Closed Loop Blood Glucose Regulation of Type

1 Diabetic Patient Using Takagi-Sugeno Fuzzy

Logic Control

Anirudh Nath1(&), Rajeeb Dey1, and Valentina E. Balas2

1
Department of Electrical Engineering, National Institute of Technology,
Cachar District, Silchar 788010, Assam, India
anirudh.nath88@gmail.com,rajeeb.iitkgp@gmail.com
2
Department of Automatics and Applied Software, Faculty of Engineering,
“Aurel Vlaicu” University of Arad, Arad, Romania
balas@drbalas.ro

Abstract. This paper presents a Takagi-Sugeno (TS) Fuzzy Logic based

intelligent control algorithm for maintaining plasma glucose regulation for Type
1 Diabetic Mellitus (T1DM) patient in presence of known meal disturbance and
parametric variations. The mathematical model considered here to describe the
interaction between glucose and insulin, is modified Bergman minimal model.
Simulation results of the plasma glucose concentration and insulin infusion rate
validate the effectiveness of the designed control law.

Keywords: Takagi-Sugeno (TS)
Fuzzy logic control (FLC)
Bergman

minimal model
Type 1 diabetes
Blood glucose

1 Introduction

Diabetes is one of the most challenging and wide-spread diseases around the world.
Huge amount of money is invested every year in order to find effective treatment, alone
the United States spent about $132 billion USD in 2002 [1]. There are mainly two
forms of the disease, namely, Type 1 Diabetes Mellitus and Type 2 Diabetes Mellitus.
Type 1 Diabetes Mellitus is basically a class of chronic and autoimmune disease which
is characterized by b-cell destruction resulting in severe hyperglycemia. Insufficient or
negligibly small amount of insulin production results in failure in maintaining the blood
glucose level in the safe range (70–180 mg/dL) [2]. The long-term consequences may
be renal failure, neural damage, cardiac arrest, lower-limb amputations, retinopathy and
diabetic related blindness [3].
Enormous research have been carried out for control and management of this
disease. Globally, one of the aspects of research is towards the development of efficient
Artificial Pancreas system (APS), where the development of efficient control algorithm
is a key research issue. The key features of the mathematical model considered in this
work which is a modification of the Bergman minimal model (based on Intravenous
Glucose Tolerance Test (IVGTT)) [4], is that the glucose is measured subcutaneously
and insulin is injected intravenously.

© Springer International Publishing AG 2018

V.E. Balas et al. (eds.), Soft Computing Applications, Advances in Intelligent
Systems and Computing 634, DOI 10.1007/978-3-319-62524-9_23
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 Closed Loop Blood Glucose Regulation 287

The control problem of regulating the blood glucose level for T1DM patient has
been solved using both classical and various variants of PID control schemes [9, 10]. In
[11] H-infinity control has been attempted to make the controller robust in presence of
parametric uncertainty and disturbance attenuation. In [12, 13] different sliding mode
control (SMC) techniques have been applied for regulating blood glucose in the
presence of parametric uncertainty and unmodelled dynamics. But the control signal in
SMC is affected by the chattering phenomenon and further research is going on to
eliminate chattering in the control signal. Model predictive control algorithms are
proposed in [14, 15] which are based on both simple and complex dynamical models of
glucose-insulin regulatory system. MPC solves the problem of blood glucose regula-
tion but require identification of linear and nonlinear time series models which needs to
be validated against clinical data, and also the calculation of the control law at an given
instant requires prediction of future values of blood glucose level which may result in
inappropriate control signals if the predictions are not good enough. Neural Network
based control is designed in [16] which requires large amount of input-output data for
training of the network and may face the problem of computational burden. Fuzzy logic
control is essentially an expert knowledge based system [5] and finds a wide range of
applications in the field of Biomedical engineering [6–8]. Different fuzzy logic con-
troller based on Mamdani inference system have been designed for the blood glucose
regulation in T1DM patients in [17–20]. In order to reduce the computational burden
which arise from the need of defuzzification of the fuzzy output in Mamdani based
FLC, a TS FLC scheme is proposed here to keep the blood glucose level in the normal
range (70 mg/dL–120 mg/dL) and avoid any instance of post prandial hyperglycemia
(>180 mg/dL) or hypoglycaemia (<70 mg/dL). The proposed controller is robust with
respect to parametric variations of the model and have a simple design structure and is
computationally more efficient than its fuzzy counterparts which are based on Mamdani
inference system.
The paper is organized as follows. In Sect. 2, the Bergman minimal model and
modified minimal model representing the T1DM patient are briefly presented. The
adopted model is nonlinear dynamical in nature. In Sect. 3, a TS FLC is proposed for
studying the closed loop performance of glucose control in T1DM patients. The details
about the controller synthesis are also discussed. Then, in Sect. 4, the simulation results
for modified minimal model with both nominal parameters and with parameter varia-
tions are presented. Finally, several conclusions are drawn in Sect. 5.

2 Glucose-Insulin Dynamical Model

Many mathematical models have evolved over the years to describe the dynamics of
glucose-insulin regulatory system. Bergman minimal model is probably the first model
to depict the dynamics of glucose-insulin regulatory system intravenously [21]. In the
last couple of decades, an attempt has been made to develop more realistic situations of
T1DM patients by considering the glucose-insulin dynamics subcutaneously [24–27].
However, the evolution of the models have not taken into account the control oriented
modelling approach. In this paper, we have considered simple mathematical model for

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T1DM patients yet realistic than that of Bergman minimal model. We describe the
details of modelling in the succeeding subsections.

2.1 Bergman Minimal Model IVGTT

Bergman’s minimal model is basically a single compartmental model which assumes
the body as a compartment with basal concentrations of glucose and insulin. There are
two minimal models, one of which describes the dynamics of glucose clearance and
uptake in the body, and the other describes the delay in the active insulin (in the remote
compartment) which accounts for the glucose utilization by tissues and glucose
dynamics of the liver (uptake and production). The dynamics of the above regulatory
system is described by the following nonlinear ordinary differential equations [21]:

dGðtÞ
¼ ðp1 þ X ðtÞÞGðtÞ þ p1 Gb ð1Þ
dt
dXðtÞ
¼ p2 ðtÞXðtÞ þ p3 ðI ðtÞ  Ib Þ ð2Þ
dt

The following figure describes the dynamics graphically (Fig. 1):

Liver

Production Uptake

effect

Blood Glucose
Remote Compartment of Active Insulin Glucose Compartment
Insulin Dose

Flow
effect
Clearance Uptake

Fig. 1. Graphical representation of the minimal model [21]

The insulin minimal model which represents the insulin kinetics is given by the
following differential equations:

dIðtÞ
¼ p6 ½GðtÞ  p5  þ t  p4 ½I ðtÞ  Ib  ð3Þ
dt

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For T1DM patient, the pancreatic response is replaced by external insulin infusion
term given below where term related to the pancreatic insulin release is omitted and
external insulin infusion is introduced.

dIðtÞ U ðt Þ
¼ p4 I ðtÞ þ ð4Þ
dt VI

2.2 Modified Bergman Minimal Model

The fisher meal disturbance model [22] is introduced in the modelling of T1DM patient
in order to address the rapid changes in the postprandial plasma glucose concentration
profile just after the meal, which describes the appearance of glucose in the blood
plasma. The mathematical model describing the meal disturbance is given as follows:

DðtÞ ¼ B:expðdrate :tÞ ð5Þ

D(t) represents the rate of glucose in mg/dL entering into the blood plasma. As
suggested in the literature, derivative of D(t) is considered in the modelling in place of t.

dDðtÞ
¼ drate :DðtÞ ð6Þ
dt

Since the modern day continuous glucose monitor (CGM) devices are based on
subcutaneous glucose measurements, the controller input is chosen as subcutaneous in
place of intravenous. This choice makes the modified minimal model more realistic for
the design of closed loop control algorithms for the development of Artificial Pancreas
(AP). The model introduced here is adopted from GIM (a T1DM simulator), which
takes a delay of about 10 min for the glucose measurement to appear in the subcuta-
neous depot from the blood plasma [23].

dGsc ðtÞ 1
¼ ðGðtÞ  Gsc ðtÞÞ ð7Þ
dt T
where G(t) denotes the subcutaneous glucose concentration (mg/dL) and T denotes the
time constant. The open loop response of the modified Bergman minimal model rep-
resenting a T1DM patient with very high basal glucose concentration (Gb = 200
mg/dL) and zero Ib and assuming that no external insulin is infused and a meal
disturbance of a rate of 10 mg/dL/min at time, t = 100 min with the following
parameters are given below [21] (Figs. 2 and 3):

p1 ¼ 0:028735; p2 ¼ 0:028344; p3 ¼ 5:035  105 ; Gb ¼ 200; Ib ¼ 0

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290 A. Nath et al.

Fig. 2. Fisher disturbance model [12]

Fig. 3. Open loop response of plasma glucose concentration of modified minimal model

3 Closed Loop Control: Design Strategy

The modified minimal model represents the virtual patient which has exogenous
intravenous insulin infusion as the input and plasma glucose concentration as the
output. The meal disturbances act as additional disturbance input to the system. The
main objective of the controller is to generate appropriate control signal based on the
subcutaneous glucose measurements so that the blood glucose level is maintained in
the safe range [70 mg/dL–180 mg/dL] in the presence of known meal disturbances. It
is assumed that controller is acting in the closed loop system for some time and a basal
concentration of plasma glucose, Gb and basal insulin concentration, Ib is established.

3.1 Controller Synthesis

In this section, fuzzy logic control for blood glucose regulation of T1DM patient is
described briefly. The structure of the controller is based on zero order Takagi-Sugeno

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(TS) fuzzy logic architecture with two inputs, error in subcutaneous glucose concen-
tration, e(t) which is the difference between the target glucose level and the current
subcutaneous glucose concentration at that instant, and the second input is the
derivative of Gsc(t). The output of the controller is the exogenous insulin infusion rate.
Both the inputs have the same normalized universe of discourse [−1, 1]. Three
membership functions are used to partition the input universe of discourse of both the
inputs and the type of membership functions are chosen as Gaussian functions:
Negative, Zero and Positive for both the inputs. The universe of discourse for the
output fuzzy variable is [−2, 2] and the range of insulin infusion rate is 0–10 U/min and
the output membership functions are chosen as constants namely, Negative Big (NB),
Negative Small (NS), Zero (Z), Positive Big (PS), Positive Small (PB). The input
membership functions are presented in Fig. 4. A total of nine fuzzy IF–THEN rules are
defined to calculate the output and are presented in Table 1. MIN–MAX laws are used
to derive the appropriate fuzzy output for a given set of inputs and Weighted Average
method of defuzzification is used to calculate the final output of the TS fuzzy logic
controller. Three scaling factors namely, GE, GCE and GU are used to scale the input
and output variables and these are nothing but nonlinear gains which are tuned
manually.

Fig. 4. Membership functions for error and derivative of Gsc(t)

4 Results

In this section, the results from the simulation studies are presented to validate the
proposed non-linear intelligent closed loop control algorithm based on TS fuzzy logic
control paradigm. The simulation studies are classified into two broad cases, (i) Sim-
ulation studies with nominal model parameters and (ii) Simulation studies with realistic
model with known parametric variations.
The following assumptions are made for the simulation studies:
• The nominal non-linear modified minimal model has fixed parameters for controller
design [14].

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Table 1. Fuzzy rule base

e cy
N Z P
N NB NS Z
Z NS Z PS
P Z PS PB

Table 2. Parameters/variables for modified Bergman minimal model [21]

Parameter/Variable Unit Description
T Min Time
G(t) mg/dL Plasma glucose concentration
Gb mg/dL Basal glucose concentration
X(t) 1/min Effect of active insulin
I(t) mU/L Plasma insulin concentration
Ib mU/L Basal insulin concentration
D(t) mg/min Rate of glucose entering blood
Gsc ðtÞ mg/dL Subcutaneous glucose concentration
p1 1/min Glucose clearance rate independent of insulin
p2 1/min Rate of clearance of active insulin
p3 L/min2.mU Glucose clearance rate dependent on insulin
p4 1/min Decay rate of blood insulin
p5 mg/dL Threshold for blood glucose concentration
p6 mU.dL/L.mg.min Rate of pancreatic release after glucose bolus
T 1/min Time lag between subcutaneous depot and plasma

• Parametric variations in the considered model for known ranges have been intro-
duced. The ranges of parameter variation are adopted from [16] which effectively
represent the worst case of parametric variations which may arise due to
inter-patient and intra-patient variability.
• The amount and timing Fisher meal disturbances is assumed to be exactly known.
• Initial value of plasma glucose concentration is very high 200 mg/dL.

4.1 Case I: Simulation Studies with Nominal Model Parameters

The nonlinear modified minimal model is used to represent the glucose- insulin
interactions of the T1DM patient with nominal parameters provided in Table 3. The
trajectory of plasma glucose concentration in T1DM patient with nominal parameters
after applying the control action is shown in Fig. 5a. A set point of 81 mg/dL has been
used. The simulation result depicts that the designed control logic could track the
set-point, thus avoiding the events of both postprandial hyperglycemia and hypogly-
caemia. The control signal is shown in Fig. 5b. depicts the nature of external insulin
infusion intravenously. The control signal remains steady throughout the simulation

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 Closed Loop Blood Glucose Regulation 293

Table 3. Different parameters for realistic modified Bergman minimal model

S. no. p1 p2 p3 p4
1 0.0284735 (nominal) 0.028344 (nominal) 5.035  10−5 (nominal) 0.0925 (nominal)
2 0.0143675 (−50%) 0.018991 (−33%) 2.517  10−5 (−50%) 0.0537 (−42%)
3 0.0431025 (+50%) 0.037698 (+33%) 7.552  10−5 (+50%) 0.1315 (+42%)
4 0.0215513 (−25%) 0.024092 (−15%) 3.776  10−5 (−25%) 0.0740 (−20%)
5 0.0355188 (+25%) 0.032596 (+15%) 6.293  10−5 (+25%) 0.1111 (+20%)

time except overshoots are observed. The reason for the overshoot in control signal is
for compensating the meal disturbance effects.

4.2 Case II: Simulation Studies with Known Parameter Variations

In this study four sets of parameters are presented in Table 3. The main objective of
this study is to analyze the robustness of the proposed control algorithm with respect to
parametric variations which may arise due to inter-patient and intra-patient variability.

Fig. 5. a. Closed loop response of plasma glucose concentration for nominal parameters.
b. External insulin infusion rate

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294 A. Nath et al.

(a)

(b)

(c)

(d)

Fig. 6. Closed loop response of plasma glucose concentration in presence of meal disturbance
and parametric variations

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 Closed Loop Blood Glucose Regulation 295

The structure of the controller is kept constant for parametric variations without any
changes in the structure of the controller. After introducing meal disturbances at three
different times of a day, the plasma glucose concentration is maintained not only in the
safe range [70–180 mg/dL] but also the events of postprandial hyperglycemia and
hypoglycemia are avoided for all the four different cases considered. The results for the
above referred cases are placed in Fig. 6a, b, c and d respectively.

5 Conclusion

In this work TS fuzzy logic based closed loop control algorithm for maintaining plasma
glucose concentration within postprandial safe range of (70–180 mg/dL) is proposed.
Simulation results reveal the effectiveness of the closed loop control algorithm in terms
of prevention of the occurrences of severe postprandial hyperglycemia and hypo-
glycemia. The proposed control algorithm is robust with respect to a wide range of
parametric variations of the modified Begman minimal model.

References
1. Takahashi, D., Xiao, Y., Hu, F., Lewis, M.: A survey of insulin-dependent diabetes-part I:
therapies and devices. Int. J. Telemed. Appl. 2008, 2 (2008)
2. González, A.A., Voos, H., Darouach, M.: Glucose-insulin system based on minimal model:
a realistic approach. In: Proceedings of the 2015 17th UKSIM-AMSS International
Conference on Modelling and Simulation, pp. 55–60. IEEE Computer Society (2015)
3. Al-Fandi, M., Jaradat, M.A., Sardahi, Y., Al-Ebbini, L., Khaleel, M.: Intelligent control of
glucose concentration based on an implantable insulin delivery system for type I diabetes. In:
Applied Electrical Engineering and Computing Technologies (AEECT), IEEE Jordan
Conference, pp. 1–6 (2011)
4. Bergman, R.N., Phillips, L.S., Cobelli, C.: Physiologic evaluation of factors controlling
glucose tolerance in man: measurement of insulin sensitivity and beta-cell glucose sensitivity
from the response to intravenous glucose. J. Clin. Invest. 68(6), 1456–1467 (1981)
5. Wang, L.X.: A Course in Fuzzy Systems and Control. Prentice-Hall, Upper Saddle River
(1997)
6. Meier, R., Nieuwland, J., Zbinden, J.M., Hacisalihzade, S.S.: Fuzzy logic control of blood
pressure during anesthesia. IEEE Control Syst. Mag. 12(6), 12–16 (1992)
7. Duckstein, L., Bilinowska, A., Verroust, J.: Fuzzy classification of patient state with
application to electro-diagnosis of peripheral polyneuropathy. IEEE Trans. Biomed. Eng. 42
(8), 786–792 (1995)
8. Buisson, J.C., Garel, A.: Balancing meals using fuzzy arithmetic and heuristic search
algorithm. IEEE Trans. Fuzzy Syst. 11(1), 68–78 (2003)
9. Marchetti, M.B.G., Jovanovic, L., Zisser, H., Seborg, D.E.: An improved PID switching
control strategy for type 1 diabetes. IEEE Trans. Biomed. Eng. 55(3), 857–865 (2008)
10. Li, C., Hu, R.: PID control based on BP neural network for the regulation of blood glucose
level in diabetes. In: Proceedings of the 7th IEEE International Conference on Bioinfor-
matics and Bioengineering, Boston, pp. 1168–1172 (2007)

balas@drbalas.ro
296 A. Nath et al.

11. Chee, F., Savkin, A.V., Fernando, T.L., Nahavandi, S.: Optimal H-infinity insulin injection
control for blood glucose regulation in diabetic patients. IEEE Trans. Biomed. Eng. 52(10),
1625–1631 (2005)
12. Abu-Rmileh, A., Garcia-Gabin, W., Zambrano, D.: Internal model sliding mode control
approach for glucose regulation in type1 diabetes. Biomed. Signal Process. Control 5, 94–
102 (2010)
13. Shtessel, Y., Kaveh, P.: Blood glucose regulation using higher-order sliding mode control.
Int. J. Robust Nonlinear Control 18, 557–569 (2008)
14. Lynch, S.M., Bequette, B.W.: Model predictive control of blood glucose in type 1 diabetics
using subcutaneous glucose measurements. In: Proceeding of the American Control
Conference, Anchorage, May 2002, pp. 4039–4043 (2002)
15. Hovorka, R., Canonico, V., Chassin, L., Haueter, U., Massi-Benedetti, M., Federici, M.,
et al.: Nonlinear model predictive control of glucose concentration in subjects with type1
diabetes. Int. J. Control 25, 905–920 (2004)
16. Ali, S.F., Padhi, R.: Optimal blood glucose regulation of diabetic patients using single
network adaptive critics. Optim. Control Appl. Methods 32(2), 196–214 (2009)
17. Ibbini, M.S., Masadeh, M.A.: A fuzzy logic based closed-loop control system for blood
glucose level regulation in diabetics. J. Med. Eng. Technol. 29(2), 64–69 (2005)
18. Maleki, A., Geramipour, A.: Continuous control of blood glucose in TIDM using fuzzy logic
controller in insulin pump: a simulation study. In: 2nd International Conference on Control,
Instrumentation and Automation, pp. 122–127 (2011)
19. Yasini, S., Naghibi-Sistani, M.B., Karimpour, A.: Active insulin infusion using fuzzy-based
closed-loop control. In: Proceedings of 3rd International Conference on Intelligent System
and Knowledge Engineering, Xiamen, November 2008, pp. 429–434 (2008)
20. Campos-Delgado, D.U., Hernandez-Ordonez, M., Femat, R., Gordillo-Moscoso, A.: Fuzzy-
based controller for glucose regulation in type-I diabetic patients by subcutaneous route.
IEEE Trans. Biomed. Eng. 53(11), 2201–2210 (2006)
21. Friis-Jensen, E.: Modeling and Simulation of Glucose-insulin Metabolism, Dissertation,
Technical University of Denmark (2007)
22. Fisher, M.E.: A semi closed-loop algorithm for the control of blood glucose levels in
diabetics. IEEE Trans. Biomed. Eng. 38(1), 57–59 (1991)
23. Dalla Man, C., Raimondo, D.M., Rizza, R.A., Cobelli, C.: GIM, simulation software of meal
glucose-insulin model. J. Diabetes Sci. Technol. 1(3), 323–330 (2007)
24. Makroglou, A., Li, J., Kuang, Y.: Mathematical models and software tools for glucose-
insulin regulatory system and diabetes: an overview. Appl. Numer. Math. 56, 559–573
(2006)
25. Dalla Man, C., Rizza, R.A., Cobelli, C.: Meal simulation model of the glucose-insulin
system. IEEE Trans. Biomed. Eng. 54(10), 1740–1749 (2007)
26. Sorensen, J.T.: A physiologic model of glucose metabolism in man and its use to design and
assess improved insulin therapies for diabetes (1985)
27. Dalla Man, C., Toffolo, G., Basu, R., Rizza, R.A., Cobelli, C.: A model of glucose
production during a meal. In: Proceedings of the IEEE EMBS Conference, pp. 5647–5650
(2006)

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