CHAPTER 2

LITERATURE REVIEW

2.1 Diabetes Mellitus

Diabetes mellitus is a type of metabolic disorder and is categorized as chronic

hyperglycemia, which involves the disturbances of carbohydrate, fat, and protein
metabolism. It may be cause by lack of insulin secretion, defects in insulin action or
both[3]. In 2008, for adults aged over 25 years old, the global prevalence is estimated
to be 10%. The percentages keep increasing years to years due to the changes in
humans lifestyle[4]. The main causes of diabetes mellitus is still unrevealed, but it is
closely related to body weight, gender, diet, genetic and physical activities[1]. There
are three common types of diabetes mellitus, Type 1, Type 2 and gestational diabetes.

Type 1 diabetes does not only occurs among children, teenagers and, adults but
also in elderly people. The occurrence may be due to two causes; either the pancreas
produces little insulin or the pancreas is not able to produce any insulin at
all. This happens because the insulin producing cells in the pancreas may have been
destroyed. Physicians call this type of diabetes as insulin dependent diabetes mellitus
(IDDM)[5].

Type 2 diabetes classified as non-insulin dependent diabetes mellitus

(NIDDM). Contrary to Type 1 diabetes, the pancreas produces enough insulin but the
cells are resistant to any insulin action. Usually, adults over 40 years old have a higher
tendency to get the Type 2 diabetes[5].

The abnormalities diabetes which usually occurs during pregnancy is also

known as a gestational diabetes. Commonly, it affects the pregnant mother temporarily
and will disappear after delivery. As the baby grows, the hormones from the placenta
will help the baby to develop. But, in this case the hormones block the action of the
mothers insulin in her body. So, the pregnant mother may need up to three times as
much insulin for her body. This situation is called insulin resistance. Gestational
diabetes can increase the risk of health problems in unborn babies if not well treated.
It can be controlled by using insulin injection and diet control[5].

Early detection of diabetes can be seen from several symptoms such as,
increased thirst, constant hunger, excessive weight loss and constant tiredness[6]. As
of now, there is still no cure yet for diabetes. But it can be controlled by taking
medicine and insulin injections. In addition, healthy diet and physical activities can be
practiced to maintain a normal and safe glucose level in blood.
2.2 Blood Glucose Measurement

To ensure that the glucose level is always within the normal range, a continuous
monitoring of glucose level is required. Blood glucose measurement are categorised
into three techniques; invasive, minimally invasive, and non-invasive[2].

2.2.1 Invasive Technique[7]

Invasive techniques in glucose measurement devices are widely used as it has

a high measurement accuracy. The most common invasive technique used is finger
prick where blood is extracted from the finger by using a lancet (small, sharp needle)
to withdraw the blood sample. The blood sample is dropped on a test strip and placed
into a glucometer will display the blood glucose level. Some common practice allow
the blood extraction to be obtained from other sites of the body such as the upper arm,
forearm, base of the thumb and thigh. However the reading of blood glucose level
might vary compared to the reading obtained from the fingertip.

For a continuous blood glucose monitoring, multiple finger pricks are not
desirable as it is painful and has higher risk of infections. To reduce the pain and risk
of infections, an alternative technique is introduced, known as minimally invasive
blood glucose measurement.
2.2.2 Minimally Invasive Technique

Schichiri et al.(1985) were the first to introduce the minimally invasive

technique by the development of subcutaneously implantable needle-type electrodes.
The used of subcutaneous implantation technique able to avoid infection problems
such as septicaemia, fouling with blood clots, and embolism[8]. They have designed a
glucose sensor with a fine needle, or flexible wire and the active sensing element is
implemented on the tip of it and implanted in the subcutaneous tissue. Nowadays, there
are various types of continuous glucose monitoring systems which has been
commercialized. Example of such systems may be using electrochemical detection or
and optical detection of glucose oxidase to measure glucose in blood[8].

Recently, Medtronic MiniMed Inc has introduced a latest continuous glucose

monitoring system, as shown in Figure 2.1 which uses electrochemical detection of
glucose in blood. To measure the glucose levels in a tissue fluid, a glucose sensor in
the form of a tiny electrode is inserted under the skin and connected to the
transmitter[9]. The transmitter will send the signal through wireless radio frequency to
a monitoring and display device. Afterwards, the device will detect and notify the
patient if their glucose level is less or more than the normal range. The advantage of
the system is it is able to continuously measure glucose levels in real time throughout
the day and night.

Another approach using electrochemical detection is proposed by Jui et

al.(2011) from the National United University Taiwan. The application uses an
electrochemical sensor which consists of a potentiostat with a glucose test strip and an
automatic test system[10]. In 2006, Dachao Li et al.(2006) from Tianjian University
of China had proposed a new approach using ultrasonic. They have
combined the interstitial fluid transdermal extraction with the surface of plasma
resonance detecting[11]. Both results showed that the techniques used are able to
measure the glucose concentration in blood the blood accurately.

Even though minimally invasive technique helps to reduce the pain and risk of
infection , it is still not desirable for some diabetic patient as it still involves direct
contact with the tissue. Besides that, the measurement are sometimes not accurate due
to the noise and artefacts resulted from the patients movement and the reaction
between electrodes and other reactants in blood[12].
 Figure 2.1: Continuous glucose monitoring by Medtronic[9]

2.2.3 Non-Invasive Technique

The major reason for continuous research efforts in the field of non-invasive
blood glucose measurement is because that it is the only way to develop a pain free
glucose monitoring system. Instead of extracting blood, other fluids such as the saliva,
sweat, urine, or tears can be used as an alternative to measure glucose concentration.
Besides that, glucose levels can also be measured through direct measurement of body
tissues such as, the skin, tongue, aqueous humor of the eyes and oral mucosa. Figure
2.2 exhibits the technology that has been used in blood glucose measurement[13].
 Figure 2.2: Overview of the blood glucose measurement technologies[13]

The latest research regarding measurement of the glucose level in sweat was
conducted by Oscar et al.(2013). The approach uses the electronic nose technology
and implemented 32 metal oxide semiconductor (MOS) sensors, operating at different
temperatures to detect the glucose level in sweat[14]. Another research group from
New Jersey has been applying the non-invasive technique using Raman spectra to
detect glucose in porcine eyes[15]. The glucose solution was injected into the porcine
eyes and the concentration was controlled. Afterwards, the Raman spectra were
measured using a compact spectroscopic system with a laser excitation wavelength at
785nm. From the results, both approaches proved to have high viability in glucose
detection[15][14].

In addition, the non-invasive technology has been developed using various

types of method such as absorbance spectroscopy, photoacoustic spectroscopy,
polarimetry, fluorescence and dielectric spectroscopy. Among these methods,
absorbance is the most commonly used as the light will reflects, scatters and transmit
when its focused on biological tissues which depends on the structural and the
chemical composition of the sample[13].

2.3 Absorbance Spectroscopy

The common absorbance spectroscopy method has been widely used using
near infrared (NIR) and mid infrared (MID).

2.3.1 Near Infrared

The wavelength of near infrared is in the range of 750 nm-2500 nm[12]. Within
this range, it is able to penetrate around 1 mm-100 mm deep into the tissue. The main
focus of the technique is to measure the glucose levels in finger, skin of forearm, ear
lobe, lip mucosa, oral lip, cheek and arm. Near infrared have different characteristics
for different region of wavelength as shown in Table 2.1.
 Table 2.1: Characteristic for different wavelength region[2]

Wavelength Characteristic
700 nm-1300 nm Have higher orders of glucose overtone
regions
Have little glucose absorption
Have low light absorption by water
1500 nm-2500 nm Have highest glucose absorption
Does not get effected by excessive water
attenuation
Have relative minimum in water
absorption spectrum.

By using the Monte Carlo method, Katsuhiko et al. (2003) has developed a
non-invasive system using near infrared[16]. To detect the glucose level, they had
developed fibre optic probes that consist of a source and detector optical fibres. Both
source and detector are separated by 0.65 mm, placed on the skin surface. They
reported that the correlation coefficient of blood glucose predicted by near infrared and
finger prick was 0.928 with a standard error of prediction of 32.2 mg/dL[16]. Another
research based on near infrared has been done by Ilan Gabriely, MD et al.(1999)[17]
They were using transcutaneous near infrared spectroscopy system to monitor blood
glucose levels during euglycemia and hypoglycaemia. The results proved that near
infrared can be used to predict the glucose levels in humans[17].
2.3.2 Mid Infrared

The spectrum range of mid infrared is 2500 nm-10000 nm[12]. The

measurements using mid infrared is similar to the near infrared with an advantages that
it reduces scattering and increases the absorption as the wavelength is higher. In this
field, a research was conducted by Uemura et al. (1999). They measures the spectra of
mucous membrane of the lips using attenuated total reflectance (ATR) prism and
chalcogenide optical fibre. The experiment results correlation is 0.920[18].

2.4 Portable Glucose Sensor

Diabetic patients should continuously monitor their glucose levels. A self -

monitoring system is needed to ensure their glucose levels, is always in the normal
range and it may also help them to maintain their diet and physical activities. One of
the earliest portable non-invasive blood glucose device was introduced by Arlene
Duncan et al. (1995) which used pulsed laser photoacoustic spectroscopy to detect the
glucose concentration in blood from the finger[19]. Takahashi et al. (2013) has
developed a portable glucose monitoring system by using implantable fluorescent-
hydrogen sensor, wearable photo detector, microcontroller, wireless device, and
software for transdermal. The experiment was conducted by attaching the portable
device to the rats ear and fluorescent intensity was measured for three days. Another
approach of developing a portable glucose sensor was conducted by J.R. Blanco et al.
(2006)[20]. They had designed a low cost portable potentiostat for amperometric
biosensors. The device measures the faradaic current that originated by the electronic
interchanges between specific substance and biological recognition
system which is present on the electrode and kept at an appropriate potential. Both
approaches applied invasive technique to measure the glucose levels and shown to be
reliable and accurate in measuring glucose level in blood[20][21].

The reported researches proved the non-invasive techniques used were

appropriate to develop portable non-invasive glucose monitoring systems.

2.5 Insulin

Islet of Langerhans is a region of specialized cells in the pancreas which

produces the insulin in the human body. The main function of insulin is to facilitate
the glucose entering the cells[6]. Glucose is a product of digestion and it is needed by
body cells to produce energy. However, without insulin, the glucose cannot get into
the cells. Figure 2.3 explains the production of insulin in the human pancreas.
 Figure 2.3: The production of insulin in human pancreas[22]

In the abdomen, the pancreas is seen to be adjacent to the duodenum. Figure

2.3 shows the cross-section of the pancreas which displays the islet of Langerhans that
is the functional unit of endocrine pancreas. The beta cell in the image functions to
synthesize and secretes insulin and is located adjacent to blood vessels. The Beta cell
will adjust then insulin production if there are changes in blood glucose[22].

There are four known types of insulin; rapid acting, regular, intermediates, and
long acting insulin[23]. Each of the insulin has different characteristic in their onset of
action (when drugs first take effects), duration of action (how long medication stays in
the body) and peak (when medical exerts its maximum effect). Insulin does are in mg
or mL but in Units. Table 2.2 shows the characteristic of different types of insulin[23].
 Table 2.2: Insulin characteristic

Type of insulin Characteristic

Onset of Action Peak Duration of
Action.
Rapid acting 15 minutes A couple of hours 4-5 hours
after administration

Regular 30 minutes 2-4 hours after 6 hours

administration

Intermediates 1-2 hours 4-10 hours after 24 hours

administration

Long acting Require only one injection a day

Last up to 24 hours

2.6 Artificial Pancreas

The main objective in developing artificial pancreas is to improve the insulin

therapy system. Besides that, it is one of the approaches to reduce the difficulty face
by the insulin dependent diabetic patient. There are two common approaches of
artificial pancreas; medical equipment, and bioengineering[24]. Medical equipment
approaches consist of three parts: continuous glucose sensing, dosing algorithm, and
automated insulin delivery as shown in Figure 2.4. The control systems consist of a
dosing algorithm used to determine the insulin dose needed. There are many reliability
control techniques that have been used to develop the artificial pancreas.
 Figure 2.4: Artificial pancreas scheme[25]

Shanshan Li et al. (2008) uses an adaptive feedback control method to develop

two new nonlinear feedback control schemes based on artificial pancreas; known
insulin glucose dynamics and unknown dynamics[25]. The experiment were
conducted in the presence of patient insulin-glucose characteristic, actuation
disturbance and feedback sensor uncertainties. The nonlinear feedback controller was
developed for known insulin, glucose dynamic while the adaptive controller was
designed for unknown insulin glucose dynamics. The simulation results show that
there were problems for adaptive feedback control as it has adaptive disturbance
rejection, sensor uncertain actuation, and sensing lag compensation[25].
 The bioengineering approach uses the development of bio-artificial
pancreas. It consists of a biocompatible sheet encapsulated beta cells which will be
implanted in the human body and act as the endocrine pancreas and is viable for
years. A research was conducted by the National University of Singapore in which
the researchers designed an artificial pancreas to be applied in wireless medical
implant[26]. Particularly, they had developed a bio-artificial pancreas with low
power consumption. The block diagram of the system is shown in Figure 2.5. To
conduct the experiment, they had proposed a virtual patient system to evaluate
control algorithms and communication protocol. The results show that the system
is reliable to use as a bio-artificial pancreas as it was able to function as actual
pancreas in the human body.

Figure 2.5: Block diagram of bio-artificial pancreas[26]