1027176

research-article2021
JAO0010.1177/03913988211027176The International Journal of Artificial OrgansCocha et al.

IJAO The International

Journal of Artificial
Organs
Original research article

The International Journal of Artificial

An algorithm mimicking pancreas

Organs
1­–9
© The Author(s) 2021
pulsatile behavior improves Article reuse guidelines:
sagepub.com/journals-permissions

artificial pancreas performance https://doi.org/10.1177/03913988211027176

DOI: 10.1177/03913988211027176
journals.sagepub.com/home/jao

Guillermo Cocha1, Victor Tedesco2,

Carlos D’Attellis2 and Carlos Amorena2,3

Abstract
Background: Artificial pancreas design using subcutaneous insulin infusion without pre-meal feed-forward boluses
often induces an over-response leading to hypoglycemia due to the increase of blood insulin concentration sustained in
time. The objective of this work was to create an algorithm for controlling the function of insulin pumps in closed-loop
systems to improve blood glucose management in type 1 diabetic patients by mimicking the pulsatile behaviour of the
pancreas.
Methods: A controller tuned in a pulsatile way promotes damped oscillations of blood insulin concentration injected
through an insulin pump. We tested it in a simulated environment, using nine ‘in silica’ subjects. The control algorithm
is founded on feedback linearization where through a change of variables, the nonlinear system turns into an equivalent
linear system, suitable for implementing through a PID controller. We compared the results obtained ‘in silica’ with the
volume injected by an insulin pump controlled by this algorithm.
Results: The use of this algorithm resulted in a pulsatile control of postprandial blood glucose concentration, avoiding
hypoglycaemic episodes. The results obtained ‘in silica’ were replicated in a real pump ‘in vitro’.
Conclusions: With this proposed linear system, an appropriate control input can be designed. The controller works
with a damped pulsatile pattern making the insulin infusion from the pump and blood insulin concentration pulsatile. This
operational would improve the performance of an artificial pancreas.

Keywords
Bergman minimal model, artificial pancreas, type 1 diabetes, control algorithm, closed-loop control

Date received: 8 March 2021; accepted: 3 June 2021

Introduction can deliver a continuous basal rate and programmed pre-

Type 1 diabetes is produced by an auto-immune condition,
with the destruction of β cells. As Diabetes Control and
Complications Trial concluded, maintenance of blood glu-
cose concentration between 4 and 8 mmol/L avoids dia-
betic complications, such as retinopathy, kidney damage,
heart diseases, stroke, and neuropathy.1 To overcome these
harms, people with type 1 diabetes are treated with ther-
apy, involving multiple daily injections of insulin.2
This therapy can be highly improved using continuous
subcutaneous insulin infusion pumps (CSIIP) with real-
time continuous glucose monitoring (CGM). This approach
provides information about the magnitude, duration, and
frequency of glucose fluctuations, offering efficient con-
trol throughout the day.3 CSIIP are reliable devices that
prandial bolus of insulin.4 In any case, it requires a strong
patient engagement to input information on carbohydrate
intake and mealtime boluses. Although CSIIP and CGM
are cost-effective technologies, psychosocial and educa-
tional factors limit their broad adoption.5 The development
1
 ODAPLI, Departamento de Ingenieria Eléctrica, UTN FRLP, La Plata,
C
Buenos Aires, Argentina
2
ECyT, UNSAM, San Martin, Buenos Aires, Argentina
3
CONICET National Research Council, Buenos Aires, Argentina
Corresponding author:
Carlos Amorena, ECyT, UNSAM, 25 de Mayo y Francia, San Martin,
Buenos Aires 1650, Argentina.
Email: camorena@unsam.edu.ar
2 The International Journal of Artificial Organs 00(0)
of efficient software algorithms would make these devices
more independent from the user, and it will help to over-
come these disadvantages. Such devices include a CSIIP, a
CGM, and a software algorithm for the automatic determi-
nation of insulin dose. In a closed-loop fashion, mimicking
a biological pancreas is the most promissory tool to pre-
vent further complications triggered by diabetes.6
Nevertheless, several aspects of security must be consid-
ered, particularly hypoglycaemic events.7,8 In 2016, a
device got FDA approval, but it still requires user instruc-
tions for food intake compensation.9 This device, like
many others in development, uses the subcutaneous route
for providing insulin. After a meal, blood glucose should
be bringing back to basal values within 50–90 min. In
usual operation, the controller ‘reads’ the blood glucose
and it delivers an amount of insulin enough to bring glu-
cose back to the basal value. If the physiological parame-
ters, for instance, metabolic demands, change from their
calibration values, the controller could turn dysfunctional,
resulting in an incorrect blood insulin concentration. This
is particularly relevant in a group of diabetics that have a
severely unstable form of diabetes called labile or brittle
diabetes.10 Despite intensive insulin therapy these patients
do not reach adequate blood glucose control and have fre-
quent hypoglycaemic episodes.
Blood glucose concentration is a function of the rate of
glucose entering the circulation balanced by the rate of glu-
cose removal from it. From the point of view of control,
glycaemia dynamics can be considered as a nonlinear sys-
tem. In nonlinear systems, the controller action that pro-
duces the accurate response at one operating point might
not produce a satisfactory response at another different
operating point. Because of this nonlinear feature, it is rela-
tively easy to reduce glucose values when are high, but it
takes proportionally more insulin if glucose is low. This is
a consequence of insulin saturation effects.11,12 Another
aspect of nonlinear characteristics of the glucose regulatory
system is that the insulin action profile differs from person
to person and, even in the same person, along the day.
Variable rates of absorption, glucose consumption due to
physical activity, stress, and so on, will lead to variable and
unpredictable peaks in insulin action and could cause unex-
pected both hypoglycaemic or hyperglycaemic events.12
We developed an algorithm for controlling an artificial
pancreas to deal with those above-mentioned aspects
resulting from the particular nonlinear glucose-insulin
dynamics behaviour. Particularly with the harmful effect
of hypoglycaemic events, which are a dangerous by-prod-
uct of the artificial pancreas design. By developing this
algorithm, we intended to improve the functioning of an
artificial pancreas, under the assumption that mimicking
the pulsatile behaviour of the natural pancreas would result
in improved performance of the device. The algorithm
relies on feedback linearization, a technique designed to
find appropriate compensations that make a given nonlin-
ear system behave linearly.
For testing the algorithm performance in the control of
a real insulin pump, we build a simple insulin pump with a
controller governed by this algorithm. The rate of insulin
delivery changes according to different loads of glucose
given to an ‘in silica’ individual. We simulate blood glu-
cose values through a computer and compared the meas-
ured output of the pump with the simulation obtained with
the ‘silica model’. We understand that the validation of the
algorithm using a real device strengthens its applicability.
Methods
Mathematical model
Mathematically, a set of first-order nonlinear differential
equations in a space state domain describes the insulin-
glucose dynamic system. The present algorithm is based
on the Bergman Minimal Model (BMM), a compartmental
physiological model used for developing several control
algorithms.13–18
The Bergman Minimal Model (BMM) is a compart-
mental mathematical model, initially designed for the esti-
mation of pancreatic responsiveness and insulin sensitivity,
that satisfies this requirement.
This model was modified for representing a type 1 dia-
betic. It includes three state variables and describes their
behavior. The model also assumes that insulin (u) is
infused exogenously, therefore modeling an insulin-
dependent diabetic patient. The injected insulin is distrib-
uted into the circulatory system (x3) and reaches the
interstitial tissue. The remote insulin effect (x2) promotes
the uptake of glucose (x1) into the hepatic and extrahepatic
tissues acting like the inverse of a putative impedance to
glucose transfer across the plasma membranes of insulin-
sensitive cells (representing the insulin sensitivity).
Bergman minimal model equations (*)I
x1 = − P1 x1 − x 2( x1 + Gb ) + D ( t ) (1)
x 2 = − P2 x 2 + P3 x3 (2)
u (t )
x 3 = − n ( x3 + I b ) + (3)
V
where:
x1 = basal value of blood glucose concentration
x2 = insulin action on hepatic glucose and periphery tar-
get tissues
x3 = insulin concentration
P1 = rate of glucose uptake from the extracellular space,
independently of the influence of insulin [1/min].
P2 = fractional rate of insulin appearance in the active
compartment;
P3  = fractional removal of insulin from active
compartment;
Gb = basal blood glucose concentration
Cocha et al. 3

Ib = basal blood insulin concentration. Table 1.  Sets of parameters obtained from Neatpisarnvanit
u(t) = infusion of external insulin. and Boston.24
n = rate constant that represents clearance of extracel- Subject# p1 [1/min] p2 [1/min] p3[(min)-1  n [1/min]
lular insulin. (µU/ml)-1]
t = time.
V = extracellular volume (12 L). 1 2.27E-02 2.65E-02 1.20E-05 2.40E-01
D(t) = meal disturbance 2 5.87E-02 1.30E-02 6.58E-06 1.82E-01
3 3.32E-04 2.85E-01 5.09E-06 1.92E-01
As equations (1), (2), and (3) show, BMM is a nonlinear
4 2.85E-07 1.78E-01 6.43E-05 1.51E-01
system.
5 6.38E-02 1.18E-02 4.23E-06 2.00E-01
6 2.00E-03 9.53E-02 3.48E-05 2.42E-01
Feedback linearization based control 7 2.47E-03 1.00E-01 1.47E-05 1.26E-01
8 1.38E-02 3.45E-01 3.74E-04 1.64E-01
Bergman Minimal Model (BMM) is nonlinear and allows 9 8.66E-02 2.02E-02 2.63E-05 3.14E-01
exact linearization.19,20 Nonlinear differential geometric
control is a theory developed in the 1980s for dealing with Values of cases 4 and 5 are from obese people. The numbers eight and
nonlinear systems using the know-how and experience nine were dogs.
obtained with linear systems. In feedback linearization
(FL), a change of coordinates eliminates the nonlinearities
de ( t )
of the process, and it lets find suitable compensations mak- D = kD (7)
ing a given nonlinear system behave like a linear one. The dt
nonlinear change of coordinates allows us to see the origi-
Where k C , k I and k D are the gains.
nal nonlinear system as a linear one and the nonlinear
The validity of FL theory depends on the supposition
observer permits the reconstruction of the non-measurable
that the model represents exactly an actual system.
variables. After the change of coordinates, the system per-
Sensitivity to parameter variability makes it susceptible to
forms like a linear one, and the linear control theory is
lose the exact cancellation of nonlinearities resulting in a
applicable. Thus, the nonlinear transformation allows us
less robust control technique. That is why currently, this
for looking at the system as a linear and controllable one.
technique does not suit well for biological control pur-
Thus, a linear closed-loop controller can be imple-
poses. In this work, the robustness of the feedback lineari-
mented on the augmented system using blood glucose as
zation control strategy is achieved by the pulsatile
the feedback variable and insulin as the acting variable.
behaviour of the PID component. It is obtained via the
(For further details see Appendix)
transient dumped pulsatile of insulin supply.

PID control
The mechanical device
Linear controllers such as PID, an acronym for the math-
The mathematical model used for the simulation in silica
ematical terms Proportional, Integral, and Derivative, can-
was adapted for its use on a PC. Case # 4 (Table 1) was
not deal appropriately with nonlinear systems behavior
picked up for the assay and, from it, the data for simulation
and, in the case of blood glucose control, it requires an
was collected. The arrangement of the prototype consisted
additional pre-meal bolus of insulin.21
of four blocks: first, the oscillatory control; second, the
The PID controller is the most used algorithm in pro-
simulated experimental case; third, the collection of input
cess control. The output of the PID algorithm is the insu-
and output data (data-logger); and fourth, the transfer of
lin delivery rate as a function of the deviation of
data and analysis. A scheme of the implemented device is
measured blood glucose from its desired set-points. This
shown in Figure 1.
deviation or difference is the error e(t). Equation of PID
For transferring commands, a UART port of the com-
is given by
puter was used to drive the controller by a serial device
USB-UART converter CP2102. The data sent and magni-
1
t
de ( t )
v ( t ) = kce ( t ) + ∫ e ( t ) dt + k D (4) tude and signs respected.
ki 0 dt

Where: Hardware
P = k c e ( t ) (5) The speed of the insulin volume to inject is low in compari-
son with the processing speed of a standard microcontroller.
t The used board (Mbed LC1768) has a processing velocity
1
e ( t ) dt (6)
k I ∫0
I= of 100 MHz, enough for the present development and the
library Mbed OS V5 facilitates the control of the motor for
4 The International Journal of Artificial Organs 00(0)
Figure 1.  Scheme of the arrangement of the insulin pump for
testing the proposed pulsatile algorithm.
UART: universal asynchronous receiver-transmitter; PWM: Pulse Width
Modulation; Balance: analytical balance (210 g × 0.1 mg).
PWM and the communication, allowing the subject simula-
tion by a computer and obtaining the values of the injected
volume. The conversion from rotational to a linear dis-
placement was implemented through a threaded motor
shaft, with a pitch of 1 mm per revolution. We use a small
motor (Mini Metal Gear Motor GA12-N20) weighing 10 g
with high torque and low revolutions (100 RPM min).
We evaluate the response of the mechanical pump by
gravimetric procedures. Thus, the volume of liquid injected
by the pump is proportional to the amount of insulin car-
ried by the device, and it will depend on insulin concentra-
tion in the solution, which in the test conditions of this
model can be arbitrarily varied. The whole system consists
of a virtual glucose sensor, a controller that executes the
instructions of the algorithm and drives the rate of the
pump and the insulin pump.
We measured the response of the mechanical prototype,
that is, the volume injected by the syringe under different
conditions, and compared it with the Simulink® response,
obtained ‘in silica’.
Results
The model consists of glucose and insulin subsystems,
where insulin in the plasma enters a remote compartment
where it exerts its action. The pulsatile activity of the insu-
lin pump promotes pulsatile behaviour in blood insulin.
The pump’s pulsatile mode emerges from the linear trans-
formation of the equations (1) to (3) and PID tuning.
We have simulated the functionality of the whole model
using a MATLAB® Simulink environment using a set of
virtual patients. The PID transient pulsatile behaviour is
achieved using the automatic tune tool of Simulink by fit-
ting for a frequency of around 10−3 Hz.22 The PID gains
used are P = 4.83, D = 0.07 and I = 0.21.23
Simulations ran on a set of nine different individuals
obtained from Neatpisarnvanit and Boston,24 each one of
them with its BMM parameters exhibiting a great inter-
subject variability (Table 1).
We simulated four punctual meals, along 24 h, two of
80 g, and two of 40 g of carbohydrates, with a night-time
fasting period. The meal ingestion (term D(t) in the equa-
tion (1)), acts as the disturbance, changing glycaemia. We
also simulated one hypoglycemic episode, to verify that
the controller can also deal with this event. To evoke the
hypoglycaemia event, we changed the sign of the term
D(t). To evaluate our algorithm, we compare its perfor-
mance against the Cohen-Coon's (CC) PID tuning
method.25,26 The controller acts on each virtual subject
based on the response of the one single patient randomly
chose to close the loop. Figure 2(a) shows the response on
the blood glucose concentration resulting from using the
CC method when the cases were challenged with a meal.
Four of nine fall into hypoglycaemia. As the controller
design is based on a model with nominal parameters, a
mismatch of parameters between the nominal model and
patient ones leads to severe hypoglycaemic events.
When the PID controller, tuned in pulsatile mode with a
frequency of 2 × 10−3 Hz (8 min), was applied to the whole
set of virtual patients, none of the subjects suffer hypogly-
caemia (Figure 2(b)).
Figure 3 shows insulin oscillations in the blood of every
single patient. As the loop is closed with only one of the
patients, the rest search for an equilibrium point unique for
each case. This equilibrium point goes from 8 to 45 µ/UL
and is directly related to the parameters of each particular
patient. Observe that the controller maintains the oscilla-
tory pattern in the neighbourhood of the basal value.
Blood glucose during fasting times is kept just around
the basal value. A change of parameters would eventually
lead to unsuited glycaemia values because of the integral
action of the PID control.27 For assessing the performance
of the controller when faced with fluctuating conditions,
that is, under conditions where parameters change in a sin-
gle subject (because of displacement from steady-state, i.e.
exercise, stress, etc.) throughout a day, we tested the con-
troller running on different individuals having different
parameters. To simulate this condition, the controller
switches between subjects randomly. This situation is
equivalent to changes occurring in a single individual
which modifies its own parameters in different circum-
stances, that is, changes in glucose demand from the tis-
sues. The superior part of Figure 4 shows the insulin
delivered by the controller in response to switching the
parameters, and the inferior side shows the blood glucose
profile resulting from this maneuver. Observe that blood
glucose varies no more than 0.1 mmol/L.
Figure 5(a) shows the response obtained ‘in silica’ (dot-
ted line) and the response of the real pump controlled by the
present algorithm (continuous line). The lower curve shows
the evolution of plasma glucose after an initial load (40 g
-a-) and a larger load (80 g-b-). There was a high corre-
spondence between both outputs, that of the silica model
and the real pump. Figure 5(b) shows the relationship
between the volume injected by the pump and the simulated
Cocha et al. 5

Figure 2.  The loop is closed in only one of the patients and the rest run in an open-loop mode founded on the input of that
patient: (a) The controller tuned with Cohen-Coon method, (a.a) insulin delivered to the set of patients, (a.b) the blood glucose
concentration in each one of the virtual patients. (b) Blood glucose changes with oscillatory insulin infusion, (b.a) The pattern
of insulin delivered to the set of patients, (b.b) The blood glucose concentration in each subject. The arrow indicates when the
hypoglycaemic event was induced.

glucose plasma level in the vicinity of normal glycaemia.
The volume injected by the real pump copies the oscillatory
insulin pattern, induced by the algorithm.
Figure 5(c) shows the numerical values obtained by
simulation with the output of the pump. The volume
injected by the pump was measured by weight. The slope
was 1.02 with a correlation coefficient of 0.68. This result
supports the view that the controller can be satisfactorily
employed on a real insulin pump.
Discussion
Algorithms for the control of insulin secretion by the artifi-
cial pancreas are a cornerstone in the development of
6 The International Journal of Artificial Organs 00(0)

Figure 3.  Blood insulin concentration of the set of patients when exogenous insulin infusion is delivered in an oscillatory mode.

Figure 4.  Controller response (insulin delivered) and blood glucose level originated by a change of parameters on a single
individual. The controller adjusts insulin dose, faced with each change in glucose concentration.

efficient devices for the treatment of type 1 diabetes. Lately,
some useful algorithms were developed, able to deal with
an important issue of AP, that is, hypoglycaemia.17,28
Insulin secretion during a meal has a pulsatile nature
and involves a series of pulses with amplitude and fre-
quency modulated by glucose.29–31 Insulin discharging in a
pulsatile mode requires the electrical coordination of the
secretory activity between β-cells in parallel with oscilla-
tion of intracellular Ca2+. Phase modulation of insulin
pulses enhances glucose regulation and enables inter-islet
synchronization.32–34 Glucose induces insulin release from
the β-cell by repetitive oscillations of the membrane poten-
tial. The duration and frequency of each burst of electrical
activity are a function of glucose concentration.29,35 This
pulsatile electrical activity evokes the pancreas to generate
pulses of insulin at a stable frequency, responding to
increased glucose loads by increasing the amplitude of the
pulses.29,36 The insulin released from the β-cells results in
Cocha et al. 7
Figure 5.  (a) Response to simulated loads of glucose of
40 g (a) and to 80 g (b) respectively. Continuous line (-), silica
simulated insulin injection; dashed line (- -), volume injected by
the real pump; dotted line (•), silica simulated blood glucose
level. All values are arbitrarily normalized. (b) Changes in the
volume injected by the real pump (continuous line) and plasma
glucose (dotted line) near to its control value after a meal.
Arbitrary scale. (c) Correlation between numerical values
obtained from the model, (x) and volumes obtained from the
pump, (y). Volume values injected by the pump are scaled to
match with the output of the computer model.
insulin oscillations, one with a period of around 140 min
(1.2E−4 Hz) and the other at a higher frequency, with a
period of 5–8 min (3.3E−3 − 2.0E−3 Hz) approximately.30,31
Consequently, the frequency chooses for the algorithm
used in this work was 3.0E−3.
Studies showed that insulin action is improved when insu-
lin is presented to the liver in a pulsatile fashion. The liver
rapidly responds to fluctuations in insulin secretion,
extracting insulin delivered in pulses.33,37,38 Furthermore, an
early marker of diabetes is the disruption of insulin pulsatility,
observed in pre-diabetics and relatives of patients with diabe-
tes who lack significant metabolic abnormalities. Changes in
insulin sensitivity, a characteristic feature for type 2 diabetes,
correlates with the frequency of secreted insulin.35,39,40 These
reasons support the importance of design an artificial pan-
creas mimicking as much as possible the actual one.
PID controller incorporated in artificial pancreas acts
acceptably well. However, an oscillating response in the
transfer function has led to instability of the blood glu-
cose.40 To obtain a satisfactory glucose regulation through
the Proportional-Derivative (PD)/Proportional-Integral-
Derivative (PID) control, the parameter settings for closed-
loop responses of short rise time requires steady-state error
elimination and, overshoot and setting time decrement.40
Feedback linearization is not regularly used for the con-
trol of biological systems because of its drawbacks. As the
method is based on the exact cancellation of nonlinearities,
when parameters vary in time cancellation is no longer
exact, and the performance became degraded. The addition
of the linear pulsatile PID controller improves the perfor-
mance of the FL controller making it apt to control biologi-
cal processes. In this paper, we use classical feedback
linearization and PID linear controller and introduce a new
insight for closed-loop blood glucose control. Instead of get-
ting a zero-error signal, the controller produces a pulsatile
response. The output of the controller is naturally tuned with
the glucose system of the patient. Before a meal, the control-
ler reacts in a pulsatile way, just as an actual pancreas does.
We have simulated the functionality of the whole model
using a MATLAB® Simulink environment. The novelty of
this model relies on the linear section of the controller tun-
ing. Quite contrary to classical tuning methods for PID con-
trollers, where derivative and integral components are tuned
to reduce the transient oscillations, we use pulsatile behav-
iour for mimicking the biological pancreas functionality.
Our simulations show that there are no hypoglycaemic
events, with the controller dealing efficiently with the uncer-
tainties of the model. The present simulations showed that
the efficiency of the pulsatile control is thoroughly better
than the non-pulsatile classical control alone. Variability
among different diabetic patients as well as variability along
the time in the same patient is appropriately compensated.
Furthermore, we compare the results of the ‘silica
model’ of type 1 diabetes, with the operation of a real insu-
lin pump. The real insulin pump responded fittingly to the
simulated glucose loads. We use a gravimetric procedure
to estimate the performance of the insulin pump as well as
the controller and the algorithm. We were interested in
contrast to the qualitative results obtained by the ‘silica
model’ and the real insulin pump. Thus, we did not scale
the volume injected by the pump with the real ones need
for practical purposes. One relevant aspect of this work is
that the ‘silica model’ robustness is validated by the per-
formance of a real pump.
8 The International Journal of Artificial Organs 00(0)
Although the benefit of insulin pulsatile delivery is
dated from some time ago,41 this work is, to our knowl-
edge, the first report showing the potential relevance of
insulin delivery mimicking the natural-occurring pattern.
We consider that this procedure of insulin delivery could
result, eventually, in the great benefit of insulin-dependent
diabetic patients. In conclusion, we present a controller
that improves the classical controller of blood glucose by
closed-loop systems and tests it with a real pump.
Author’s Note
Carlos D’Attellis Centro de Matemática Aplicada, ECyT,
UNSAM, Argentina.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
Funding
The author(s) disclosed receipt of the following financial sup-
port for the research, authorship, and/or publication of this arti-
cle: This work has been supported by CONICET (PIP No.
11220110100730CO) and FUNDACION UNSAM INNOVA.
We thanks UTN for its aid (ICIPNLP4975).
ORCID iD
Carlos Amorena https://orcid.org/0000-0001-6744-8465
Notes
I. For practical purposes, to simplify modelling, glucose
and insulin concentration in blood and interstitial fluid are
considered at instantaneous equilibrium without consider-
ing delays due to insulin distribution and transfer across
endothelial barriers. We are aware that the use of this model,
in real conditions, transit times must be taken into account.
II. An exhaustive description of the procedure is detailed by
Isidori19 and D’Attellis.20
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