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(mmol=l)73.5); it reflects 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 first phase of

post-load insulin secretion.

(3) Area under 0 120min 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 IS14 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 first 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 5.02

program (SAS Institute Inc., Cary, NC.). Results were

expressed as means s.d. for each subject group and eachvariable. 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 significance was calcu-

lated according to Duncans multiple range22 to

P0 1 n1 ffiffiffiffiffiffiffiffiffiffiffiffi

1 Pp

, whereP0.05 andn 6. Thefinal critical

value of significance was therefore set at 0.01.

ResultsPrevalence of IGR and DM according to ADA and WHO

criteria

When analysed according to ADA (fasting BG) and WHO

criteria (fasting BG plus 2 h 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 2 h DM).

In 528 cases (18%) the two criteria led to discordant

diagnoses (Table 1). A total of 452 subjects with isolated

IGT and 76 2 h DM would have been misclassified 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 2 h BG. IGR increased

four-fold (from 4.6 to 19.6%; chi-square, 317.6; P

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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 significantly higher in isolated IFG (4.78 3.47%), incomparison to isolated IGT (3.922.37;P

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misclassified 47% of patients with DM, by not considering

OGTT values. Similar data were published by Mannucci et

al23 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 reflecting 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 glucoseregulation identified by ADA and WHO criteria. Open bars are subjectswith normal glucose regulation; dashed bars are subjects with isolatedfasting hyperglycaemia (either IFG or DM); dotted bars are subjects withisolated 2 h hyperglycaemia (either IGT or DM); closed bars are subjectswith IGR or DM with combined fasting and post-load hyperglycaemia.Data are presented as means and 95% confidence intervals. Note thatHOMA-IR is a measure of insulin resistance. In IGR and DM, all indices aresignificantly different from values measured in normal subjects. The P-value of differences between discordant categories of IGR or DM arereported, whenever significant.

Figure 2 Indices of insulin secretion according to the classes of glucoseregulation identified by ADA and WHO criteria. For classes, see legend toFigure 1. TheP-value of differences between discordant categories of IGRor DM are reported, whenever significant. *Significantly different fromnormal values.

International Journal of Obesity

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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 profiles10,24 and increased death risks.11

Applying the HOMA method to a small series of subjects

undergoing an OGTT, Davies et al9 showed that patients with

fasting hyperglycaemia had a reduced B-cell function. How-

ever, the group with IGT was characterised by decreased

insulin sensitivity, confirmed 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 OGTT curves

diagnostic for IGR or DM),12 subjects with isolated IFG were

characterised by basal insulin resistance, measured by

HOMA-IR. The first-phase insulin response to glucose was

normal in IFG, and blunted in IGT and 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, basedon 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 first-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 withincreasing 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 first-phase insulin secretion.

In conclusion, the present results, based on parameters

easily derived from a commonly performed test, confirm that

ADA and WHO classifications 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 eventuallyto 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 2 h DM, and is charac-

terised by increased peripheral insulin resistance (SI index)

and reduced first-phase insulin secretion (IRG index). The

two pathways may meet at the level of combined IFG and

IGT or combined fasting and 2 h 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 specific

pharmacological interventions. Follow-up studies are needed

to confirm 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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