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CHAPTER 2

2 LITERATURE SURVEY

2.1 INTRODUCTION

The World Health Organization (WHO) has taken survey that over
180 million people have the problem of Diabetes Mellitus (DM) in
worldwide. Also guaranteed that over 360 million people will have this
disease during 2030 (Cobelli et al 2009). The pancreas in the human body
handles blood glucose control for maintaining normoglycemia within the
range of 70-120 mg/dl. The beta cells in the pancreas conceal insulin when
the blood glucose level is high. Insulin is a hormone that is used to allow the
glucose to enter into the cells of the human body for providing energy. The
primary hormones involved in the blood glucose regulations Insulin and
glucagon. In case of high blood glucose concentration, the pancreas secretes
insulin. Insulin develops the uptake of glucose into the body cells and the
storage of glucose in the liver as glycogen. If the blood glucose is lower than
normal, the pancreas starts to produce glucagon. Glucagon has the opposite
effect, i.e., Promotes the breakdown of glycogen into glucose. This regulatory
mechanism is explained in Figure 2.1. Type 1 Diabetes Mellitus (T1DM)
occurs due to the damage of pancreatic beta cells by the body's immune
system.

Clinical studies by the Diabetes Control and Complication Trial


Research Group (Control & Group 1993, 1995, 1998), and others (Bergenstal
et al 2010) show that frequent blood glucose control of diabetes patients,
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results in smaller variations of glucose concentration. A decrease in the


incidence of secondary diabetic disorders in turn increases the patient‘s
quality of life and reduces healthcare cost. Also, the global health care
expenditure to treat complications related to diabetes is also going to increase
significantly within next years, from approximately 375 billion dollars to
nearly 490 billion dollars. The evolution of the number of people with
diabetes in the USA, Europe, India, China, Brazil and Africa for 2010 and
2030 is shown in Figure 2.2 (Boiroux et al 2012). Type 1 diabetic patient,
earlier known as, juvenile diabetes or insulin - dependent diabetes. In
Denmark, the number of people with T1DM is estimated to 30,000 (Cobelli
et al 2009). T1DM is an autoimmune disease caused by the destruction of the
insulin-producing β-cells in the pancreas. Therefore, people with T1DM do
not produce insulin and need frequent injections of exogenous insulin to
survive. Presently, people with T1DM have the responsibility of deciding on
their insulin dosage. Too little insulin may lead to periods of high blood
glucose (hyperglycemia), which has long-term difficulties, like blindness,
kidney disease, and nerve disease or. Conversely, overdosing the insulin may
lead to low blood glucose (hypoglycemia), which has immediate effects, such
as seizures or even death.

Figure 2.1 Blood Glucose Regulation in Healthy People


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Figure 2.2 Estimation of the number of people with diabetes in the


USA, Europe, India, China, Brazil and Africa in 2010 and
2030 (Boiroux et al 2012)

The traditional treatment for people with T1DM consists of


multiple daily injections (MDI) of slow-acting insulin once per day and rapid
-acting insulin several times per day with a needle. The decisions on the
amount of injected insulin are based on discrete blood glucose measurements.
The slow-acting insulin mitigates the endogenous glucose production from
the liver. The rapid-acting insulin compensates for the carbohydrates coming
from meals. To avoid the insulin injection manually and also to limit the
significant variation in blood glucose concentration, an artificial pancreas is
developed. Thus, successful development of a fully-automated closed-loop
system (artificial pancreas) for blood glucose control will benefit both insulin-
dependent diabetic patients and the health-care system. Prevention and
treatment of the complications of diabetes mellitus have been made during
1995 (Wood et al 1995).

The components of the artificial pancreas are glucose monitor,


insulin pump, and control algorithm. This controlled framework is called
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Automatic Blood Glucose- Insulin (ABGI) regulatory system and it is shown


in Figure 2.3.

Figure 2.3 Design of an Artificial Pancreas (Boiroux et al 2012)

With the inability of traditional therapy to achieve satisfactory


glycemic control, and the development of continuous glucose monitoring
(CGM) systems and the developing use of insulin pumps. The idea of
developing an artificial pancreas is observed as the ideal resolution for
glycemic control for monitoring T1DM (Bequette 2005, Hovorka et al 2006,
Kumareswaran et al 2009). The artificial pancreas is an automatic closed-loop
system that controls blood glucose levels within the desired range and limits
hypoglycemia while minimizing or eliminating the need for patient
intervention. An increasing number of people with type 1 diabetes are using a
Continuous Subcutaneous Insulin Infusion (CSII) pump combined with a
CGM. The insulin pump continuously injects small amounts of rapid-acting
insulin during the day, and can inject larger amounts before mealtimes. The
amount of basal insulin can be adjusted to the patient's daily variations in
insulin needs. The CGM provides frequent measurements of the subcutaneous
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glucose. This therapy results in a better control of blood glucose compared to


the one based on multiple daily injections.

Diabetes mellitus treatment has been steadily improving with the


progressive development of science. The artificial pancreas replaces the β-
cells functions in glucose sensing and insulin delivery. It consists of three
principal components (Figure 2.4): the first component is glucose sensor to
identify the glucose concentration of Type-1 diabetics. The second component
is control pump which is used for insulin delivery, and the third component is
closed-loop controller algorithm in order to link among the measurements of
glucose, and the dose of insulin to be delivered. As other medical devices, the
architecture of closed-loop artificial pancreas should meet strict safety
measures. Also, it is executed as security module or supervision system, to
evaluate the execution of the control algorithm and implement fault detection
techniques (Doyle et al 2007).

The main problem with satisfactory closed-loop control is the


appearance of significant disturbances (meals and physical activity). The
delays in the effect of meals and subcutaneous insulin on glycemia, and also
from glycemia to calculated subcutaneous glucose. Moreover, the control
system must convince constraints on both plasma glucose levels and insulin
delivery rates. These features explain the complications encountered when
pattern proportional integral derivative (PID) controllers are employed. Model
predictive control (MPC) is likely to be the most appropriate approach to
design control systems in the presence of delays and constraints.
Compensation for delays by using of feed-forward action, as well as
constraint handling, is naturally incorporated in the design process.

Control of blood glucose level after a meal is one of the foremost


challenges (Abu-Rmileh & Garcia-Gabin 2011) for the fully developed
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artificial pancreas. The meals lead to a significant glucose flux into the blood
stream. If feedback control is used to reduce the meal effect, the controller
reacts only after an increase in glucose has occurred and been detected by the
CGM sensor. Elevated glucose level can lead to insulin overdosing, resulting
in postprandial hypoglycemia (Steil et al 2006).

To pass up the constraint of purely reactive feedback control action


and progress the controller response against meal effect, for Feed-forward
control (meal announcement) can be used. This Feed-forward is a well-known
control technique used to eradicate the interference effect when the source of
interference can be estimated. In glucose control, the meal intake can be
observed as a known source of disturbance, and Feed-forward control can be
used for meal announcement. In case, the information is given to the artificial
pancreas system about the upcoming meal (size and time), a feed forward
scheme may be implemented to deliver additional insulin bolus.

The different configurations of feed forward (static, dynamic, and


predictive). These configurations are being used in the artificial pancreas
research, and their utility in increasing the overall controller performance has
been shown in Figure 2.4 (Boiroux et al 2012). It has been proved in different
clinical and simulation studies. (Abu-Rmileh & Garcia-Gabin (2010a,b), Lee
& Bequette (2009), Marchetti et al (2008), Weinzimer et al (2008). Since the
feed-forward action starts to deliver insulin before the meal effect appears in
the CGM feedback loop, lower variations in glucose levels are observed, with
the higher percentage of time within the acceptable glycemic range. It should
be mentioned that meal statement must be done cautiously since an excess of
insulin or badly-timed bolus may induce unwanted hypoglycemia episodes.
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Figure 2.4 Artificial Pancreas Components with patient in the loop

The artificial pancreas has been a subject of interest for almost


50 years (Dormand & Prince (1980), Gustafsson (1992) Hovorka et al (2004).
Early versions of the AP like the Bio-stator used intravenous glucose
measurements and Intravenous Insulin and glucagon injections. However, this
setup cannot be used for controlling the blood glucose in everyday life. In the
recent years, the improvements in CSII pump technologies, insulin analogs
and CGMs increased the potential of a fully automated artificial pancreas
(Leineweber et al 2003, Rao et al 1998, Mayne & Rawlings 2009). For the
commercial purpose, this type of Computer controlled devices have opened
up the possibility of creating an artificial pancreas is still not available. The
literature survey is made in the following phases of ABGI regulatory system.

Phase I : Virtual Patient Models

Phase II : Controller Algorithms

Phase III : Patient Model and Controller Parameters Tuning

Phase IV : Controller Performance Measurements


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2.2 VIRTUAL PATIENT MODELS

The artificial pancreas automatically controls the blood glucose


level based on the glucose measurements, the insulin infusions and in model-
based control strategies, on the mathematical insulin-glucose model (diabetic
patient model) applied to design the controller. Also, these models are
required for testing and proving the artificial pancreas in simulation
comparisons (in-silico) before setting it into clinical use with actual patients.
Without models, improvements are difficult to achieve (Tim Wasmuth 2013)
unless one is willing to make substantial investments in a real-life scenario
(like in vivo clinical research). A good model must behave properly in the
context of the intended optimization. It does not correspond to reality or
represent a 1:1 process. A distinction is made between real-models, which
you can ―touch‖ and virtual-models, which are based on a mathematical
algorithm. The translation from real-systems to virtual-models is realized by
computational modeling (in silico). These virtual-models mostly describe a
system by variables as well as equations that establish relationships between
the variables. The simulation time depends on the computing power and the
complexity of the model. For most models, the ordinary personal computer is
adequate to run a simulation unless it is about simulations of weather
forecasts or something similar.

Before applying an artificial pancreas into clinical use with real


patients, it should be tested and validated through simulation studies using
Virtual Patient Models (VPMs). Virtual-models (mathematical models) of the
glucose-insulin-metabolism have been developed for the diabetes treatment
and research. It can help to understand better the dynamic metabolism of the
human body and testing devices in the improvement phase for the treatment
of diabetes. Thus, one necessary task in the development of artificial pancreas
is to obtain a model of T1DM patient, which can help in the improvement of a
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closed-loop control system. Several models with different structures and


degrees of complexity are being used to describe the glucose-regulatory
system mainly as insulin-glucose and meal-glucose relationships – in T1DM.
Most of these are first basic models described by differential and algebraic
equations and based on existing information and explanations regarding the
underlying physiological system. Various mathematical models have been
introduced to the insulin-glucose regulatory system, additionally. Early
models were just structured and linear, which considered only the insulin and
blood glucose. After that, Bergman et al (1981) proposed the first class of
minimal models (Furler et al 1985) proposed more models with physiological
parameters.

Some other models are used for glucose-insulin regulations, such as


ordinary differential equations (ODEs), delay differential equations (DDEs),
partial differential equations (PDES), Freehold integral equations (FIES) (in
the estimation of parameters problem), stochastic differential equations
(SDEs) and integral-differential equations (IDEs). ODE with negative
feedback, DDE with one time delay, DDE with periodic time delay, and DDE
with two - time delays have also been introduced. These models not only
show the interaction between the insulin and glucose in the body but have
better agreement with physiological data (Li et al 2006). However, the first
three models have some drawbacks, for example, some of them they neither
time delay model within the incrementation in blood glucose and insulin
excretion nor estimate the time delay of liver glucose production.
Furthermore, to accomplish the periodic uncertainty, insulin must be divided
into two portions, the plasma insulin, and intra-cellular insulin.

In the fourth model, these problems were resolved (Li et al 2006).


This model, which was pro- posed by Li and Kaung, models the insulin-
glucose regulatory system considering two - time delays simultaneously,
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which were ignored in previous models. The profiles of this model are in
more agreement with physiological data. Among the models that have been
repeatedly used models are Minimal Model (Bergman et al 1981), Hovorka
Model (Hovorka et al (2004) and Dall Model (Man et al 2007). VPM
encourage the development of an advanced control algorithm to regulate
glucose concentration by normalizing the insulin injection.

Bergman et al (1981) proposed a three-compartment minimal


model to analyze the glucose disappearance and insulin sensitivity during an
intravenous glucose tolerance test. The glucose-insulin dynamics model
consists of three compartments in total. One compartment represents the
plasma glucose level. The second one describes the action of insulin. Finally,
the third one depicts the insulin concentration. Its simplicity makes it famous
for modeling people with type 1 diabetes. Bergman‘s model is the most
popularly utilized model in the literature, and it estimated the dynamic
response of a diabetic patient‘s blood glucose absorption to the insulin
injection (Neatpisarnvanit et al 2002). Modifications have done to the original
minimal model to include various physiological effects of glucose and insulin.
Cobelli et al (1986) explained a revised minimal model to separate the effects
of glucose generation utilization. The over evaluation of glucose effectiveness
and the underestimation of insulin sensibility by the minimal model were
approached in yet another publication by Cobelli et al (1999).The second
non-accessible glucose compartment was added to the original model.
Hovorka et al (2002) continued the original minimal model by adding three
glucose and insulin sub - compartments to capture absorption, distribution,
and disposal dynamics, respectively.

Hovorka et al (2004) represent the glucose-regulatory system that


includes sub-models representing absorption of subcutaneously administered
short-acting insulin Lispro and gut absorption. The Hovorka model is a
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nonlinear compartmental model with three subsystems for glucose, insulin,


and insulin action. It has two inputs, meal disturbances, and insulin infusions
and simulates the glucose and insulin concentration in the body in response to
these inputs. It represents the relationship between input variables,
subcutaneous insulin infusion rates (basal and bolus), and the output variable,
intravenous glucose concentration. This model also includes a sub model for
meal ingestion. The values of the model parameters were determined from
experimental data for both normal and diabetic subjects.

Another model for people with type 1 diabetes is the Sorensen


model (1985). This model can simulate both healthy people and people with
type 1 diabetes. This model consists of 19 states in total. This model is rarely
used for simulations due to its high complexity. Examples of publications
using the Sorensen model for modeling and/or control are (Parker et al 2000;
Ruiz-Velasquez et al 2004; Kovacs & Kulcsar 2007).

A new meal simulation model has been introduced by Dalla man


(2007) with their team. The novelty and intensity of this model are that it is
based on virtually model-independent measurements of the various glucose
and insulin fluxes happening during a meal. In fact, the system is very
difficult, and only the availability of glucose and insulin fluxes, also to their
plasma concentrations, has allowed us to minimize structural uncertainties in
modeling the various processes. The model consists of 12 nonlinear
differential equations, 18 algebraic equations, and 35 parameters. User-
friendly simulation software of this model would be of great help, especially
for investigators without particular expertise in modeling. The University of
Padova and the University of Virginia developed a virtual clinic of people
with type 1 diabetes based on the model from Kovatchev et al (2009).
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This clinic can simulate up to 300 patients (100 adults, 100


adolescents, 100 children), and is recommended by the FDA (Food and Drugs
Administration) as a substitution to animal trials. Consequently, this clinic is
often used to test in silico closed-loop controllers for blood glucose. Examples
of works using this virtual clinic are Lee et al (2009), Miller et al (2011),
Campetelli et al (2011). The main drawback of this model is the inability to
vary model parameters (example- insulin sensitivities) during the simulation.
A more recent model is the Medtronic Virtual Patient (MVP) model
(Kanderian et al 2009). This model contains the same compartments as the
minimal model. Its main difference is its identifiability. Thus, the 8 model
parameters can be identified from a sufficiently large collection of clinical
data.

2.3 CONTROLLER ALGORITHMS

The ‗artificial endocrine pancreas‘ has been the lengthy research


since the 1970s. The first generation of control approaches was planned for
intravenous glucose sampling and intravenous insulin infusion. The initial
work was conducted independently by Albisser et al (1974) and Pfeiffer et al
(1974). Developed the glucose controlled insulin infusion system (GCIIS)
managing to the development of ‗Biostator‘ (Clemens et al 1977). In terms of
titration algorithms, insulin admixture was linked to the rate of glucose
change by Albisser et al (1974). The development of advanced algorithms
followed (Fischer et al 1990, Fisher & Teo 1989, Kienitz & Yoneyama 1993,
Ollerton 1989, Salzsieder et al 1985, Shichiri et al 1983, Swan 1982). An
excellent review of control algorithms based on intravenous insulin delivery is
made by Parker et al (2001).

The subcutaneous delivery of insulin is less invasive than the


intravenous insulin delivery and suitable for use with a wearable extra
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corporal artificial pancreas. However, it has been well recognized that


subcutaneous insulin delivery poses problems to efficient glucose control due
to the additional delay associated with the absorption of subcutaneously
infused insulin (Cobelli & Mari 1985) and only with the availability of short-
acting insulin (Howey et al 1994) could the next generation of control
algorithms have been developed (Brunetti et al 1993, Candas & Radziuk
1994, Shichiri et al 1998, Shimoda et al 1996, Trajanoski & Wach 1998).

Medical sciences place more emphasis on prevention, and in case


of illness, only offer a general treatment. In recent years, to improve treatment
of diabetes, new instruments are designed using biomedical engineering for
the instance insulin pump. The insulin pump is a medical device used for the
administration of insulin in the treatment of diabetes mellitus, also known as
continuous subcutaneous insulin infusion therapy. The insulin pump has
application in the treatment of both types of diabetes (Kesavadev et al 2008,
Conget Donlo et al 2006, Alsaleh et al 2010, Kesavadev et al 2009) but what
is important here is designing of an appropriate controller for insulin pump.
The main features of the appropriate glucose controller are

(1) The controller should minimize the taken dosage of insulin


Chase et al (2002a & 2002b)

(2) The controller should lower blood glucose level in the


shortest possible time till its allowed range, i.e. among 70
and 120 mg/dl before meals and under 180 mg/dl after meals
Kovacs et al (2008), Li & Hu (2007), Beyki et al (2010) and

(3) Because the diabetes model of every individual is exclusive


by itself, the controller should have a suitable performance
for all diabetic patients. It means that the controller must have
robust performance against parameter uncertainties that exist
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in parameters of diabetes model (Acikgoz & Diwekar 2010,


Kovacs et al 2006, Garcia-Gabin 2008)

The ABGI framework differs from conventional insulin pump


therapy through the use of a control algorithm. This could automatically
reduce and increases the subcutaneous insulin delivery, according to sensor
glucose levels. The control algorithms could automatically reduce and
increases the subcutaneous insulin delivery according to sensor glucose levels
to VPM. Various control algorithms were proposed for ABGI regulatory
system. The most widely used controllers are Proportional Integral Derivative
(PID) (Li & Hu 2007), Model Predictive Controller (MPC) (Hovorka et al
2004), Fuzzy Logic Controller (FLC) (Ibbini & Masadeh 2005) and robust
controller (Parker et al 2000). In recent years, a hybrid approach of above
models makes ABGI framework to achieve stabilized blood glucose-insulin
control for T1DM patient by reducing the risk of hypoglycemia and also
solving the problem of hyperglycemia.

PID algorithms adjust insulin delivery by considering deviations


from a target glucose level (Proportional component), the area under the curve
between the measured and the target glucose level (Integral component), and
the rate of change in the measured glucose levels (Derivative component)
(Steil et al 2004). The model predictive control (MPC) (Camacho & Bordons
1999) is an emerging methodology to facilitate control of systems with long
time delays and open loop characteristics. When combined with adaptive
capabilities, it promises to tackle successfully problems such as the control of
glucose concentrations in subjects with type 1 diabetes. Model predictive
control has been at the forefront of recent research endeavours with
contributions, for example, by Parker et al (1999) and Lynch & Bequette
(2001).
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MPC algorithms apply a mathematical model of human glucose


regulation to link insulin delivery and glucose excursions as described in
computer-simulation studies. Insulin delivery is calculated by minimizing the
difference between estimated glucose concentrations and the target glucose
levels over a prediction window of 1.5 to 3 hours, or longer. FLC incorporates
the use of a human ‗expert‘ operator‘s knowledge in the control of a system
without the need for detailed knowledge of underlying dynamics of a system.
The controller is based on fuzzy rules with linguistic variables, using IF
(input) –THEN (output) structure. The combination of above models makes
ABGI framework to achieve tight glycemic control in T1DM by reducing the
risk of hypoglycemia while solving the problem of hyperglycemia

The fuzzy logic has developed as a powerful tool to apply expert


knowledge about the ABGI systems for implementing appropriate control
flow. Ibbini & Masadeh (2005) compared the efficiency of the fuzzy closed-
loop controller with ordinary PID controller, in the presence of intense
primary conditions including an exceptional, meal disturbance, variations in
parameters of the system and white noise that indicates sensor error. The
results prove that FLC performs better as compared with PID with respect to
sensor delay, sensor noise, and no disturbances. Notwithstanding the good
performance of these controllers, they do not have the abilities to deal with
ambiguities in biological models. Moreover, the classical controllers cannot
appropriately counter nonlinear and complex systems. As a result, if these
controllers are used in practice it is likely that they would fail while
implementing to an actual patient. In recent years, researchers have greatly
used the fuzzy logic for modeling, identification and control of highly
nonlinear dynamic systems (Prasad & Walker 2003)

Many researchers have taken steps to handle blood glucose


regulation using a fuzzy controller. Chen et al (2008), Li & Hu et al (2009),
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Ibbini & Masadeh (2005) and Ibbini (2006). A comparative study between
ordinary PID and a fuzzy logic controller with the hypothesis of continuous
insulin infusion has been described. Whereas both controllers are planned for
the purpose that maintaining blood glucose level around 65–100 mg/dl before
eating and under 140-150 mg/dl after eating. In Li & Hu et al (2009), a fuzzy
controller based on ordinary PID controller is designed. In Ibbini & Masadeh
(2005), the efficiency of the fuzzy closed-loop controller has been compared
with typical PID controller in the ubiquity of intense initial conditions. It
includes an unusual, meal disturbance, variations in parameters of the system
and white noise that indicates sensor error. In Ibbini (2006), the advantage of
fuzzy PI controller over the other controllers has been pointed. Also to quick
reply, it eliminates errors caused by intense initial circumstances and restores
blood glucose level to its basal amount in the duration of nearly an hour.

There have been many developments of ABGI regulatory system


models by the researchers since the development of artificial pancreas for the
T1DM patients. A robust H controller was developed (Parker et al 2000) to
deliver insulin via a mechanical pump in Type I diabetic patients. A primary
nonlinear diabetic patient model was linearized and then decreased to a third-
order linear form for controller synthesis. Ambiguity in the nonlinear model
was characterized by up to 40% variation in eight physiological parameters. A
sensitivity analysis identified the three-parameter set having the most
significant impact on glucose and insulin dynamics across the frequency
range of interest [0.002, 0.2]. This uncertainty was represented in the
frequency domain and incorporated in the controller design. Controller
performance was evaluated in terms of its capacity to follow a
normoglycemic set point (81.1 mg/dl) in acknowledgment to a 50 g meal
disturbance. In the simple continuous-time case, the controller supported
glucose gatherings within 3.3 mg/dl of set point. A controller tuned to provide
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ambiguity yielded a maximum deviation of 17.6 mg/dl for the worst-case


parameter variation.

Hovorka et al (2004) have used their glucose-insulin model along


with MPC Controller. Hovorka model employs a compartment model that
represents the glucose regulatory system and includes sub-models
representing the absorption of subcutaneously administered short-acting
insulin Lispro and gut absorption. The controller uses Bayesian parameter
estimation to determine time-varying model parameters. Steil et al (2004)
proposed a time-discrete PID control strategy in preliminary clinical trials
using the subcutaneous control route.

Ibbini & Masadeh (2005) compared the efficiency of the fuzzy


controller with PID controller with respect to changes in parameters of
system, different meal disturbance, and white noise that indicates sensor error.
The results prove that FLC performs better as matched with PID with respect
to sensor delay, sensor noise, and no disturbances. Cobelli et al (2007)
included a continuous extended version of that PID control algorithm for
closing the loop virtually in their simulation platform that has discretized for
the real-life control application. The result reveals that PID performs well, but
the empirical parameter tuning methods have not provided the proper
efficiency.

The utility of closed-loop artificial pancreas systems and their


benefit over traditional treatment has been determined in many clinical
studies. (Atlas et al 2010, Clarke et al 2009, Hovorka et al 2010, Steil et al
2011 & 2006, Weinzimer et al 2008), and a broad spectrum of control
algorithms has been offered to close the control loop, including classical and
modern control approaches. However, blood glucose control in T1DM is one
of the difficult control problems to be resolved in biomedical engineering. In
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extension to the inherent complexity of the glucose-regulatory system, that


involves the presence of nonlinearities, and time-varying and patient-specific
dynamics. There exist other difficulties, such as noisy measurements, defects
of the models used to generate the control algorithms. As well as the
conditions of the subcutaneous range used for glucose sensing and insulin
control (e.g. technological and physiological stays and subcutaneous tissues
dynamics). The challenges mentioned above make it very complicated to find
a general and positive solution to the nonlinear difficulty of glycemic control.
Hence, the design of a robust closed-loop control algorithm is an essential
step for the progress of the artificial pancreas.

Hovorka et al (2004) proposed the controller that employs a


compartment model that represents the glucose regulatory system and
includes sub-models representing the absorption of subcutaneously delivered
short-acting insulin Lispro and gut absorption. The controller uses Bayesian
parameter calculation to decide time-varying model parameters. Moving
target trajectory facilitates the slow, controlled normalization of raised
glucose levels and quicker normalization of low glucose values. The
auspicious capabilities of the model have been evaluated using data from 15
clinical experiments in subjects with type 1 diabetes. This method is not
considering the meal disturbances of type 1 diabetic patients and also the
percentage efficiency of blood glucose regulation slightly mismatch with the
database of clinical experiments. Table 2.1 represents the overview of
Controller Algorithms Performance (Lunze et al 2013). Table 2.2 represents
the overview of Controller Algorithms Performance based on Meal (Lunze
et al 2013).
Table 2.1 Overview of Controller Algorithms Performance (Lunze et al 2013)

Control algorithm
Publication Input Output Manual
Control strategy Internal model Sampling time Glucose target Adaptation
glucose(t) IIR(t) input
Steil (2006) PID - s.c. s.c. - 5min (CGMS) 120mg/dl √
20 min BG i.v.
Man (2007) PID - s.c. s.c. - continuous 130Mg/dl -
Gantt (2007) Adaptive OI - s.c. s.c. - 81Mg/dl √
Marchetti (2008) Extended PID - Filt s.c. Switch time 5min 80Mg/dl √

Palerm (2008) Run-to-run - i.v. s.c. - 5times/day 80Mg/dl √

Parker (1999) Linear MPC Sorensen and i.v. i.v. Disturbance -


With kalman filter Lehman D
Lynch & Bequette Linear MPC Minimal model, s.c. i.v. - 5min 81.3mg/dl -
(2001) With kalman filter Lehman/Fisher
Gillis (2007) Linear MPC Minimal model, s.c. s.c. D 5min 80mg/dl √
With kalman filter part, Hovorka
Magni (2007) Linear MPC Reduced Dalla Man s.c. s.c. Body 30min 112mg/dl √
Weight.D
Magni (2009) NonLinear MPC Dalla Man s.c. s.c. BW.D 30min 135mg/dl -
Hovorka (2004) NonLinear MPC Hovorka i.v. s.c. - 15min 6mmol/L √
(self adapting) Time-variant
Marchetti (2008) Feedforward-feedback Extended Hovorka i.v. s.c. D 5min Time-variant √
control strategy

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Table 2.2 Overview of Controller Algorithms Performance based on Meal (Lunze et al 2013)

Publication Control evaluation


meal ln silico In vivo Setting time Future adaptation
Steil (2006) 40-90g - 10 type 1 - More robust for noise, faster settling time
Man (2007) 45-70g, Dalla Man - - Discrete measurement, robust noise response
adaptive
Gantt (2007) 3-33mg Modified minimal model - - Response to meal uptake more aggressively
Marchetti (2008) 60g Extended Hovorka - - Automatic control switch-off, s.c. glucose measurement
Palerm (2008) Not given Extended Hovorka - - Continuous time-dependant insulin infusion
Parker (1999) 50g Yes - Approx. 3h s.c. glucose measurement
possibly s.c. insulin infusion
Lynch & Bequette 50g Model unknown - Approx. 3h s.c. glucose measurement
(2001) More aggressively performance
Gillis (2007) 50g Sorensen Advisory Approx. 6h Reduction of BG undershoot
mode
Magni (2007) 45-80g Hovorka+noise - Approx. 6h s.c. glucose measurement
Historical data
Magni (2009) 45-85g Dalla Man(full) - Unclear s.c. glucose measurement
Hovorka (2004) - Evaluation Algorithm 10 type 1 - Meal response s.c. glucose measurement
Marchetti (2008) 60g±50% Ext.Hovorka - Mins. 5h s.c. glucose measurement

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2.3.1 Hypoglycemia and Hyperglycemia in Closed-Loop Artificial


Pancreas

Untreated T1DM causes the blood glucose concentration


permanently above 180mg/dl that will cause long - term complication of
neuropathy, retinopathy and even death. This state is called hyperglycemia.
Hypoglycemia occurs in diabetic patients if the amount of injected insulin is
too high when compared to the blood glucose concentration (for example
below 70mg/ dl). Hypoglycemia is the most common complication of insulin
therapy in T1DM and continuously limits the efforts to improve glycemic
control. Hyperglycemia may affect individuals who are critically ill even if
they have no prior history of diabetes Bequette (2007), Van Herpe et al
(2009), Chase et al (2006), & Chase et al (2011). The hyperglycemic
response, due to acute stress, can be attributed both to endogenous
contributors (e.g., increased counter - regulatory hormones, increased insulin
resistance, decreased glucose uptake) and to exogenous contributors
(e.g., medications) (Kovalaske et al 2009). Stress-induced hyperglycemia is
strongly associated with adverse outcomes in subjects with acute myocardial
infarction, stroke, and trauma.

For closed-loop artificial pancreas system to be optimal


(Abu-Rmileh & Garcia-Gabin 2011) and replicate the normal insulin
secretion, the insulin therapy should respect the fact that hypoglycemia is not
a naturally occurring episode in T1DM. Also, hypoglycemia is believed to be
more dangerous in the short term than hyperglycemia. Therefore, in order to
achieve tight control while not substituting the problem of hyperglycemia for
the life-threatening hypoglycemia, the insulin therapy in T1DM should be
optimized so that it reduces the risk of hyperglycemic events in both
frequency and magnitude, without provoking significant or severe
hypoglycemia as a result of excessive or ill-timed insulin infusion.
36

Therefore, hypoglycemia prevention should be unavoidably


considered among the main objectives of the development of the closed-loop
artificial pancreas systems. Severe hypoglycemia episodes are a
Hypoglycemia Prevention in Closed-Loop Artificial Pancreas for Patients
with Type 1 Diabetes well-known cause of death in diabetic patients and are
more commonly seen during the night than during the day. Given that the first
generations of the artificial pancreas are not expected to achieve complete
regulation of the glucose levels during the 24 hours period, first generations
of the artificial pancreas might be focusing on critical aspects like preventing
hypoglycemia episodes during night (Hovorka et al 2010).

Currently, the vast majority of closed-loop artificial pancreas works


focuses on the achievement of tight control during daily life conditions
(i.e. 24 hours control), and therefore addresses both hyper- and hypoglycemia
in fasting and postprandial conditions. Various strategies are employed in
these works to avoid fasting, postprandial and nocturnal hypoglycemia.
Mostly, the control algorithms use changes in the target blood glucose to
adjust the doses of insulin to prevent hypoglycemia (i.e. higher target glucose
level during night and postprandial periods) (Eren-Oruklu et al 2009,
Marchetti et al 2008, Weinzimer et al 2008). In other works, hypoglycemia
prediction algorithms were tested, and short-term suspension of insulin pump
was used as safety approach when hypoglycemia is predicted (Lee &
Bequette 2009).

Also, variations in insulin sensitivity during the day (due to the 24


hours circadian cycle in insulin sensitivity), have been considered in the
design of artificial pancreas control algorithms, and used to adjust the basal
insulin requirements during the day (Garcia-Gabin et al 2009, Steil et al 2004,
Wang et al 2009). Another strategy used to avoid hypoglycemia is the double
hormone closed-loop system, which uses glucagon infusion in response to
37

low glucose levels. In T1DM, insulin deficiency is often accompanied by the


loss of glucagon secretary response to hypoglycemia. Furthermore, insulin
therapy causes even more degradation in the functionality of other counter-
regulatory hormones (Briscoe & Davis 2006), and consequently, results in
higher possibility for hypoglycemic risk. Different artificial pancreas studies
have demonstrated that glucagon infusion significantly reduces the risk of
insulin-induced hypoglycemia in T1DM (Castle et al 2010, El-Khatib et al
2009 & 2010, Ward et al 2008).

2.4 PATIENT MODEL AND CONTROLLER PARAMETER


TUNING

An uncertainty will occur during the following phases:

 Virtual Diabetic Patient Models Parameter Tuning

 Controllers Parameter Tuning

 Fuzzy Rules and Membership Function Formations.

The performance degradation is frequently occurring in a controller


with incorrect values of the model parameters. A variation in model
parameters makes uncertainty due to the differences between an actual patient
and the diabetic patient model. In any artificial pancreas scheme based on
subcutaneous insulin delivery and/or glucose measurement, there is great
difficulty in dealing with the long actuation/sensing delays, and also the large
inter and intra patient variability. Due to the fact that the system is highly
uncertain and time-varying, it is clear that some tuning to patient-specific
characteristics is necessary to achieve high closed-loop performance .Hence,
these model parameters are selected by optimizing the controllers and diabetic
patient models.
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Although there are a number of distinguished advantages of the


fuzzy logic controllers over the classical controllers (PID, MPC) such as they
are not so sensitive to the variation of system structure, parameters and
operation points as well as can be easily implemented in a large-scale
nonlinear system, but, one drawback of them is the lack of systematic
methods to define fuzzy rules and fuzzy membership functions. Most fuzzy
rules are also based on human knowledge and differ among persons despite
the same system performance. On the other hand, it is difficult to assume that
the given expert‘s knowledge captured in the form of the fuzzy controller
leads to optimal control. Consequently, the effective approaches for tuning the
membership function and control rules without a trial and error method are
significantly required. A Ziegler-Nichols method and Fuzzy based tuning of
controller parameters makes the number of procedures to be increased with
respect to inter-patient variations and also decreases the settling time.

Nature has been a main source of inspiration for many optimization


algorithms. Such algorithms are increasingly becoming popular among
control engineers for the optimal tuning of PID ,MPC ,Fuzzy controllers and
Diabetic Patient model parameters ,for example, such as Bergman ,Hovorka
and Dalla man Models. Because of this, a Bio-inspired Meta-Heuristic
Algorithms (BMHA) (Fogel 1995) (Edwards & Engelbrecht 2005) had
become a research focus to address the issues of parameter tuning. Some of
the BMHA algorithms are Genetic Algorithm (Holland 1992), Particle Swarm
Optimization (PSO) (Eberhart & Kennedy 1995) , Ant Colony Optimization
(ACO) (Dorigo et al 1996), and Cuckoo Search (CKS) (Yang & Deb 2009,
2010).

Al-Fandi et al (2011) proposed a Fuzzy PI Controller for glucose


concentration using Genetic Algorithm (GA). The parameter tuning by GA
has taken time due to GA operators such as mutation, crossover, and selection
39

operator. This GA operator shows that convergence was guaranteed, but time
for convergence was uncertain, and parameter updation was not
straightforward.

Abadi et al (2014) proposed an optimal fuzzy-PI controller based


on the Mamdani-type structure for blood glucose in diabetic patients. In the
core of the proposed controller, a heuristic algorithm, namely linearly
decreasing weight (LDW) in PSO, which has been utilized to optimize the
membership functions, PI controller, and insulin infusion signal
simultaneously. To evaluate the performance of the proposed controller, it is
tested by three different sets of parameters that relate to three different
patients. With regard to the existing limitations in insulin injection rate, the
proposed controller has minimized the insulin injection rate and time margin.
The premature convergence may occur in certain generations.

2.5 PERFORMANCE MEASUREMENTS

The blood glucose and insulin injection are automatically stabilized


as like natural pancreas. The proposed control algorithms have to be evaluated
in silico to obtain the results for virtual diabetic patient model and then results
about consequences for real-life situations (in vivo). The performance index is
defined as a quantitative measure to depict the system performance of the
designed controller. Using this technique an ‗optimum system‘ can often be
designed and a set of controller parameters in the system can be adjusted to
meet the required specification. For a controlled system (Soni et al 2013),
there are often three indices to depict the system performance: such as
Integral Square Error (ISE), Integral Absolute Error (IAE), Integral Time
Absolute Error (ITAE), and Mean Square Error (MSE).

The controller is used to minimize the error signals, or we can


define more rigorously, in the term of error criteria: to minimize the value of
40

performance indices mentioned above. Therefore, for the heuristic algorithm


based tuning, these performance indexes are used as the fitness function. The
objective in the optimization is to seek a set of controller parameters such that
the feedback control system has minimum performance index. All the
measures require a fixed experiment to be performed on the system (fixed set
point or disturbance change), and the integrals are evaluated over a fixed
period.

Kishnani et al (2014) have applied a very recent nature inspired


meta-heuristic technique known as Cuckoo Search Algorithm ,is used for the
optimal tuning of PID controller. Though several conventional techniques
have been proposed to sufficiently optimize linear plant systems, but the
desired performance indices, such as settling time, overshoot, rise time, etc.
are comparatively higher than the response attained by heuristic algorithms.
Here, a study is done on PID controller optimized by Cuckoo Search
Algorithm for different fitness functions are IAE, ISE, ITAE and ITSE and
their responses are compared with one such conventional method.

2.6 SUMMARY

A method for optimal continuous insulin therapy for diabetes


patients has been sought since the early 1970s. Although technical and
medical advances have been made, a fully automated artificial pancreas to
replace the functions of the natural organ is still a research aim. Various
diabetic virtual patient models are analyzed for in-silico testing. This review
compared the recent control algorithms for type 1 diabetic patients which
automatically connect continuous glucose monitoring and insulin injection,
without patient intervention. Various control strategies are described and
performance measures of control algorithms are identified, with a focus on
their feasibility of implementation in a real-life situation. The diabetic patient
41

model and control parameters tuning methods are analyzed .Meta heuristic
algorithms are used to overcome the problems in parameters tuning.

In conclusion, an accurate control strategy has not yet been


proposed, mainly because most control algorithms rely on continuous blood
glucose measurement, which is not yet available. Modeling the effect of
glucose ingestion as an external disturbance on the time evolution of blood
glucose concentration is now the standard for the control community. In
contrast, the effects of physical activity on the metabolic system are not yet
fully understood and remain an open issue. Moreover, clinical studies on
evaluation of control performance are scarce. Therefore, research on blood
glucose control needs to concentrate on advanced patient modeling, control
optimization and control performance evaluation under realistic patient-
oriented conditions.