148 IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, VOL. 46, NO.
2, FEBRUARY 1999
A Model-Based Algorithm for Blood
Glucose Control in Type I Diabetic Patients
Robert S. Parker, Francis J. Doyle, III,* and Nicholas A. Peppas
Abstract—A model-based predictive control algorithm is devel-
oped to maintain normoglycemia in the Type I diabetic patient
using a closed-loop insulin infusion pump. Utilizing compartmen-
tal modeling techniques, a fundamental model of the diabetic
patient is constructed. The resulting nineteenth-order nonlin-
ear pharmacokinetic–pharmacodynamic representation is used
in controller synthesis. Linear identification of an input–output
model from noisy patient data is performed by filtering the
impulse-response coefficients via projection onto the Laguerre
basis. A linear model predictive controller is developed using the
identified step response model. Controller performance for un-
measured disturbance rejection (50 g oral glucose tolerance test)
is examined. Glucose setpoint tracking performance is improved
by designing a second controller which substitutes a more detailed
internal model including state-estimation and a Kalman filter for
the input–output representation. The state-estimating controller
maintains glucose within 15 mg/dl of the setpoint in the presence
of measurement noise. Under noise-free conditions, the model-
based predictive controller using state estimation outperforms
an internal model controller from literature (49.4% reduction in
undershoot and 45.7% reduction in settling time). These results
demonstrate the potential use of predictive algorithms for blood
glucose control in an insulin infusion pump.
Index Terms—Compartmental modeling, diabetes, glucose, in-
fusion pumps, insulin, Kalman filter, model identification, model
predictive control, state estimation.
I. INTRODUCTION
D IABETES mellitus is characterized by the inability of
the pancreas to control blood glucose concentration.
Inadequate secretion of insulin by the diabetic pancreas results
in poor maintenance of normoglycemia (defined as blood
glucose 70–100 mg/dl) with elevated blood glucose con-
centrations, sometimes upward of 300 mg/dl. It is thought
that most of the long-term complications associated with
diabetes, such as nephropathy and retinopathy, result from
sustained hyperglycemia (arterial blood glucose 120 mg/dl).
The current treatment methods for insulin dependent dia-
betes, subcutaneous insulin injection or continuous infusion
of insulin, can result in significant, and sometimes frequent,
glucose concentration variation due to their inherently open-
loop nature. Consequently, it would be beneficial to develop
Manuscript received May 21, 1997; revised June 12, 1998. This work was
supported by the Showalter Trust and by the National Science Foundation
(NSF) under Grant CTS 9257059. Asterisk indicates corresponding author.
R. S. Parker is with the Department of Chemical Engineering, University
of Delaware, Newark, DE 19716 USA.
*F. J. Doyle, III, is with the Department of Chemical Engineering, Univer-
sity of Delaware, Newark, DE 19716 USA (e-mail: fdoyle@udel.edu).
N. A. Peppas is with the School of Chemical Engineering, Purdue Univer-
sity, West Lafayette, IN 47907-1283 USA.
Publisher Item Identifier S 0018-9294(99)00823-X.
0018–9294/99$10.00  1999 IEEE
a closed-loop device capable of maintaining normoglycemia
over extended periods of time.
A device of this type would contain three major compo-
nents: i) a mechanical pump; ii) an in vivo glucose sensor;
and iii) a mathematical algorithm to regulate the pump given
a sensor measurement. Extracorporeal and implantable insulin
pumps have been in service for over 15 yr [1], [2]. Initially
these devices had a single delivery rate, but technological
advances have allowed a wide variety of programmable and
variable-rate infusion pumps to be available currently [3]. Re-
search shows [4], [5] continuous infusion and programmable
pumps are effective for insulin therapy. By utilizing a variable-
rate pump in a closed-loop framework, further improvements
in glucose control and normalization of the glucose distribution
in the body are possible.
Current blood glucose monitoring is accomplished through
invasive methods, such as a finger prick, but use of a nonin-
vasive monitor would increase patient comfort and therefore,
compliance to the insulin therapy. An implantable glucose
concentration sensor would measure diabetic patient blood
glucose levels online and eliminate the patient from the
feedback loop. Significant work has been performed on the
development of an implantable glucose sensor [6]–[8], and
the duration of in vivo sensor reliability continues to increase.
A significant effort has been put forth toward the devel-
opment of a closed-loop algorithm for blood glucose control
[9]–[12]. These approaches have utilized almost exclusively
feedback control to maintain normoglycemia, even for the
purpose of disturbance rejection. This paper takes a different
approach, specifically the use of model-based predictive con-
trol (MPC). The unconstrained controller guarantees optimal
drug delivery through solution of an optimization problem at
each time step. A motivating factor for utilizing this strategy
is the success of MPC when applied to other biomedical
control problems, including blood pressure control [13], [14]
and anesthesia delivery [15], [16]. This controller architecture
is particularly well suited to the multivariable nature of these
systems, as well as the inherent constraints involved in the
respective control problems. To date, successful controller im-
plementation has been bedside in nature, due to the significant
computing power required for the calculations.
Computational power and speed aside, one benefit of using
predictive control in place of a classical control algorithm is
the estimation of future glucose behavior based on the past in-
sulin inputs, with measurement of the patient’s actual glucose
levels used as a feedback signal to correct the glucose concen-
tration predictions. As a result, the MPC controller takes action
for a predicted hypo- or hyperglycemic excursion well before
PARKER et al.: BLOOD GLUCOSE CONTROL IN TYPE I DIABETIC PATIENTS 149

it occurs, while a feedback-only controller responds after the

effect of the disturbance is manifested. Similar to the other
biomedical applications, the human glucose-insulin control
problem has inherent input rate and magnitude constraints
as well as an output magnitude constraint which MPC can
easily handle. The aforementioned feedback controllers require
special formulations to compensate for these same types of
constraints, and performance degradation can result. Hence,
the MPC controller algorithm exhibits a range of appropriate
characteristics for the blood glucose control problem.

II. STATE-SPACE PATIENT MODEL

A mathematical representation of the system is necessary to
implement a model-based control scheme. Many approaches
to modeling the human glucose-insulin system have been
taken [9], [17]–[19], starting from the initial glucose mod-
eling work of Bolie [20]. These methods can be divided
into semiempirical and fundamental methods. An empirical
approach attempts to capture the behavior of a system from
input–output data alone. Usually, a model structure is chosen
a priori, containing a certain number of parameters to be
identified. The linearized model studied by Ackerman et
al. [21] has this form. Imposing the linear structure, two
parameters for glucose effects (one for self-removal and one
for glucose effect on insulin) and two for insulin effects (one
for self-induced removal and a second for glucose removal
through insulin induced pathways) are identified to match the
model to data. Normally, individualized empirical parameters
are determined through a series of tests performed on each
patient. This is a time and resource consuming process. An
alternative model structure, which adds additional physiologic
detail, is the so called semiempirical or hybrid model. Such
a model incorporates physiologically based structure, such as
that derived in Cobelli et al. [9], where the insulin model
has equations representing dynamic behavior and kinetics. A
compartmental approach like that of Bergman et al. [17] can
be taken, such that a chosen number of compartments (in
this work, three) utilizing an arbitrary number of identifiable
parameters (in this work, six) fully describes the diabetic
patient. The structure results from subdividing the insulin
compartment into a plasma space and a compartment remote
to the plasma which affects glucose uptake. Finally, purely
fundamental models can be constructed. Nomura et al. [18]
examined the -cells of the pancreas in vitro and constructed
a fundamental model for their behavior from the insulin
release data. Fundamental models can also be generated by
mathematically representing known system behavior, such
as underlying kinetics or material transport, and identifying
parameters though an extensive literature search of available
data. This results in a model representing the average behavior
of the studied population.
In this paper a pharmacokinetic–pharmacodynamic ap-
proach to fundamental modeling is taken. The model of
the human glucose-insulin system used in this study results
from initial work by Guyton et al. [22] which was updated
by Sorensen [23]. Significant modification of this model to
include disturbances such as meals and exercise, as well as
Fig. 1. Compartmental diagram of the glucose or insulin system in a diabetic
patient.
parameters for uncertainty analysis, is ongoing work by the
current authors.
Utilizing compartmental modeling techniques, the diabetic
patient model is represented schematically in Fig. 1. Individual
compartment models are obtained by performing mass bal-
ances around tissues important to glucose or insulin dynamics.
Subcompartments, such as those in the brain and periphery,
are included where significant transport resistance (e.g., time
delay) exists. In this model, the periphery represents the com-
bined effects of muscle and adipose tissue while the stomach
and intestine effects are lumped into the gut compartment.
The controlled output for this system is the arterial glucose
concentration, which is regulated by the manipulated variable,
insulin infusion rate. A disturbance variable, glucose uptake
from the gut compartment, is added to the model to simulate
the diabetic patient ingesting a meal. The mathematical repre-
sentation of the meal submodel is described in Lehmann and
Deutsch [24].
III. INPUT–OUTPUT CONTROLLER MODEL
The linear model predictive controller utilizes an internal
model to estimate the future output values based on a series
of past inputs. The model form chosen for this work is the
linear step-response model. Assuming the system begins at
rest, the step-response coefficients, , represent the system
response to a unit increase in the input variable
(1)
150 IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, VOL. 46, NO. 2, FEBRUARY 1999
It is assumed that the system reaches a new steady-state after
sample times, where is known as the model memory. In
the case of the diabetic patient model, the system approaches
steady-state after 180 min (1.5% of total change remaining),
and the dynamic character of the response is completed.
The choice of a sample time, which determines memory
length, is a combination of three factors: model dynamics
and accuracy, complexity of the identification problem, and
equipment constraints. For an accurate model, the sampling
rate must be rapid enough to adequately capture the fastest
dynamics of the system. A heuristic bound is that the sampling
rate should be no slower than 20% of the fastest time constant.
The open-loop constant time of the diabetic patient model is
approximately 55 min, meaning a sample must be taken at
least once every 11 min. Fewer parameters make models easier
to identify. This suggests larger sample times, yielding fewer
step response coefficients and a less complex identification
problem. Finally, samples can be taken no faster than the
equipment can determine glucose concentration; this creates
a sampling rate lower bound. Researchers in the sensor field
report the ability to sample glucose every 4 min utilizing
an electrochemical biosensor [6]. To simplify the math, and
decrease the number of parameters, the chosen sample time is
5 min, and therefore the model memory, , is 180/5 36
sample times.
Assuming superposition, a linear approximation of the out-
put can be calculated given the past input profile
(2)
Here, the first term accounts for the response of the model
to the input change over the memory of the model, and the
latter term represents the steady-state of the process prior to
the input change. The predicted output value and input changes
are given by and , respectively. Step-response coefficients
are calculated from an identified impulse-response (IR) model
of the system by
(3)
(4)
where are the identified impulse response coefficients and
are the past inputs.
The structure of the impulse-response model in (3) is
similar to that of the first-order Wiener functional, . To
identify Wiener functionals, Gaussian white noise (GWN)
input sequences are typically used. However, identification of
a physical system model using GWN is unrealistic due to the
tremendous strain placed on the input regulator (e.g., pump or
valve). Lee and Schetzen [25] derive a cross-correlation for-
mula for computing Wiener kernels in the case of a Gaussian
white-noise input, which can be modified to account for non-
GWN inputs [26]. This method is mean squared error (MSE)
optimal, meaning that it minimizes the MSE between the actual
output and the predicted output. The non-GWN sequence used
for diabetic patient model identification is given by (5) and
can be treated as a special constant-switching-pace symmetric
random signal (CSRS)
with probability
with probability
with probability (5)
If the input is in deviation form, is the maximum symmetric
input deviation from its steady-state value, and is the
number of data points in the record. In the diabetic patient
model, the nominal insulin delivery rate is 22.33 mU/min
and the minimum delivery of insulin is 0 mU/min which
yields a value of 22.33 mU/min for . Accurate parameter
identification requires the pulses to be separated by at least
points, and that the second pulse is at least points from the
end of the data record. Based on the earlier choice of ,
the minimum number of data points required is . The
calculation using the modified Wiener functional method is
outlined next.
Using the special CSRS, the th-order discrete modified
functional form is given by
(6)
Here, is the modified Wiener functional and is the
order of the functionals used to estimate . Truncating after the
linear terms , can be described by the following
equations:
(7)
(8)
Therefore, in trying to identify the functionals from in-
put–output data, the following structure is utilized:
(9)
which can be restructured to yield
(10)
Equation (10) results from the knowledge that the zeroth-order
modified functional, , is the mean of .
Using this description of , the output data in deviation form
is given by . Note that (10) has a form
identical to that of (3). The impulse-response coefficients,
represented by the functional , are identified using the
aforementioned cross-correlation method, accounting for the
statistical properties of the input signal through division by
the second-order moment, [equivalent to the variance for
PARKER et al.: BLOOD GLUCOSE CONTROL IN TYPE I DIABETIC PATIENTS
the mean-zero process ]. Therefore, the impulse-response
coefficients are given by
(11)
Using this cross-correlation method, the developed coefficients
minimize the prediction error variance, ,
between the predicted and the measured output value.
Impulse response coefficients developed by minimizing
MSE are accurate if the output signal is noise-free. If the
output contains noise, as a signal from any biological system
would, performance of the identification algorithm degrades,
and the coefficients show significant noise effects. Filtering
provides a smoother set of coefficients which should im-
prove the quality of any prediction by reducing noise-induced
variations. The impulse-response coefficients are filtered by
projection onto the Laguerre basis, utilizing smooth Laguerre
functions to approximate the noisy coefficients. Expansion
of the Laguerre functions returns smoothed impulse-response
coefficients, which are an optimal estimate of the noise-
corrupted coefficients in the MSE sense [27].
In discrete time, the th-order Laguerre function is [28]
(12)
such that is the unit step function, for
. The Laguerre pole, denoted , , as the controller will be updated at 5 min intervals with
determines the rate of exponential asymptotic decay of the
Laguerre functions [29]. By comparing the actual model
impulse response to that generated by the Laguerre functions,
is chosen to minimize the residual error, and is set to 0.84.
The set is orthonormal in the interval , and is
complete in . Hence, the least-squares generated impulse-
response coefficients , satisfying
and can be represented in terms
of Laguerre functions as [27]
(13)
where is the number of Laguerre functions chosen to
describe the least-squares impulse-response coefficients, and
the Laguerre parameters, , are unknown. These Laguerre
coefficients are the least-squares solution to
(14)
Here, is the impulse-response co-
efficient vector, and is the Laguerre
function matrix. The smoothed impulse-response coefficients
are generated by substituting the calculated ’s into (13).
Fig. 2 shows the impulse-response coefficients identified using
least-squares and Laguerre projection. Although the Laguerre
generated coefficients have a decreased gain, they are not
corrupted by the noise present on the measurement signal
151
Fig. 2. Impulse response models relating glucose concentration (output) to
insulin delivery rate (input); identification by linear least-squares (solid) and
Laguerre projection (dashed) compared with the noise-free impulse response
coefficients of the nonlinear model (dash-dot).
(variance 1.45 mg/dl) which affects the least-squares derived
coefficients.
A random binary sequence (RBS) is driven through the
identified model and the full nonlinear model for validation
purposes, and the results are shown in Fig. 3. Clearly, the
identified model does not include all of the gain information of
the diabetic patient model, but it does succeed in capturing the
dynamic behavior. This second component is more important,
new information, making the dynamic component significantly
more important in the control computation than the steady-
state behavior [30]. This same RBS produces much poorer
output when run using the least-squares identified parameters
(output not shown). By comparison, the sum of residuals from
the Laguerre coefficient validation is 12.1 mg/dl, while that
for the least-squares validation is 35.4 mg/dl.
IV. LINEAR MODEL PREDICTIVE CONTROL
A linear MPC algorithm is now constructed to control blood
glucose concentration based on arterial glucose sampling and
intravenous insulin delivery. The optimization problem solved
by MPC is given by
(15)
The goal is to minimize the error in setpoint tracking and the
manipulated input movement, respectively, over the sequence
of future input moves, . Here, is the
vector of future reference values while is the
vector of predicted future glucose concentrations. Vectors use
the standard statistical notation of predicting a value at time
given information up to time . Weighting matrices
for the setpoint tracking penalty and insulin move penalty
are given by and , respectively. These two matrices
can be used as tuning parameters for the controller, trading
off output performance, and manipulated variable movement.
152 IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, VOL. 46, NO. 2, FEBRUARY 1999
Fig. 3. Validation of the input–output model using a random binary se-
quence. Top: comparison of the actual nonlinear diabetic patient model ()
with the predicted output (+). Middle: residuals between the Volterra–Laguerre
model and the actual nonlinear model for the forcing sequence. Bottom: ran-
dom binary sequence used to validate the Laguerre derived impulse-response
model.
Additionally, the input move penalty serves to regulate the
magnitude of noise-induced manipulated variable movement.
When there is no noise in the diabetic patient simulation
is set equal to zero, while is used when band-limited
white noise (variance 1.45 mg/dl) corrupts the output signal.
It is straightforward to show that an analytical solution to the
unconstrained problem can be constructed [31]. One merely
calculates , the difference between the vector of
predicted future glucose concentrations from past inputs and
the vector of future reference values. The analytical solution
involves a multiplication of by , where
is given by
(16)
Here, the leading vector results from implementing only the
first calculated move for . This structure demonstrates
the ease of implementing linear MPC. Since the gain matrix
can be precalculated, the on-line computation reduces to a
simple multiplication. Therefore, the calculation could be
performed without the need for a high-powered computer, and
instead on a single digital chip, allowing for straightforward
implementation in a microprocessor-based pump.
However, the analytical solution can not be implemented
without accounting for the constraints present in the system.
An input rate constraint, , guarantees the pump does
not undergo changes in insulin delivery rate that are greater
than the mechanism can handle. As such, a rate constraint that
is conservative with respect to pump dynamics shown in the
literature [3], and can span the full range of insulin delivery
rates in a maximum of four moves is chosen. The maximum
change in insulin delivery rate is given by
mU/min per sample time (17)
Physiological conditions imply a magnitude constraint which
must be applied to the insulin delivery rate. The plasma insulin
concentration in the healthy patient is rarely above 100 mU/l.
Since the goal is to return the diabetic patient to as normal a
state as possible, the maximum insulin delivery rate from the
pump should not result in a plasma insulin concentration in
excess of 100 mU/l. Additionally, it is impossible to remove
insulin once it has been delivered to the patient. Therefore, the
input magnitude is constrained as follows:
mU/min mU/min (18)
This constraint, as well as the input rate constraint in (17),
are implemented by clipping the rate and magnitude of the
calculated pump action.
Low blood glucose concentrations in the diabetic patient
are dangerous and starve the cells of fuel. Therefore, an
appropriate output constraint is given by
mg/dl (19)
However, the inclusion of hard output constraints in the
problem statement can lead to infeasible programming prob-
lems, and will require more computational power than can
be delivered on a digital chip, given current technology. An
alternative is to include the output constraint in a “soft”
form, by adding another term to the objective function [32].
This would modify the analytic solution to the unconstrained
problem, and solution of a nonlinear programming problem
may be required depending on the formulation of the added
term. To avoid the potential problems with including an
output constraint, it is treated through careful selection of
the controller tuning weights to yield the soft constraint
formulation
subject to: mU/min mU/min
mU/min per sample time
mg/dl checked (20)
Tuning this controller is an ad hoc procedure, using the two
available parameters: , the move horizon, and , the predic-
tion horizon. These parameters are determined by performing
a two-dimensional search over and , while subjecting the
diabetic patient to an unmeasured meal disturbance with no
measurement noise. The criterion used to evaluate performance
is sum of squared error (SSE) over the time-course of the
simulation, providing the output tracks the reference. The
controller settings minimizing SSE over the simulation length
while eliminating output oscillations are , ,
, and .
Using the SSE optimal tuning parameters as a starting
point, the controller is detuned to accommodate a measurement
signal with noise of variance 1.45 mg/dl. This detuning is
necessary due to violation of the glucose concentration lower
bound in response to a 50 g OGTT. Increasing the prediction
horizon to ten successfully detunes the controller yielding
satisfactory performance. In order to reduce the chatter in the
manipulated input signal, the weighting matrices, and ,
PARKER et al.: BLOOD GLUCOSE CONTROL IN TYPE I DIABETIC PATIENTS
are adjusted until the constraints are satisfied and chatter in
the manipulated input is reduced.
V. MPC WITH STATE ESTIMATION
Model predictive control with state estimation, MPC/SE, has
several advantages over standard MPC. The increased amount
of information provided to the controller yields tighter control,
and additional tuning parameters (a Kalman filter and the
reference filter) are included to adjust closed-loop performance
[33].
The internal model structure in MPC/SE is changed from
the input–output form of (2) to the linear state-space form
(21)
(22)
This model is constructed from the continuous nonlinear
diabetic patient model discussed in Section II in two steps,
the latter using commands from the MPC toolbox. First, the
nonlinear model is linearized analytically to yield a linear
continuous-time model of the diabetic patient. Then, the con-
tinuous linear model is converted to a discrete-time minimum-
phase representation for use in simulation, yielding , , and
.
Using the internal model of (21) and (22), the controller
can estimate the state of the plant and the output using the
following equations:
(23)
(24)
The Kalman filter, , has several practical applications in
the MPC/SE algorithm developed in this paper. By updat-
ing the internal controller model with current measurement
information using the Kalman filter, mismatch between the
actual patient and the internal controller model is significantly
reduced. Therefore, the predictions using the updated model
are more accurate than those of the static input–output model.
The Kalman filter can also be tuned to infer an unmeasured
disturbance value so that the controller takes appropriate
action to counteract the detected disturbance. Noise filtering
is achieved by adjusting the Kalman filter gain based on the
reliability of the measurement signal, which reduces noise
induced manipulated input movement. The tradeoff between
disturbance inference and noise filtering will be addressed
below.
Kalman filter design is accomplished using the discrete
linear system model and the known noise characteristics of
disturbances [33]. This formulation of the MPC/SE algorithm
utilizes the steady-state Kalman filter, , which is calculated
iteratively off-line, to minimize controller algorithm computa-
tion requirements as
(25)
(26)
153
Here, and are from (21) and (22), above. Tuning the
Kalman filter is accomplished using the matrices , ,
and [33]. The initial state covariance matrix,
, is the expected value of the
square of the initial deviation between the actual state and the
best linear estimate of that state. The matrix is cho-
sen to represent an initial uncertainty of 1 mg/dl in the glucose
concentrations or 1 mU/l in the insulin concentrations, and
satisfies the requirement . The measurement noise
covariance matrix, , is dependent on the statistics of the
measurement noise. When incorporated, band-limited white
noise with power 0.1, gain 0.85 mg/dl, and sample time
equal to 0.05 min, corrupts the glucose measurement signal.
These noise characteristics define a nearly white sequence with
mean 0 mg/dl, and maximum deviation of 5 mg/dl yielding
. The third parameter of the steady-state Kalman
filter is , the process noise covariance matrix.
From the mathematically rigorous derivation of the discrete
time Kalman filter, the matrix is constructed using the
available knowledge of the unmeasured disturbances. These
disturbances are assumed to be random, with zero mean and
known covariance, and quasi-stationary. However, inaccuracy
introduced by the model (through plant-model mismatch)
and unknown disturbance characteristics force a change in
formulating . It is utilized as a tunable parameter, which
is adjusted until output performance is satisfactory. The in-
dividual matrix entries are varied on an element by element
basis, under the assumption that the process noise is diagonal,
as off-diagonal components lack a physical basis. Excellent
performance in the noise-free case results from combining two
effects. First, the elements of are weighted according to
relative importance in detecting a glucose meal disturbance.
The glucose states (1–8) will vary more significantly than
the insulin, glucagon, or auxiliary equation states, hence
larger weights are used for those elements. Knowledge of the
mismatch between the linear internal model and the actual
nonlinear model of the diabetic patient is also accounted
for. The linear controller estimates of the first 17 states are
very close to the actual output of the nonlinear model, but
the glucagon states showed significant deviation between the
estimates and the actual values. Therefore, the weighting in
the matrix is increased for these two elements, resulting in
diag (27)
where is an -length vector of ones.
The approach used here for controller development is sim-
ilar to that of Ricker [34] for MPC with state estimation.
Constraints identical to those of the linear MPC algorithm,
(17)–(19), are enforced by clipping the manipulated input
and checking the output constraint a posteriori. The objective
function is modified due to the existence of reference model
dynamics, which adjust the reference value based on the
desired closed-loop performance for the system. The math-
ematical derivation can be found in [34]. It is worth noting
that the unconstrained version of the state-estimating MPC
algorithm also admits a convenient analytical solution which
can be easily implemented on a digital chip.
154 IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, VOL. 46, NO. 2, FEBRUARY 1999

The problem now reduces to tuning the controller. A three-

dimensional (3-D) search is performed over , , and the
reference filter , such that sum-squared error is minimized,
and the constraints are satisfied. By utilizing the Kalman filter
in the controller, a more aggressive formulation with
and is possible, taking . To account for
measurement noise, the controller is detuned by increasing the
prediction horizon to as well as retuning the matrix
such that all weights are less than 1.0, yielding

diag (28)

VI. NONLINEAR QUADRATIC DYNAMIC

MATRIX CONTROL WITH STATE ESTIMATION
An alternate control methodology which takes greater ad-
vantage of the nonlinear model of the diabetic patient is
nonlinear quadratic dynamic matrix control with state esti-
mation (NLQDMC/SE). This is a logical extension of linear
MPC with state estimation, with compensation for the known
nonlinearity of the controlled process, as explained in Gattu
and Zafiriou [35]. These changes include the use of the
nonlinear model by the controller and updating of the linear
model based on the current operating point.
When calculating the effects of the past inputs on the output
prediction in NLQDMC/SE, the nonlinear model is used in
place of the linear discrete model. This yields a more accurate
prediction of future behavior since the nonlinearity is included.
In solving the optimization problem, the effect of future insulin
delivery rates on future glucose behavior is determined using
the linear model, as in linear MPC/SE, thereby requiring the
solution of only one quadratic programming problem online
[36]. The sum of the nonlinear and linear effects is then used
to calculate the vector of future input moves necessary to drive
the system to track the reference value.
NLQDMC/SE takes advantage of the nonlinear model once
more during the controller computation sequence. The estima-
tion of the future plant states given the current information,
including the newly calculated insulin delivery rate, is accom-
plished through integration of the nonlinear model updated by
. disturbance rejection simulation results.
the correction term,
A 3-D search over the move horizon , the prediction
horizon , and the reference filter is performed to tune
the controller. The criterion is to minimize the sum-squared
error over the time course of the simulation. Under noise-free
conditions, the resulting parameters are , , and
. Similar to MPC/SE, the weighting matrix values
are and . Simulation results are compared to
those of the other controllers in Section VII.
VII. RESULTS AND DISCUSSION
A blood glucose controller will be expected to operate in
the presence of measurement noise, and the ability of the
aforementioned linear algorithms to reject a simulated meal
disturbance is shown in Fig. 4. The minimum arterial glucose
concentration during postprandial hypoglycemia under linear
MPC is 65.6 mg/dl, which is only slightly above the output
constraint of 60 mg/dl. The maximum glucose concentration
Fig. 4. Response of the initially controlled diabetic patient to a 50 g OGTT
administered at time = 50 min, with measurement noise of variance = 1.45.
Solid: linear MPC controller with parameters m p
= 2, = 10, 0y = 3, and
m
0u = 1. Dashed: linear MPC/SE controller with parameters = 2, = 8, p
0y = 1, and 0u = 1.
resulting from the OGTT is 95.5 mg/dl which lies well
within the normoglycemic range. Superior performance can be
achieved using MPC/SE, where the postprandial hypoglycemia
reaches 68.5 mg/dl. This represents a 19% decrease in under-
shoot from the 81-mg/dl reference when compared to linear
MPC.
Simulation study results are promising for both the lin-
ear MPC and MPC/SE algorithms. To provide a basis for
comparison, the internal model controller (IMC) controller
employed by Sorensen [23] is considered. The nonlinear
model in Section II is approximated by a first-order plus
time-delay (FOTD) transfer function, and the IMC controller
is designed from the linear approximation. For simulation
using the MATLAB/SIMULINK environment, this controller
is implemented in a discrete framework for comparison against
the inherently discrete MPC formulations. Fig. 5 shows the
The IMC algorithm shows superior performance to the
linear MPC algorithm for undershoot (11% decrease) but is in-
ferior in terms of settling time (9% increase). These controllers
are comparable for the noise-free case, but are both inferior
to the more advanced algorithms. The increased information
available to the MPC/SE algorithm, in combination with the
Kalman filter, yields greater than 40% performance improve-
ment in both undershoot and settling time. In a comparison
of the state-estimating algorithms, the nonlinear controller
(NLQDMC/SE) offers 18% less undershoot with a nearly
negligible (6%) increase in settling time when compared to
the linear state-estimating controller. Tabulated results can be
found in Table I. Clearly, the utilization of state-estimation
combined with a more detailed controller model provide
significant performance improvement.
There are important aspects of the problem other than
controller algorithm selection that need to be addressed. One is
time delay in the sensor measurement. The assumption to this
PARKER et al.: BLOOD GLUCOSE CONTROL IN TYPE I DIABETIC PATIENTS 155

Fig. 5. Disturbance rejection comparison of four controllers with no mea-
surement noise for a 50 g OGTT: 1) linear MPC (solid) (m = 2, p = 8,
0y = 1, and 0u = 0), 2) MPC/SE (dashed) (m = 2, p = 7, 8r = 0:65,
0y = 1, and 0u = 0), 3) NLQDMC/SE (dotted) (m = 2, p = 5, 8r = 0:57,
0y = 1, and 0u = 0), and 4) Discrete IMC (dash-dot).
Fig. 6. Disturbance rejection using the linear MPC controller (m = 2,
p = 10, 0y = 3, and 0u = 1). Comparison of unknown measurement
dead times. No dead time (solid, for reference), 5 min dead time (dashed),
10 min dead time (dash-dot), and 15 min dead time (dotted). Feedback signal
contains noise with variance = 1.45. Top: Noise-free glucose concentration
data. Bottom: Insulin delivery rate.

TABLE I
DISTURBANCE REJECTION RESULTS
TABLE II
Undershoot Settling Time TIME-DELAY DISTURBANCE REJECTION RESULTS. AN M AFTER THE NUMBER
Controller DENOTES THE INTERNAL MODEL INCLUDES DELAY (KNOWN DELAY). VARIANCE
(mg/dl) (min)
= 1.45 mg/dl MEASUREMENT NOISE PRESENT ON OUTPUT SIGNAL
IMC w/filter 8.7 376
linear MPC 9.7 343 Time Settling Constraint
Undershoot
Delay Time Equations
MPC/SE 4.4 204 (ml/dl)
(min) (min) (17)-(19)
NLQDMC/SE 3.6 216
0 15.4 315 Reference
5 17.7 316 Satisfied
5M 18.8 358 Satisfied
point has been that an accurate measurement of the arterial glu- MPC 10 21.1 327 Satisfied
cose concentration is instantaneously available at each sample 10 M 21.9 378 Violated
15 39.0 551 + Violated
time. Existence of delay in a system has a destabilizing effect,
15 M 25.1 364 Violated
and large enough delays result in unstable closed-loop systems.
In addition, measurement delay causes a loss in performance. 0 12.5 262 Reference
To determine the degree of performance loss, the linear MPC 5 15.3 494 Satisfied
and MPC/SE controllers are subjected to measurement delays 5M 15.7 551 + Satisfied
MPC/SE 10 24.8 551 + Violated
of 5, 10, and 15 min. Two cases are analyzed: i) unknown 10 M 17.6 551 + Satisfied
measurement delay, where the delay is not accounted for in 15 29.7 551 + Violated
the internal model and ii) known measurement delay. For the 15 M 25.6 536 Violated
latter case, a new internal model is identified for each increase
in time delay. A typical result for unknown delay is shown
in Fig. 6. The MPC controller without state estimation utilizes
a model identified from input–output data, while the state- of 15 min has a destabilizing effect, inducing sustained os-
estimating controller is adjusted by placing rows of zeros in cillation in most controllers (except for a known delay in the
the step response matrix, such that a row of zeros is added for linear MPC controller, plot not shown). In addition, each of
each sample time of delay. For either controller and known the simulations with 15-min measurement delay resulted in
measurement delay, the prediction horizon is increased by violation of the glucose lower bound. Hence, it is necessary
the number of sample times of delay in the measurement (e.g., to keep the measurement delay less than or equal to 10 min
time delay sample time rounded to the next positive integer). (as described in Table II).
All results are tabulated in Table II.
Clearly, small dead times ( 5 min) do not significantly
affect performance, as only slight degradation occurs (a max- VIII. CONCLUSIONS
imum of 21% increase in undershoot). Both controllers main- Model-based predictive control of insulin infusion pumps
tain glucose concentration well above the constraint of 60 requires development of an accurate model of the human
mg/dl in this case. As described earlier, the large dead time glucose-insulin system and design of a constrained controller.
156 IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, VOL. 46, NO. 2, FEBRUARY 1999
A nonlinear model of the diabetic patient is developed us-
ing compartmental modeling theory and literature data. A
novel identification algorithm is applied to develop a linear
input–output representation of the nonlinear system in the
presence of measurement noise. Model-based predictive al-
gorithms for insulin infusion pump control are developed. The
constraint handling and prediction capabilities of MPC provide
an excellent framework for the glucose control problem. Linear
MPC is sufficient for controlling blood glucose, but results in
glucose concentrations near the output lower bound. Linear
MPC with state estimation, utilizing a Kalman filter and a
more accurate internal model, yields improved control when
compared to the linear MPC scheme and a discretized IMC
controller from literature. Additionally, the digital nature of
these control algorithms allows potential implementation onto
chip technology when sensors can guarantee long in vivo
lifetimes.
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Robert S. Parker was born in Rochester, NY, in 1972. He received the B.S.
degree in chemical engineering from the University of Rochester, Rochester,
NY, in 1994, and began Ph.D. research in chemical engineering at Purdue
University, West Lafayette, IN, in the fall of that year under Prof. F. J. Doyle,
III, and Prof. N. A. Peppas. In September 1997, he moved with Prof. Doyle
to the University of Delaware to complete the doctoral degree.
His research focuses on model-based control of biomedical and biological
systems.
PARKER et al.: BLOOD GLUCOSE CONTROL IN TYPE I DIABETIC PATIENTS
Francis J. Doyle, III, was born in Philadelphia, PA, in 1963. He received the
B.S.E. degree from Princeton University, Princeton, NJ, in 1985, the C.P.G.S.
degree from Cambridge University, Cambridge, U.K., in 1986, and the Ph.D.
degree from the California Institute of Technology, Pasadena, in 1991, all in
chemical engineering.
From 1991–1992, he was a Visiting Scientist in the strategic process
technology group at the DuPont Company, Wilmington, DE. From 1992–1997,
he was an Assistant and Associate Professor at the School of Chemical
Engineering at Purdue University, West Lafayette, IN. Since 1997, he has
been an Associate Professor at the Department of Chemical Engineering at
the University of Delaware, Newark. His research interests include nonlinear
dynamics and control with applications in process and biosystems control,
nonlinear model reduction, and the reverse engineering of biological control
systems.
Dr. Doyle received the National Young Investigator Award from the
National Science Foundation in 1992, an Office of Naval Research Young
Investigator Award in 1996, an ASEE Section Outstanding Teacher Award in
1996, and a Tau Beta Pi Section Teaching Award in 1996.
157
Nicholas A. Peppas received the Dipl.Eng. degree in chemical engineering
at the National Technical University of Athens, Greece, in 1971 and the
Sc.D., degree at the Massachusetts Institute of Technology in 1973. He did
postdoctoral research at the Arteriosclerosis Center of MIT.
He is the Showalter Distinguished Professor of Chemical and Biomedical
Engineering in the School of Chemical Engineering of Purdue University,
West Lafayette, IN. He joined Purdue as an Assistant Professor in 1976 and
was promoted to Associate Professor in 1978 and Professor in 1982. His
research contributions have been in several areas of polymers and biomedical
engineering, especially in controlled delivery of drugs, peptides and proteins,
development of novel biomaterials, biomedical transport phenomena, and
biointerfacial problems.
Dr. Peppas has been recognized by various awards including the 1995 APV-
International Pharmaceutical Technology Medal, the 1994 Pharmaceutical and
Bioengineering Award of AIChE, and the 1988 Curtis McGraw Award of
ASEE for best engineering research under the age of 40. He is a founding
Fellow of the American Institute of Medical and Biological Engineering, a
Fellow of the American Physical Society, a Fellow of the Society for Bioma-
terials, a fellow of the American Association of Pharmaceutical Scientists, and
an honorary member of the Italian Society of Medicine and Natural Sciences.