IMA Journal of Mathematics Applied in Medicine & Biology (1994) 11, 245-266

A mathematical model of insulin secretion

A. G. SHANNON AND J. M. HOGG
School of Mathematical Sciences, University of Technology, Sydney,
P.O. Box 123, Broadway, NSW 2007, Australia

R. L. OLLERTON
Department of Mathematics, University of Western Sydney, Nepean,
P.O. Box 10, Kingswood, NSW2747, Australia

S. Luzio AND D. R. OWENS

Diabetes Research Unit, University of Wales College of Medicine,
Cardiff CN4 4XN, Wales

[Received 17 November 1992 and in revised form 14 September 1994]

Diabetes mellitus is a chronic state of excessive blood glucose levels (hyperglycaemia),

which may result from many environmental and genetic factors, often acting jointly.
The major regulator of glucose concentration in the blood is insulin. It is known
that about 50% of the insulin is taken up by the liver on passing through it after
secretion from the pancreas. The precise value of this fractional uptake is not known,
so the prehepatic insulin secretion rates cannot be readily estimated from the plasma
insulin concentration levels. By utilizing the equimolar secretion of insulin and
connecting peptide (C-peptide) from the pancreas, a noninvasive method has been
formulated. This was based on a compartmental model which involved the pancreas,
liver, and plasma. The resulting differential equation yielded a gamma variate solution
which could be readily linearized. The model was then tested on 56 normal (51
nonobese and 5 obese) subjects, and three groups of subjects with diabetes who could
be labelled as mild, moderate, and severe (based on the fasting plasma glucose
concentration) with 83, 88, and 64 subjects respectively. We have focused on the
human patient environment of the clinician to produce a distinct model which gave
a consistent pattern within all four groups with good fits between observed and
theoretical values of the plasma insulin levels. The consequent rates for insulin
secretion were consistent across the groups and were clinically meaningful.

Keywords: diabetes mellitus; insulin secretion; gamma variate; nonlinear regression.

1. Introduction
Diabetes mellitus is a chronic state of excessive concentration of glucose in the blood.
The major regulator of glucose concentration in the blood is insulin, a hormone
synthesized in and secreted by the beta cells of the islets of Langerhans in the pancreas.
High blood sugar may be due to a lack of insulin and/or to excess of factors that
oppose its action causing insulin resistance. This imbalance leads to abnormalities
245
\; Oxford Univeraty Praj 19*4
246 A. G. SHANNON ET AL.

PANCREAS

Insulin C-peptide
R(t) R(t)

LIVER

FR(t) R(t)

C(t)
PLASMA

FIG. 1. Compartment model of peptide secretion.

of carbohydrate, protein, and lipid metabolism. The major effects of diabetes include
characteristic symptoms, the progressive development of disease of the capillaries of
the kidney and retina, damage to the peripheral nerves, and accelerated arteriosclerosis
(WHO, 1980). Owens (1986) presents a historical summary of the disease and Bliss
(1982) relates the human drama and scientific enterprise behind the discovery of
insulin.
Figure 1 is a compartmental model of the release of the peptides (insulin and
C-peptide) from the pancreas to the liver via the portal vein. (The symbols are
explained in the next section.) This paper introduces a noninvasive method for
calculating prehepatic in vivo insulin secretion rates from plasma C-peptide concen-
tration levels. Knowledge of these secretion rates is of use clinically for establishing
therapeutic regimens and to aid research into the development of different human
insulin preparations and analogues of human insulin produced by genetic engineering
(Brange et al, 1990) in an attempt to normalize plasma glucose concentrations. The
motivation of developing this approach was to provide the clinician with a method
which could be readily used and interpreted and which would give consistent results
based on the fasting plasma glucose levels and the degree of obesity of the subjects
(Shannon et al, 1991).

2. The model
We base our model on evidence that insulin and C-peptide are co-secreted in
equimolar quantities (Rubenstein et al., 1969) and that C-peptide is not taken up
by the liver (Polonsky et al, 1983). This approach of utilizing C-peptide levels to
 A MATHEMATICAL MODEL OF INSULIN SECRETION 247

estimate insulin secretion has been adopted by Volund et al. (1987), Cobelli & Pacini
(1988), and Van Cauter et al. (1992). The latter two groups used two-compartment
models, whereas we have assumed one-compartment disappearance kinetics for both
peptides (as did Volund and his colleagues). We opted for this approach on the basis
of its relative simplicity of use in the clinical situation. Results confirm that the extra
complication of a two-compartment model is not essential. Unlike the other authors,
we also have access to a comparatively large sample of human subjects, which we
considered first in groups defined according to fasting blood glucose levels during
meal tolerance tests and then by aggregating the results for the individuals within
these groups. In this way, we were able to use analyses of variance as statistical
commentaries on the plausibility of the work.
Some of the symbols to be used are as follows:
f time in minutes;
R(t) rate of secretion from the pancreas into the portal vein of both insulin and
C-peptide (nmol/1 min);
C(t) concentration of C-peptide in the plasma (nmol/1);
I(t) concentration of insulin in the plasma (nmol/1);
F fraction of insulin not taken up by the liver during the first passage;
b,,b c first-order clearance indices of insulin and C-peptide from the plasma
compartment (min"1);
at,ac first-order secretion indices of insulin and C-peptide into the plasma
compartment (dimensionless).
We further assumed that the rate of clearance of each peptide, R(t), from the plasma
is proportional to the level of concentration with coefficients of proportionality b,
and bc.
Suppose R(t) is the rate of secretion from the pancreas into the portal vein of
both the insulin and the C-peptide. Then we can represent the flow of the peptides
from the pancreas through the plasma by the compartment model of Fig. 1. To
accommodate the initial response by the pancreas to a glucose load, we assumed the
rate of secretion of each peptide is directly proportional to the concentration in the
plasma and inversely proportional to time with respective coefficients of propor-
tionality a, and ac. This is a pragmatic assumption based on experimental observations
of results where the glucose challenge is derived from oral glucose and meal tolerance
tests. This assumption was originally prompted by work on the two-pool model for
insulin secretion. In this, one pool is conceived as a small compartment available for
rapid insulin release, and the other for sustained insulin release tightly coupled to
insulin synthesis (Porte & Pupo, 1969). Beyond that, the use of the assumption leads
to consistent results, which are the concern of this article, rather than any underlying
mechanism. In any case, the hypothesized multiphasic close temporal associations
between pulses of insulin secretion and of blood glucose levels are the object of
considerable debate (Polonsky et al, 1988; Lang et al, 1979). We seek R(t) = dC/df.
The C-peptide kinetics can then be described by the first-order differential equation

dt t
248 A. G. SHANNON ET AL.

a solution of which can be given by

'"'1, (2)
in which A is a scaling factor.
As we are primarily concerned with the index of secretion ac, we consider briefly
the sensitivity of the model to errors in the parameter ac. We use an Eulerian
approximation to differentiate
In C = In A + ac In t - bct, (3)
where

C =C-C0, — = Aac\nt, — =— _-,

C ac ac\nt C
so that theoretically the relative error in ac for any given bc should be a decreasing
proportion of the relative error in C-peptide measurement as t increases, though the
values for ac are unduly sensitive to the choice of time points for the secretion phase
because In t < t and is small for small t (minutes). This is a mathematical limitation
of the model and means that agreed times of sampling would be necessary for repro-
ducibility and comparisons. However, we believe that this weakness is compensated
by the goodness of fit and ease of use of the model.

3. Materials and methods

To obtain the plasma peptide values 235 patients with non-insulin-dependent diabetes
mellitus (NIDDM) were studied. All patients had normal kidney and liver function
tests, though as an indication of glycaemic control the glycosylated haemoglobin
(HbAl) concentration of the patients varied from 6.7 to 19.3% (mean 11.6, SD 2.5%).
(For comparison, a normal range is 5.5-7.8%.) The patients were also divided into
obese and nonobese subgroups according to body mass index (BMI). (BMI = body
mass/height 2 (kg/m 2 ) and is commonly used rather than other measures because it
partly accounts for distribution of body mass.) A BMI of less than 26.5 kg/m 2 can
be taken as nonobese. This is a figure consistently used by the present group (e.g.
Owens et al., 1986), though where obesity is actually denned by writers demarcation
figures vary in the literature from 20 to 30 kg/m 2 . In addition 56 normal subjects of
similar age range and no family history of diabetes were studied. The study was
approved by the local ethics committee and informed consent was given by each
subject.
All subjects were studied on two consecutive days. They were given an oral glucose
tolerance test (OGTT) or a meal tolerance test (MTT) after a 10 hour overnight fast
in random order. (Farrow & Leyland (1991) have considered some statistical aspects
of the interpretation of OGTT results.) The glucose challenge during the OGTT
consisted of 75 g glucose dissolved in 200 ml of water. The meal used in MTT
contained approximately 500 kcal made up of 20% protein, 20% fat, and 60%
carbohydrate (Table 1). The subjects were allowed 10 minutes to consume the meal.
The OGTT was conducted in accord with the World Health Organisation recom-
mendations.
 A MATHEMATICAL MODEL OF INSULIN SECRETION 249

TABLE 1
Composition of meal tolerance test (MTT) as in Jones et al. (1989)

Total Starch +
Energy Protein Fat CHO Sugars dextrins Diet
Food (kcal) (g) (g) (g) (S) (g) fibre

15gWeetabix 51 1.71 0.51 10.55 0.92 9.98 1.9

10 g skimmed milk powder* 35.5 3.64 0.13 5.28 5.28 0 0
250 ml pineapple juice 132.5 1.0 0.25 33.5 33.5 Tr 0
50 g white meat chicken 71 13.25 2.0 0 0 0 0
60 g Hovis bread 136.8 5.82 1.32 27.06 1.44 25.62 2.70
9 g butter 66.6 0.04 7.38 Tr Tr 0 0

Totals 493.4 25.46 11.59 76.39 41.14 35.6 4.6

Percentage calories 100% 20% 20% 60%

a Made up to 200 ml volume with water.

After the overnight fast, the subjects were admitted to a metabolic unit, where they
remained on bed-rest throughout the study; smoking was not permitted. Mixed
venous blood samples were taken from a forearm vein at 08.30 h and immediately
prior to the administration of the OGTT or MTT at 09.00 h, and then at 30 minute
intervals for 4 hours. We shall confine our discussion here to the MTT results.

4. Use of the model

The main purpose of the study was to determine if consistent results could be
obtained, namely that as fasting plasma glucose levels increased the insulin secretion
rate decreased in response to a carbohydrate challenge and that obese subjects had
a lower insulin secretion rate than nonobese subjects.
One approach to this problem involves the application of nonlinear regression.
Because the normal equations that are solved to obtain least-squares parameter
estimates are themselves nonlinear, such a technique requires the application of
numerical methods, that is, an iterative process. It is important to note that there is
no guarantee that the solution obtained is the global least-squares estimate. Because
the procedure is iterative, it is necessary to make reasonably accurate initial estimates
of the parameters. This initial seeding requirement has proved a problem for some
clinicians.
A second approach involves the use of a log-linear model. The concentration
formula (2) can be linearized to obtain equation (3) so that a fit can be carried out
using a multiple linear regression of In C ' o n l n t and t. This method may be used
to find parameters A, ac, and bc in closed form without initial guesses for the
parameters. This method requires an estimate of the basal level Co which may be
approximated by the average of the — 30 and 0 minute samples.
The first step in applying either of these techniques involves a choice of suitable
subgroups. Here subjects were classified by reference to their fasting plasma glucose
250 A. G. SHANNON ET AL.

(FPG) levels. The range for FPG for normal subjects is approximately 4-6 mmol/1.
The choice of ranges for the three NIDDM subgroups of subjects with diabetes was
somewhat arbitrary. Those with FPG levels less than 10 mmol/1 were classified as
mild, while those with FPG levels more than 14 mmol/1 as severe.
The next step normally involves calculation of the average C-peptide values for
each of the subgroups, so that parameters may be estimated by applying the chosen
fitting procedure to each of the four averaged sets of data. This approach is suitable
provided that each subgroup appears to be drawn from a reasonably uniform,
possibly normal, population. This method was abandoned when it became obvious
that the populations were skewed. Figure 2 shows plots of the C-peptide concen-
trations at 30 minute intervals for each subgroup. The vertical bars showing the
twenty-fifth percentile, the median, and the seventy-fifth percentile indicate that the
subgroups are drawn from skewed populations.
The focus of the investigation now moved to the required study of individual
patient data. Nonlinear regression was applied using the SAS procedure NLIN
(SAS/STAT™, 1988) to the concentration data for each of the individual subjects,
so that an analysis of variance could be used to compare aspects of the different
groups. For these comparisons, a grid of starting values was specified for all
parameters. Derivatives of the model with respect to the parameters were also
specified. The NLIN procedurefirstexamines the grid of starting values and evaluates
the residual sum of squares at each combination to determine the best set for starting
the required iterative procedure.
From equation (2), we have

— = Aacf*-le-h<<-Abcta*e-b<', (4)
dt
which, in conjunction with equation (1), makes it reasonable to refer to the first term
on the right-hand side of (4) as the secretion term and the second term as the clearance
term. If we accept that insulin and C-peptide are secreted at equimolar rates into the
portal vein, then from Fig. 1 the prehepatic insulin secretion rate equals the
posthepatic C-peptide secretion rate, Aact°*~l e~bc'.
If a long interval is considered, the total amount secreted is given by

S = Aac P f*-1 e-"<'d£ = acAT{ac)lb%,

Jo
where T represents the gamma function (and hence the curve is often referred to as
the gamma variate function). For the same long time interval, this may easily be
shown to equal the total amount cleared. For short time intervals, the total amount
cleared may be considerably less than the total amount secreted.
Similar use of equation (1) and equation (2) yield the time for peak concentration,
tm = ajbc,
the peak above basal concentration,
c ; = A(ajcbcy,
 A MATHEMATICAL MODEL OF INSULIN SECRETION 251
FPG = NORMAL FPG = MILD
FPG < 6 mmoM 6<FPG<10mmol/l
3.0

0.0
0 30 60 90 120 150 180 210 240 0 30 60 90 120 150 180 210 240
Time (minutes) Time (minutes)
10<FPG<14mmol/l FPG>14mmof/l
3.0

^ 2.0
o
c

0.0
0 30 60 90 120 150 180 210 240 0 30 60 90 120 150 180 210 240
Time (minutes) Time (minutes)

FIG. 2. Plots of the C-peptide concentrations at 30 minute intervals for each subgroup. The vertical bars
show the twenty-fifth percentile, the median, and the seventy-fifth percentile. The fit of the model to the
averaged values is shown in Fig. 6.

the slope of the peak concentration versus time for peak concentration line,

the time for peak secretion,

= (fl e -l)/fc e fora^l,
252 A. G. SHANNON ET AL.

and the peak secretion rate,

5. Results
After fitting the model to individual patient data, boxplots for the estimates of the
above quantities were constructed in an attempt to identify outliers. The criteria
(based on the ninety-fifth and fifth percentile) used to classify fits as acceptable are
given in Table 2.
Of the 291 sets of patient data studied, 96 were classified as poor fits (19 normal,
25 mild, 23 moderate, and 29 severe subjects) and were not included in the remainder
of the study. The study was therefore confined to 37 normal subjects and 158 patients
with diabetes (38 female, 120 male). The classification of these patients into obesity
subgroups is given at Table 3. It is likely that the number of poor fits could be
reduced by more frequent sampling times.
Figure 3 compares the fits obtained when a quadratic polynomial, a cubic
polynomial, a log-linear model (equation (3)), and a nonlinear exponential model
(equation (2)), are applied to the concentration levels for a typical individual patient.
The improvement in fit is evidenced by the decreasing residual sum of squares
obtained for each model (see Table 4).
Figure 4 is a plot of peak concentration versus time for peak concentration for
each of the four groups of subjects. The most interesting feature of this plot is the
location of the normal subjects in relation to the patients with diabetes. A measure
of this difference is given by the slope of the peak concentration versus time for
peak concentration line. Boxplots for this slope are given in Fig. 5(f).

TABLE 2
Criteria used to classify fits as acceptable

0.5 < ac < 6.29

0.994 s; 0< 26.0 where 0 • In A
0.0 < bc =g 0.0921
0 < C'm < 4.0
0 < £m «S 240

TABLE 3
Classification of patients into MTT and BMI subgroups

MTT

BMI Normal Mild Moderate Severe Total

Nonobese 32 19 25 12 88
Obese 5 39 40 23 107
Total 37 58 65 35 195
 A MATHEMATICAL MODEL OF INSULIN SECRETION 253

2.5 i

2.0-
—
1.5-

<D

1.0- L Log - linear ^ ^ ^

/ / / N Nonlinear
O
C Cubic
0.5- ^y Q Quadratic
o Observed data

0.0 -I
30 60 90 120 150 180 210 240
Time (minutes)

FIG. 3. Fits obtained when quadratic, cubic, log-linear, and nonlinear models are applied to the
concentration levels for an individual patient.

a Normal
• Mild
Moderate
3- Severe
o

CD
•
g 2- „ ° ° °*° •• ' ; .'
•
O
S
Q.

•
o4
30 60 90 120 150 180 210 240
Time (minutes)
FIG. 4. Plots of the peak concentration (C'm) versus time for peak concentration (im) for each of the
four MTT subgroups.

Figure 5 gives boxplots for each subgroup to compare the secretion indices, the
clearance indices, the parameter ft = —In A, the peak concentration, the time for peak
concentration, the slope of the peak concentration versus time for peak concentration
line, the peak secretion rate, the time for peak secretion, and the total amount secreted.
The thick vertical boxes show the tenth and the ninetieth percentiles. The medians
are joined by straight lines. The thin vertical lines, or whiskers, extend from the boxes
as far as the data extends. Detailed information relating to these comparisons is given
in Table 5.
Figure 6 compares the curves for the theoretical plasma concentration levels for
254 A. G. SHANNON ET AL.

TABLE 4
Comparison of quadratic, cubic, log-linear, and nonlinear fits for an individual patient. The
improvement in fit is evidenced by the decreasing sum of squares of the residuals. Refer to
Fig. 3 for the corresponding plots
Quadratic Regression

Sum of Mean
Source DF squares square F value Prob > F

Model 2 1.41669 0.70835 11.577 0.0087

Error 6 036713 0.06119
C Total 8 1.78382

Cubic Regression

Sum of Mean
Source DF squares square F value Prob > F

Model 3 t.45453 0.48484 7.362 0.0278

Error 5 032929 0.06586
C Total 8 1.78382

Log-linear Regression

Sum of Mean
Source DF squares square F value Prob > F

Model 2 5.47653 2.73826 47.460 0.0006

Error 5 0.28848 0.05770
C Total 7 5.76501

Note that for this model the error sum of squares relates to the logarithms of the above basal
concentrations. After talcing antilogs we can obtain a sum of squares of the residuals which may be
compared with those obtained using the other models. For this fit the value is 0.19127.
Nonlinear Regression

Sum of Mean
Source DF squares square

Model 4 16.32333 4.08083

Error S 0.10387 0.02077
C Total 8 1.78382

Asymptotic
95% confidence interval Coefficient
Asymptotic of variation
Parameter Estimate std. error Lower Upper (%)

Q 0.57743 0.13568 0.22865 0.92620 23.5

fi 11.63719 3.62359 2.32259 20.95179 31.1
A 3,23119 0.95678 0.77175 5.69064 29.6
B 0.02987 0.00845 0.00816 0.05158 28.3
 A MATHEMATICAL MODEL OF INSULIN SECRETION 255

the four subgroups classified according to MTT listed in Table 3 (i.e. 37 normal,
58 mild, 65 moderate, and 35 severe). Since these curves were obtained by applying
nonlinear regression to each of four averaged sets of data, the mean C-peptide
concentration data and SEM error bars for each MTT subgroup are also shown.
Figure 7 compares the secretion rates, while Fig. 8 compares the clearance rates using
the mean values of the parameters obtained for each of the MTT subgroups (see
Table 5).
Figure 9 compares the curves for the theoretical plasma concentration levels for
the two subgroups classified according to BMI listed in Table 3 (i.e. 88 nonobese
and 107 obese). The mean C-peptide concentration data and SEM error bars for
each BMI subgroup are also shown. Figure 10 compares the secretion rates, while
Fig. 11 compares the clearance rates using the mean values of the parameters obtained
for each of the BMI subgroups (see Table 6).

4
fc
3

oJ' (a)
Normal Mild Moderate Severe

0 08
0.07
0.06
0.05
0.04
0.03
0.02 —-

0.01
(b)
0.00
Normal Mild Moderate Severe

FIG. S. Boxplots Tor each subgroup to compare (a) the secretion indices; (b) the clearance indices.
(continued)
256 A. G. SHANNON ET AL.

30

20

10

«
! (c)
Normal Mild Moderate Severe

s
12

n
1

Normal
~-

Mild
—
I
Moderate
1!
Severe

240

210

180

150
_ "
! 120

80

60

30
(e)
0
Normal Mild Moderate Severe

FIG. 5 (continued), (c) The parameter ft (d) the peak concentration (C'm)\ (e) the time for peak concen-
tration (t m ).
 A MATHEMATICAL MODEL OF INSULIN SECRETION 257

0.08

0.06

0.04

0.02

0.00
Normal Mild Moderate Severe

0.15

0.12

S 0.09

! 0.06

0.03

(g)
0.00 J
Normal Mild Moderate Severe

1DU

120

c
80
_ _ — — •

40 ^ ^

t ;

(h) • *
0
Normal Mild Moderate Severe

FIG. 5 (continued). (f) The slope of the peak concentration versus time for peak concentration line (X);
(g) the peak secretion rate (rp); (h) the time for peak secretion (i p ). (continued)
258 A. G. SHANNON ET AL.

18

15

12

9
I
6

• (i)
I
Normal Mild Moderate Severe

FIG. 5 (continued), (i) The total amount secreted (S). (See Table 5.)

Figure 7 suggests, as hoped, that there is a steady decrease of insulin secretion

rates as one goes from nonobese normal subjects to those with increasing fasting
blood glucose levels. The subjects with diabetes provide an internal criterion of
consistency for the model and the normal subjects lend some external credence to
its validity. Quantitative pancreatic insulin secretion and portal venous insulin levels
in the absence of invasive catheter placement and in response to oral nutrient
ingestion have not been reported (Eaton et al., 1980). The values of the fractional

FPQ = NORMAL FPQ = MILD

FPG < 6 mmot/l 6<FPG<10mmol/l
3.0

0 30 60 90 120 150 180 210 240 0 30 60 90 120 150 180 210 240
Time (minutes) Time (minutes)
Fio. 6. Comparison of the curves obtained by applying nonlinear regression to the four averaged sets of
C-peptide concentration data with SEM error bars shown for each MTT subgroup.
 A MATHEMATICAL MODEL OF INSULIN SECRETION 259
FPG = SEVERE
FPG = MODERATE
FPG >14mmot/l
10<FPG< 14 mmol/1 3.0
3.0

0.0
0 30 60 90 120 150 180 210 240 0 30 60 90 120 150 180 210 240
Time (minutes) Time (minutes)

FIG. 6. (continued).

A Nornial
B Mild
C Moderate
D Severe

30 60 90 120 150 180 210 240

Time (minutes)

FIG. 7. Comparison of the theoretical curves for the secretion rates for the four MTT subgroups.

hepatic uptake of the insulin are not universally agreed, so that one cannot check
the calculation with these. F(i) is not assumed to be constant. Figure 7 also suggests
that the peak insulin secretion rate for normals is achieved earlier and is higher than
for the subjects with diabetes, while Fig. 8 suggests that the clearance rates are also
greater, the lower the FPGs of the groups of subjects are. All of these results are in
accord with theoretical expectations, but are not readily validated by external criteria
except by invasive means.
260 A. G. SHANNON ET AL.

TABLE 5
Comparison of the four subgroups in terms of secretion indices (a c ), clearance indices (b c ), the
parameter f} = — In A, peak concentration (C'm), time for peak concentration (r m ), slope of the
peak concentration versus time for peak concentration line (A), peak secretion rate (rp), time for
peak secretion (t p ), and the total amount secreted (S). Boxplots relating to these comparisons
are given in Fig. 5

Significant Significant
differences differences Significant
between the between the pairwise
Variable Subgroup Means variances means differences

Normal (A) 1.84 No Yes A-B

Mild (B) 2.52 A-C
Moderate (C) 2.64
Severe (D) 2.57
Normal (A) 0.0274 No Yes A-D
Mild (B) 0.0224
Moderate (C) 0.0218
Severe (D) 0.0189

P Normal (A) 5.60 No Yes A-B

Mild (B) 9.40 A-C
Moderate (C) 10.26 A-D
Severe (D) 10.50

cm Normal (A) 1.67 Yes Significant n/a

Mild (B) 1.34 difference
Moderate (C) 0.99 between the
Severe (D) 0.7 medians

Normal (A) 67.9 No Yes A-B

Mild (B) 123.9 A-C
Moderate (C) 129.5 A-D
Severe (D) 140.9 B-D

/. Normal (A) 0.0286 Yes Significant n/a

Mild (B) 0.0112 difference
Moderate (C) 0.0081 between the
Severe (D) 0.0060 medians

r
P Normal (A) 0.0719 Yes Significant n/a
Mild (B) 0.0365 difference
Moderate (C) 0.0266 between the
Severe (D) 0.0194 medians

'P Normal (A) 35.96 Yes Significant n/a

Mild (B) 65.85 difference
Moderate (C) 71.91 between the
Severe (D) 75.07 medians

S Normal (A) 5.68 Yes Significant n/a

Mild (B) 5.44 difference
Moderate (C) 3.94 between the
Severe (D) 3.07 medians
 A MATHEMATICAL MODEL OF INSULIN SECRETION 261
0.06

0.05

A Normal
0.04 B Mild
C Moderate
S 0.03 D Severe
to

0.02

0.01

000
0 30 60 90 120 150 180 210 240
Time (minutes)

FIG. 8. Comparison of the theoretical curves for the clearance rates for the four MTT subgroups.

TABLE 6
Comparison of the obese and nonobese subgroups in terms of secretion indices (a c ), clearance
indices (bc), the parameter /? = —In A, peak concentration (C'm), time for peak concentration,
(t m ), slope of the peak concentration versus time for peak concentration line (X), peak secretion
rate (rp), time for peak secretion (t p ), and the total amount secreted (S)

Difference Difference
Ratio of between the between the
Variable Subgroup Means variances = 1 means = 0 medians = 0

ac Obese (A) 2.406 Yes Yes Yes

Nonobese (B) 2.481

bc Obese (A) 0.0200 No No No

Nonobese (B) 0.0256

fi Obese (A) 9.185 No Yes Yes

Nonobese (B) 9.131

Q Obese (A) 1.191 Yes Yes Yes

Nonobese (B) 1.176

'm Obese (A) 128.45 No No No

Nonobese (B) 105.47
/. Obese (A) 0.0104 No No Yes
Nonobese (B) 0.0152
r
p Obese (A) 0.0321 No Yes Yes
Nonobese (B) 0.0399
f
P Obese (A) 65.12 Yes Yes Yes
Nonobese (B) 64.90
s Obese (A) 4.676 Yes Yes Yes
Nonobese (B) 4.413
262 A. G. SHANNON ET AL.

BMI - NON OBESE

BMI < 26.5

0.01
30 60 90 120 150 210 240
Time (minutes)

BMI -OBESE
BMI > 26.5 M m 2

30 60 90 120 150 180 210 240

Time (minutes)

FIG. 9. Comparison of the curves obtained by applying nonlinear regression to the averaged sets of
C-peptide concentration data with SEM error bars shown for the obese and nonobese subgroups.

The question of whether these differences are statistically significant was examined
using one-way analysis of variance. An important assumption underlying comparisons
of means using analysis of variance is that the variances of the populations from which
the samples come are equal. For this reason, a test for equality of variances was
conducted prior to the test for differences between means—if this test was not passed,
a nonparametric procedure (the Kruskal-Wallis test) was used to test the hypothesis
that the population medians are the same. In order to test for interaction between
BMI and MTT, a two-way analysis of variance for an unbalanced design was carried
out using the SAS procedure GLM (SAS/STAT™, 1988). For the comparisons
discussed below, no significant interactions were found.
 A MATHEMATICAL MODEL OF INSULIN SECRETION 263

0.04 1

E 0.03
A Obese
B Non obese
S 0.02
a '

0.01-

0.00^
30 60 90 120 150 180 210 240
Time (minutes)

FIG. 10. Comparison of the theoretical curves for the secretion rates for the obese and nonobese subgroups.

0.03

A Obese
0.02 B Nonobese

£ 0.01

0.00^
30 60 90 120 150 180 210 240
Time (minutes)

FIG. 11. Comparison of the theoretical curves for the clearance rates for the obese and nonobese subgroups.

The comparison of secretion indices (see Table 5 and Fig. 5(a)) shows that a clear
gradation among the secretion indices of the four groups relates well to their
differences in fasting blood sugar levels. This comparison emphasizes that secretion
rates differ greatly between NIDDMs and normals but do not really differ greatly
once one has NIDDM.
The comparison of clearance indices (see Table 5 and Fig. 5(b)) shows that the only
significant pairwise difference is that between the normal and severe subgroups.
The comparison of parameter ft (see Table 5 and Fig. 5(c)) is similar to the gradation
in secretion indices with NIDDMs contrasting greatly with the normals. The
parameter /? is in fact highly correlated with secretion index.
264 A. G. SHANNON ET AL.

• The comparison of peak concentration (see Table 5 and Fig. 5(d)) shows a
significant difference among the medians.
• The comparison of times of peak concentration (see Table 5 and Fig. 5(e)) is similar
to the gradation in secretion indices with NIDDMs contrasting greatly with the
normals.
• The comparison of slopes of the peak concentration versus time for peak
concentration line (see Table 5 and Fig. 5(f)) shows a significant difference among
the medians.
• The comparison of peak secretion rates (see Table 5 and Fig. 5(g)) shows a
significant difference among the medians.
• The comparison of times of peak secretion (see Table 5) and Fig. 5(h)) shows a
significant difference among the medians.
• The comparison of total amounts secreted (see Table 5 and Fig. 5(i)) shows a
significant difference among the medians.
• The comparison of total amount secreted for the obese and nonobese subgroups
(see Table 6) shows that the obese subjects have, on average, a slightly but not
significantly greater amount of insulin secreted. This follows because insulin is
secreted in proportion to the body mass index, other things being equal (Owens
et al, 1988). However, the times to peak concentration for the obese subjects are
sigificantly greater.

6. Conclusions
The model described in this paper is mathematically simple and it can be readily
applied with a computer. It does not conflict with the theoretical foundations of other
models, but the clinical results have been realistic. It does not pretend to describe
all aspects of the secretion of the insulin, and its predictive value is yet to be
corroborated by further testing. The advantages of the model are that the parameters
have a theoretical foundation and the experimental and theoretical values are in good
accord.
Another advantage of the proposed model is that it produces a variable fractional
uptake which is time dependent rather than a constant. This is in agreement with,
for example, Gibby & Hales (1983), Madsbad et al. (1983), and Horwitz et al. (1975).
It is planned to develop a specific package for the model, so that wider trials in
clinical settings may be carried out more simply.

Acknowledgement
Gratitude is expressed to the two referees for their constructive criticism of earlier
drafts of this paper.
This article is based upon a paper read at the Sixth IMA Conference on the
 A MATHEMATICAL MODEL OF INSULIN SECRETION 265

Mathematical Theory of the Dynamics of Biological Systems, held in Oxford, 1-3

July 1992.

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