# Oral Glucose Tolerance Test Minimal Model Indexes of β-Cell Function and Insulin Sensitivity

## Abstract

The simultaneous assessment of quantitative indexes of insulin secretion
and action in a single individual is important when quantifying their relative
role in the evolution of glucose tolerance in different physiopathological
states. Available methods quantify these indexes in relatively
nonphysiological conditions, e.g., during glucose clamps or intravenous
glucose tolerance tests. Here, we present a method based on a physiological
test applicable to large-scale genetic and epidemiologic studies—the
oral glucose tolerance test (OGTT). Plasma C-peptide, insulin, and glucose
data from a frequently sampled OGTT with 22 samples throughout 300 min
(FSOGTT_{300-22}) were analyzed in 11 subjects with various degrees of
glucose tolerance. In each individual, two indexes of pancreatic sensitivity
to glucose (Φ_{s} [10^{9} min^{-1}] and
Φ_{d} [10^{9}]) and the insulin sensitivity index
(*S*_{I}) (10^{5} dl/kg per min per pmol/l) were
estimated by using the minimal model of C-peptide secretion and kinetics
originally proposed for intravenous graded glucose infusion and the minimal
model approach recently proposed for meal/OGTTs. The indexes obtained from
FSOGTT_{300-22} were used as a reference for internal validation of
OGTT protocols with reduced sampling schedules. Our results show that 11
samples in a 300-min period (OGTT_{300-11}) is the test of choice
because the indexes it provides (Φ_{s} = 36 ± 3 [means
± SE]; Φ_{d} = 710 ± 111; *S*_{I} =
10.2 ± 2.4) show excellent correlation and are not statistically
different from those of FSOGTT_{300-22} (Φ_{s} = 33
± 3; Φ_{d} = 715 ± 120; *S*_{I} =
10.1 ± 2.3). In conclusion, OGTT_{300-11}, interpreted with
C-peptide and glucose minimal models, provides a quantitative description of
β-cell function and insulin sensitivity in a single individual while
preserving the important clinical classification of glucose tolerance provided
by the standard 120-min OGTT.

The simultaneous assessment of β-cell function and insulin sensitivity in a single individual is of primary importance when quantifying their relative role in the evolution of glucose tolerance in different physiopathological states. Two methods are available for this purpose: the clamp technique, which uses a euglycemic-hyperinsulinemic and a hyperglycemic-euinsulinemic clamp in the same individual (1), and the intravenous glucose tolerance test (IVGTT) interpreted by the minimal models of glucose disposal (2) and C-peptide kinetics and secretion (3). Both these approaches give accurate and precise estimates of insulin sensitivity and β-cell function in a single individual, but plasma glucose, C-peptide, and insulin concentrations achieved during these studies are relatively nonphysiological. Recently, the need to quantify β-cell function and insulin sensitivity under more normal life conditions has encouraged many investigators to use more physiological protocols, including meal-like studies (4), graded up and down glucose infusions (5), meals (6,7), and oral glucose tolerance tests (OGTTs) (8,9). However, an approach to measure indexes of β-cell function and insulin action in a single individual based on a physiological test such as the OGTT is not available. The ability to derive in a single individual important information such as the clinical classification of oral glucose tolerance while simultaneously quantifying his or her β-cell function and insulin sensitivity could provide a unique tool potentially applicable to large-scale genetic and epidemiologic studies.

Therefore, the aim of the present study was to investigate whether indexes of β-cell function and insulin sensitivity could be simultaneously assessed in a single individual from OGTT data by extending to the OGTT the up and down C-peptide minimal model (5) and the insulin sensitivity formula recently derived for a meal (7). The database consisted of a frequently sampled 300-min OGTT performed on 11 subjects with various degrees of glucose tolerance. Indexes of insulin sensitivity and β-cell function based on OGTTs with reduced number of samples were also calculated and compared with those derived from the frequently sampled OGTT to arrive at a robust clinical protocol.

## RESEARCH DESIGN AND METHODS

**Subjects.** Studies were performed on 11 nondiabetic subjects (4 men
and 7 women); 7 had normal glucose tolerance (NGT), and 4 had impaired glucose
tolerance (IGT). Mean age was 37 ± 3 years (means ± SE) (range
20-50), and BMI was 30.5 ± 2.1 kg/m^{2} (range 21.3-46.2)
(Table 1). Glucose tolerance was
determined by using the American Diabetes Association Expert Committee
criteria (10). All subjects
had a normal screening blood count and chemistries and took no medications
known to affect insulin secretion or action. All protocols were approved by
the Institutional Review Board of The University of Chicago. Written informed
consent was obtained from each subject.

**Protocol.** All studies were performed in the Clinical Research Center
at the University of Chicago starting at 0800 in the morning after an
overnight fast. Intravenous catheters were placed into antecubital veins. The
blood sampling arm was heated to obtain arterialized venous samples. At time
0, subjects ingested a 75-g glucose load. Blood samples were collected at -15,
0, 10, 20, 30, 45, 60, 75, 90, 105, 120, 135, 150, 165, 180, 195, 210, 225,
240, 255, 270, 285, and 300 min for measurement of glucose, insulin, and
C-peptide concentrations. This complete protocol, consisting of 22 blood
samples taken in a 300-min period after glucose ingestion, will be referred to
as frequently sampled OGTT (FSOGTT_{300-22}).

OGTT protocols with reduced data sets were also considered
(Fig. 1): *1*) sampling
schedule similar to the one commonly adopted for a standard OGTT, with samples
at 0, 30, 60, 90, 120, 150, 180, 240, and 300 min (9 samples throughout 300
min) referred to as OGTT_{300-9}; *2*) same as *1*) with
two additional samples at 10 and 20 min (OGTT_{300-11}); *3*)
same as *2*) but without the 300-min sample, thus shortening the
duration of the test from 5 to 4 h (OGTT_{240-10}).

**Assay.** Plasma glucose was measured immediately using a glucose
analyzer (YSI Model 2300 STAT; Yellow Springs Instruments, Yellow Springs,
OH). The coefficient of variation (CV) of this method was <2%. Serum
insulin was assayed by a double-antibody technique
(11) with a lower limit of
sensitivity of 20 pmol/l and an average intra-assay CV of 6%. The
cross-reactivity of proinsulin in the radioimmunoassay for insulin was
∼40%. Plasma C-peptide was measured as previously described
(12). The lower limit of
sensitivity of the assay was 0.02 nmol/l and the intra-assay CV averaged
6%.

**β-Cell function.** The minimal model of C-peptide secretion and
kinetics originally applied to intravenous glucose graded infusion data
(5) has been applied to assess
β-cell secretion during an oral glucose perturbation.

C-peptide kinetics are described by using the well-known two-compartment
model originally proposed by Eaton et al.
(13):
where the overdot indicates time derivative; CP_{1} and CP_{2}
(nmol/l) are C-peptide concentrations above basal in the accessible and
peripheral compartments, respectively; *k*_{ij}
(min^{-1}) are C-peptide kinetic parameters; and SR (pmol ·
l^{-1} · min^{-1}) is the pancreatic secretion above
basal, entering the accessible compartment, normalized by the volume of
distribution of compartment 1.

Pancreatic secretion SR has been described as the sum of two components
controlled respectively by glucose concentration (static glucose control
[SR_{s}]) and by its rate of increase (dynamic glucose
control [SR_{d}]):

SR_{s} is assumed to be equal to the provision of new
insulin to the β-cells (*Y*)
(pmol·l^{-1}·min^{-1}):
which is controlled by glucose according to the following:

It is worth noting that SR_{s} is not linearly related to
glucose concentration but tends, with a time constant 1/α (min), toward
a steady-state value linearly related through the parameter β to glucose
concentration *G* above a threshold level *h* (mmol/l).

SR_{d}, on the other hand, represents the secretion of insulin
stored in the β-cells in a promptly releasable form (labile insulin) and
is proportional to the rate of increase of glucose:
where:

According to Eqs. 6 and 7, the dynamic control is at its maximum when
glucose increases just above its basal value *G*_{b}, then it
decreases linearly with glucose concentration and vanishes when glucose
concentration exceeds the threshold level *G*_{t}, which is
able to promote the secretion of all stored insulin. If parameter
*G*_{t} assumes an elevated value, *k*(*G*)
approximates the constant *K*_{d}.

** Indexes.** The model allows the estimation of two indexes of
β-cell function: the static and the dynamic sensitivity to glucose. In
addition, a single global index of β-cell sensitivity to glucose, which
suitably combines both the static and the dynamic control indexes, can be
calculated.

*Static.* The static sensitivity (Φ_{s}
[10^{9} min^{-1}]) is a measure of the effect of glucose on
β-cell secretion and is the ratio between SR and glucose concentrations
(above the threshold level *h*) at steady state:

*Dynamic.* The dynamic sensitivity (Φ_{d}
[10^{9}]) is a measure of the stimulatory effect of the rate at which
glucose increases upon the secretion of stored insulin. It is defined as the
amount of insulin (per unit of C-peptide distribution volume) released in
response to the maximum glucose concentration *G*_{max}
achieved during the experiment, normalized by the glucose increase
*G*_{max} — *G*_{b}:

If parameter *G*_{t} assumes an elevated value,
Φ_{d} approximates the constant
*K*_{d}·*Global*. In addition to
Φ_{s} and Φ_{d}, which give a detailed
portrait of β-cell function, it is also useful to define and derive a
single global index of β-cell sensitivity to glucose (Φ
[10^{9} min^{-1}]), which suitably combines both the static
(Φ_{s}) and the dynamic (Φ_{d}) control
indexes. This is particularly advantageous in calculating the so-called
disposition index, i.e., β-cell function × insulin sensitivity (see
below).

The global index of β-cell sensitivity to glucose is defined as the
average increase above basal of pancreatic secretion (Eq. 3) over the average
glucose stimulus above the threshold level *h*:

Φ (see APPENDIX) can be calculated from model parameter *h*,
model indexes Φ_{s} and Φ_{d}, and the area
under the curve of *G* above the threshold level *h*:

Φ has been derived from the model, but it can also be calculated by a virtually model-independent formula (see APPENDIX):

** Insulin secretion rate.** The model also provides the profile
of the insulin secretion rate (ISR [pmol/min]) during the OGTT:
where SR

_{b}(pmol·min

^{-1}·l

^{-1}) is insulin secretion in the basal state, and

*V*

_{1}(liters) is the distribution volume of the accessible compartment.

**Insulin sensitivity.** To calculate insulin sensitivity, we have
applied to the OGTT the formula for a meal recently proposed by Caumo et al.
(7). As detailed in this study,
insulin sensitivity index (*S*_{I} [10^{5} dl/kg per
min per pmol/l]) can be calculated with an area under the curve formula:
where *G* is plasma glucose concentration; Δ*G* and
Δ*I* are glucose and insulin concentrations above basal,
respectively; AUC denotes the area under the curve calculated from time 0 to
*t* → ∞; GE is glucose effectiveness (dl ·
kg^{-1} · min^{-1}); *D*_{OGTT} is the
dose of ingested glucose per unit of body weight (mg/kg); and *f* is
the fraction of ingested glucose that actually appears in the systemic
circulation. When glucose falls below basal, a slightly different formula
needs to be used (we refer to Eq. 7 in Caumo et al.
(7) for details). Calculation
of *S*_{I} requires insertion of values for GE and *f*.
Here we used the values proposed by Caumo et al.: GE = 0.024 dl ·
kg^{-1} · min^{-1} and *f* = 0.8.

**Disposition index.** The so-called disposition index (DI), i.e.,
β-cell function × insulin sensitivity
(14,15),
is a parsimonious and effective way to express β-cell function in
relation to the degree of insulin resistance. To this end, it is convenient to
use the single global β-cell function index Φ. The DI is thus defined
as follows:

**Numerical identification.** All C-peptide model parameters are a
priori uniquely identifiable. However, numerical identification of the model
requires the knowledge of C-peptide kinetics. Standard kinetic parameters were
calculated by using the method proposed by Van Cauter et al.
(16).

C-peptide model secretory parameters were estimated, together with a measure of their precision, by nonlinear least squares (17,18) using SAAM II software (19). When α was elevated and estimated with poor precision, the Bayesian approach implemented in SAAM II was used. Measurement error of C-peptide concentration has been assumed to be independent and gaussian, with zero mean with a constant but unknown variance. Glucose concentration, linearly interpolated between data, and its time derivative have been assumed as error-free model inputs. Area under the curve in the global index and insulin sensitivity formulas was calculated using the trapezoidal rule.

To evaluate the precision of *S*_{I}, Monte Carlo methods
(20) have been applied to Eq.
14 (or, when appropriate, to Eq. 7 from Caumo et al.
[7]), taking into account both
measurement errors of glucose and insulin concentrations (assumed to be
independent and gaussian, with zero mean and a constant CV of 2 and 6%,
respectively) and population variability of *f* and glucose
effectiveness (assumed to be gaussian with a CV of 10 and 25%, respectively
[7]).

**Statistical
analyses.** Results are given as means ± SE. The statistical
significance of differences between the same parameters calculated from
different sampling schedules has been calculated using the Wilcoxon's
signed-rank test. Linear regression and Spearman rank correlation analyses
were used to examine the relationship between parameters. Significance was
declared at *P* < 0.05.

## RESULTS

**FSOGTT _{300-22}.** Mean plasma glucose, C-peptide, and insulin
concentrations during the FSOGTT

_{300-22}are shown in Fig. 2. The C-peptide minimal model well describes experimental data, as shown by the weighted residual plot (Fig. 3). Average β-cell sensitivity indexes were as follows: Φ

_{d}= 715 ± 120 and Φ

_{s}= 33 ± 3 (means ± SE). They were estimated with good precision for all subjects with an average CV of 25 ± 4 and 9 ± 1%, respectively. The ISR profile was also reconstructed and is shown in Fig. 4. Average

*S*

_{I}was 10.1 ± 2.3, and its precision averaged 12 ± 1%.

**OGTT _{300-9}.** The C-peptide minimal model is obviously able
to fit the reduced data set (Fig.
3), but Φ

_{d}values (1,114 ± 224, CV 44 ± 9%) were statistically different from those estimated by using the FSOGTT

_{300-22}(Fig. 5) and were not correlated with them (Fig. 6). The early portion of the ISR profiles (not shown) was not superimposable to that calculated using the FSOGTT

_{300-22}. These results indicate that OGTT

_{300-9}does not accurately describe the early portion of the data, where the dynamic control of glucose is active. The values of Φ

_{s}(35 ± 4, CV 15 ± 4%) and

*S*

_{I}(10.1 ± 2.4, CV 13 ± 1%), on the other hand, did not significantly change (Figs. 5 and 6).

**OGTT _{300-11}.** All the indexes, including Φ

_{d}, were not different from and were well correlated with those obtained from the FSOGTT

_{300-22}(Φ

_{d}= 710 ± 111, CV 39 ± 5%; Φ

_{s}= 36 ± 3, CV 13 ± 3%;

*S*

_{I}= 10.2 ± 2.4, CV 13 ± 1%) (Figs. 5 and 6). Individual values of Φ

_{d}, Φ

_{s}, and

*S*

_{I}are summarized in Table 2, together with their precision. The average ISR profiles estimated using the two protocols were also very similar (Fig. 4), thus indicating that the more accurate description of the early portion of the experiment by OGTT

_{300-11}with respect to OGTT

_{300-9}is essential to obtain results similar to those of the FSOGTT

_{300-22}. The weighted residual plot of the C-peptide minimal model is shown in Fig. 3.

**OGTT _{240-10}.** β-Cell sensitivity indexes
Φ

_{d}(710 ± 126, CV 40 ± 7%), Φ

_{s}(35 ± 3, CV 12 ± 1%), and

*S*

_{I}(8.9 ± 2.1, CV 15 ± 1%) were well correlated with those obtained during the FSOGTT

_{300-22}(Fig. 6). However, Φ

_{d}and Φ

_{s}did not significantly change, whereas

*S*

_{I}was statistically different from values calculated during the FSOGTT

_{300-22}(Fig. 5), thus indicating the importance of the 300-min sample for an accurate estimation of insulin sensitivity. The weighted residual plot of the C-peptide minimal model is shown in Fig. 3.

## DISCUSSION

In this study, minimal model indexes of β-cell function and insulin
sensitivity have been proposed and successfully assessed during an 11-sample
300-min OGTT in individuals with various degrees of glucose tolerance. While
maintaining the possibility of estimating indexes in the single individual,
the OGTT_{300-11} offers a number of additional advantages with
respect to available approaches based on the clamp or IVGTT techniques: the
oral perturbation reproduces a physiological condition, and the test is easy
to perform, with potential application to large scale genetic and
epidemiologic studies. These features make it an appealing tool because it may
exhibit a larger statistical power than population-oriented indexes such as
those proposed by Matthews et al.
(21) and Matsuda and DeFronzo
(22).

Minimal models, through a parsimonious description of glucose/C-peptide and
glucose/insulin relationships, provide reliable indexes of β-cell
function and insulin sensitivity. More precisely, β-cell sensitivity
indexes have been calculated by extending to the OGTT data the C-peptide
minimal model recently developed for intravenous glucose graded up and down
infusion (5). The model
assumptions are particularly favorable to an OGTT protocol, i.e., a situation
where C-peptide and glucose concentrations show slow dynamics compared with
the IVGTT, where excursions are rapid and large. The model has already been
successfully used to assess β-cell function during physiological tests in
normal subjects (5) and in
individuals with various degrees of glucose tolerance
(23). It incorporates the
assumption that glucose stimulates pancreatic insulin secretion by exerting
both a static (dependent on glucose concentration) and a dynamic (dependent on
glucose rate of change) control. The model provides the insulin secretion
profile and indexes of β-cell function: the static Φ_{s}, the
dynamic Φ_{d}, and the global Φ sensitivity to glucose.

*S*_{I} has been calculated by using a formula recently
proposed for a meal glucose tolerance test
(7). The approach associates a
parsimonious parametric representation of splanchnic glucose absorption with
the minimal model description of glucose disposal. This method has been
validated by comparing its *S*_{I} estimates to those provided
by an insulin-modified IVGTT performed on the same group of 10 normal
subjects. The significant correlation between the two *S*_{I}
indexes (ρ_{s} = 0.89, *P* < 0.01) indicates that a
reliable measure of insulin sensitivity can be derived from either an oral
test or an IVGTT.

To derive reliable estimates of β-cell function and insulin
sensitivity during an OGTT, a rich database was initially used, with 22
samples taken in a 300-min OGTT (FSOGTT_{300-22}). Then, because our
objective was to propose a protocol sufficiently simple but still robust, we
examined reduced sampling schedule OGTTs by using the indexes obtained from
the FSOGTT_{300-22} as a reference for internal validation. The
results indicate that 11 samples in a 300-min OGTT (OGTT_{300-11}) are
sufficient to obtain results similar to those from the
FSOGTT_{300-22}, since the two sets of indexes show high correlation
(Fig. 6) and are not
statistically different (Fig.
5). Also, the ISR profiles are virtually superimposable
(Fig. 4). A 300-min experiment
is necessary to obtain such results because the values estimated for
*S*_{I} during a shorter experiment (OGTT_{240-10}) are
slightly lower than those estimated during a 300-min experiment
(FSOGTT_{300-22}, OGTT_{300-9}, and OGTT_{300-11}).
The accurate description of the early portion of the C-peptide and glucose
curves, provided by the 10, 20, 30 min samples after the oral glucose
ingestion, is also necessary to obtain reliable estimates of the index
Φ_{d}.

**OGTT minimal model indexes: NGT versus IGT.** The standard 120-min
OGTT, with blood samples usually drawn at 0, 30, 60, 90, and 120 min, provides
the important clinical classification of glucose tolerance
(10). The
OGTT_{300-11} we propose here includes the standard samples, thus
still allowing one to perform the standard classification of glucose tolerance
but also enabling one to estimate indexes of β-cell function and insulin
sensitivity, which help to better characterize glucose tolerance in a single
individual. From our data, when OGTT_{300-11} indexes in NGT subjects
(*n* = 7) were compared with those obtained in IGT subjects (*n*
= 4), no difference was found in the pancreatic sensitivity indexes (NGT:
Φ_{d} = 728 ± 124, Φ_{s} = 37 ± 4, Φ
= 48 ± 6; IGT: Φ_{d} = 678 ± 241, Φ_{s}
= 34 ± 6, Φ = 42 ± 9), but a statistically significant
difference was found in both the *S*_{I} (NGT 14.0 ±
2.7, IGT 3.4 ± 1.0) and the DI (NGT 678 ± 178, IGT 160 ±
80).

These results confirm that subjects with IGT are characterized by an inadequate insulin secretory response for the degree of insulin resistance (24) or, in other words, that IGT is characterized by a relative, rather than absolute, insulin deficiency.

**OGTT versus intravenous glucose infusions.** Pancreatic indexes
Φ_{s} and Φ_{d} estimated from OGTT_{300-11}
were also compared with the same indexes estimated during either IVGTT or
graded up and down glucose infusions. The IVGTT counterparts of
Φ_{d} and Φ_{s} are respectively the first- and
second-phase sensitivity indexes Φ_{1} and Φ_{2}. The
values obtained during an insulin-modified IVGTT (300 mg/kg) in normal
subjects (*n* = 15) were Φ_{2} = 10.9 ± 1.4 and
Φ_{1} = 191 ± 29
(25); β-cell indexes
obtained during graded up and down glucose infusions (0, 4, 8, 16, 8, 4, and 0
mg·kg^{-1}·min^{-1}) in nondiabetic subjects
(*n* = 8) were Φ_{s} = 18.8 ± 1.8 and
Φ_{d} = 222 ± 30
(5). Both Φ_{s} and
Φ_{d} are threefold higher during OGTT than during intravenous
tests. This can probably be ascribed to the presence of the well-known
insulin-stimulating gastrointestinal hormones known as the incretin effect,
which are secreted in response to oral but not intravenous glucose
administration (26). It will
be of interest in future studies to compare β-cell indexes and
*S*_{I} obtained from OGTTs with values obtained in the same
subjects during intravenous glucose infusions—possibly during a graded
up and down glucose infusion, which better simulates an OGTT. Preliminary
results are available on only six of the eleven subjects studied here (four
with NGT and two with IGT) who underwent both an OGTT and a graded up and down
glucose infusion. The results confirmed our expectations. Indexes of
β-cell function (Φ_{d} and Φ_{s}) were markedly
higher during the oral perturbation (OGTT: Φ_{d} = 677 ±
154, Φ_{s} = 39 ± 5; up and down: Φ_{d} = 105
± 43, Φ_{s} = 17 ± 3, *P* < 0.05). The
OGTT *S*_{I} was higher than the graded up and down
*S*_{I} (OGTT *S*_{I} = 13.1 ± 3.6; up
and down *S*_{I} = 8.8 ± 2.3, *P* < 0.05) and
showed a high correlation with it (ρ_{s} = 0.83)—a trend
already observed during meal tolerance tests
(7).

**Importance of the dynamic control of glucose on insulin secretion.**
Indexes of β-cell function have been recently proposed in the literature
based on modeling analyses of glucose and C-peptide data during a meal
(6) and a 120-min OGTT
(9). Both models assume a
control of glucose, but not of its rate of change, on insulin secretion. This
is a gross simplification because the importance of dynamic control of glucose
on insulin secretion (active when glucose concentration increases) has been
shown both in previous studies where graded up and down glucose infusion data
were analyzed (5) and in the
present study. If a model similar to the OGTT minimal model but not accounting
for the dynamic glucose control is used to analyze the data, systematic
deviations occur in the early portion of the OGTT
(Fig. 7).

The approach proposed by Cretti et al.
(9) is simplistic but
particularly appealing because it only requires five samples throughout 120
min. To compare our approach with that proposed by Cretti et al., we applied
the latter to our data by adopting the sampling schedule proposed in
(9), i.e., 0, 30, 60, 90, and
120 min. Model fit and residual plots showed a systematic underestimation of
the data between 15 and 75 min, thus indicating that the model proposed by
Cretti et al. is too simplistic to describe OGTT data. The apparent glucose
threshold θ (9) assumed
values (often ∼0) far from basal glucose, and β-cell sensitivity
σ (9) was different when
compared with the minimal model counterpart (Φ_{s}). This may
reflect the fact that σ incorporates both the static and the dynamic
glucose controls, whereas Φ_{s} describes the static glucose
control only but is more likely the consequence of numerical compensations due
to differences in the estimates of threshold θ in the Cretti et al.
model (often ∼0) and *h* in our model (always
∼*G*_{b}). In conclusion, care must be exercised in
adopting simplistic but appealing methods because structural errors can lead
to compensations among parameters and consequently to inaccurate β-cell
portraits. We think that the protocol and the methods proposed here, which
enable one to obtain a precise description of both β-cell function and
insulin action in a single individual, are a good compromise between
model/protocol simplicity and accuracy.

In conclusion, by extending to the OGTT the recently developed C-peptide
minimal model during intravenous glucose graded up and down infusion
(5) and by applying to the OGTT
the minimal model formula recently proposed for a meal glucose tolerance test
(7), we have shown that it is
possible to simultaneously assess individual parameters of β-cell
function and insulin sensitivity from an 11-sample 300-min OGTT. Of note is
that OGTT_{300-11} preserves the important clinical classification of
glucose tolerance provided by a standard 120-min OGTT. The detailed
description of β-cell function and insulin action thus available in a
single individual, together with the ease of execution of the protocol, should
make this approach a powerful tool for measuring changes in insulin secretion
and action that would also be applicable to large-scale genetic and
epidemiologic studies. The present study is the first attempt to
simultaneously assess insulin sensitivity and β-cell function in the
single individual during an OGTT and shows encouraging results in subjects
with various degrees of glucose tolerance. However, this study is definitely
unfinished and further work needs to be performed to define the domain of
validity of this approach throughout the whole range of glucose tolerance,
including patients with diabetes.

## APPENDIX

The purpose of this section is to derive the global index of β-cell sensitivity to glucose, Φ.

**Model dependent formula.** Pancreatic secretion SR is the sum of a
static (SR_{s}) and a dynamic (SR_{d}) component (Eq. 3).
SR_{s} is described in Eqs. 4 and 5. The integral from time 0 to
∞ of SR_{s} can thus be calculated by integrating Eq. 5:

Because *Y*(∞) = *Y*(0), i.e., the system returns for
*t* → ∞ to the basal steady state, the expression for
and thus for
becomes the following:

SR_{d} is described in Eqs. 6 and 7. The integral from time 0 to
∞ of SR_{d} can thus be calculated by integrating Eq. 6:
then

By using the definition of Φ_{d} (Eq. 9), the integral from
time 0 to ∞ of SR_{d} can be expressed as follows:

It is thus possible to calculate the global index of β-cell sensitivity to glucose as follows:

**Model independent formula.** By integrating Eqs. 1 and 2 from 0 to
∞:

Because CP_{1}(∞) = CP_{1}(0) and
CP_{2}(∞) = CP_{2}(0), i.e., the system returns for
*t* → ∞ to the basal steady state, the following holds:

By substituting Eq. A10 in Eq. A9, Eq. A9 becomes:

Finally, by substituting Eq. A11 in Eq. 10, Φ is given by:

## Acknowledgments

These studies were supported in part by U.S. National Institutes of Health Grants DK-02742, DK-31842, and DK-20595 and General Clinical Research Center Grant M01 RR00055.

The authors are indebted to Jacqueline Imperial, RN, at the Clinical Research Center at the University of Chicago for her expert care of the subjects who participated in the study. They also wish to thank Dr. Andrea Caumo for his constructive and helpful advice in the development of the manuscript.

## Footnotes

CV, coefficient of variation; DI, disposition index; FSOGTT

_{300-22}, frequently sampled OGTT with 22 samples throughout 300 min; IGT, impaired glucose tolerance; ISR, insulin secretion rate; IVGTT, intravenous glucose tolerance test; NGT, normal glucose tolerance; OGTT, oral glucose tolerance test;*S*_{I}, insulin sensitivity index.- Accepted September 8, 2000.
- Received June 12, 2000.

- by the American Diabetes Association, Inc.