia have worse
cardiovascular risk proles
10,24
and increased death risks.
11
Applying the HOMA method to a small series of subjects
undergoing an OGTT, Davies et al
9
showed that patients with
fasting hyperglycaemia had a reduced B-cell function. How-
ever, the group with IGT was characterised by decreased
insulin sensitivity, conrmed by clinical features commonly
associated with the insulin resistance syndrome. In a large
population-based study in patients with frank DM and their
family members (over 5000 cases and over 2000 OGTTcurves
diagnostic for IGR or DM),
12
subjects with isolated IFG were
characterised by basal insulin resistance, measured by
HOMA-IR. The rst-phase insulin response to glucose was
normal in IFG, and blunted in IGTand in DM. These subjects
were on average overweight, but no attempt was made to
correlate discordant IGR or DM with BMI.
In agreement with previous data from the literature, based
on the clamp technique,
8
insulin sensitivity, computed in
the present study by simple indices, was remarkably reduced
in all groups of IGR and DM. The categories of combined
fasting and post-load hyperglycaemia had the most pro-
nounced defect. The various indices point out that insulin
resistance is more pronounced at hepatic level for isolated
IFG and at peripheral level for isolated IGT. The same applies
to the subcategories of DM. Differences are also present in
basal and rst-phase insulin secretion, as previously demon-
strated in the Botnia study.
12
The indices of insulin sensitivity and secretion had the
expected behaviour among the different classes of BMI,
showing an increasing insulin resistance and secretion with
increasing BMI. In normal weight, overweight and obese
patients the indices maintained the ability to discriminate
between peripheral and hepatic sensitivity to insulin, and
between defects in basal and rst-phase insulin secretion.
In conclusion, the present results, based on parameters
easily derived from a commonly performed test, conrm that
ADA and WHO classications identify subcategories of
patients with different defects in insulin sensitivity and
secretion, and underline the need for OGTT, mainly in
overweight and obese subjects. Apparently the progression
from normal glucose tolerance to IGR and DM may follow
two different pathways. In a few patients, the deterioration
of glucose tolerance progresses through IFG and eventually
to isolated fasting DM. It is characterised by a progressive
increase in hepatic insulin resistance (HOMA-IR), and
reduced basal insulin secretion (HOMA-IS). The second
leads to isolated IGT and isolated 2h DM, and is charac-
terised by increased peripheral insulin resistance (SI index)
and reduced rst-phase insulin secretion (IRG index). The
two pathways may meet at the level of combined IFG and
IGT or combined fasting and 2h DM, which represent an
awful outcome, where both defects are present.
The possibility to identify these different routes by easily
computed indices able to discriminate the site of insulin
resistance and the defect in insulin secretion (mainly HOMA-
IR, HOMA-IS, SI, IRG) might be of help in planning specic
pharmacological interventions. Follow-up studies are needed
to conrm difference in the risk of passing from IGR to
DM,
7,25
or in the risk of cardiovascular disease and mortality
associated with fasting and post-load hyperglycaemia and
hepatic vs peripheral insulin resistance.
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