1
Potential Benefits of a Systems Biology
Approach to the Study of Non-insulin
Dependent Diabetes Mellitus
Michelle L. Cooper, M.A.Sc. Candidate

Abstract—The incidences of Non-insulin Dependent Diabetes
Mellitus (NIDDM), more commonly called Type II Diabetes, has
been steadily increasing for the past 20 years. NIDDM is a serious
disease, which left untreated, could result in kidney failure, heart
disease, blindness nerve damage and perhaps amputations. It is
a disease that is characterized by an increase in insulin resistance
followed by a dysfunction in insulin secretion. Current biological
theories consisting of genetic or non-genetic factors have failed to
demonstrate the multifaceted mechanisms associated with
NIDDM. In this article it is proposed that a systems biology
approach for studying NIDDM would provide a suitable solution
for understanding both genetic and non-genetic factors and how
they work together to induce NIDDM Through a systemic
approach a holistic view of NIDDM can be obtained. Hopefully,
through the use of systems biology practices a solution will be
found, which will provide effective treatment and/or cure for
diabetes.
Index Terms—insulin resistance, insulin secretion, Non-insulin
Diabetes Mellitus, systems biology
I. INTRODUCTION
T
YPE II Diabetes, (more often called Non-Insulin
Dependent Diabetes Mellitus (NIDDM)) presently
represents 90 % of all diabetes cases world wide[1]. It is a
disease that has been known since ancient times with
progressive study carried out extensively in the past 75 years
[2]. According to The World Health Organization (WHO) an
estimate of 135 million people will suffer from NIDDM in
2004. This quantity is expected to double by the year 2025
[3]. In 2002, there were 18.1 million people in the United
States with NIDDM and that number is increasing 5-8% per
year [3]. The National Diabetes Clearinghouse estimates
diabetes cost the United States 132 billion dollars each year
[3]. NIDDM is characterized by multiple abnormalities in
insulin action and insulin release, which are both essential
elements in the development of the disease [4]. Aging, obesity
and genetic factors predispose one to the disease [5]. In
extreme cases even with effective therapy there is still a risk of
developing complications such as; kidney failure, heart
Manuscript received November 1, 2004. Michelle Cooper is with the
Mechanical and Industrial Engineering Department at the University of
Toronto, ON, CAN; e-mail: cooper@ mie.utoronto.ca
disease, blindness, nerve damage and amputations [6]. With
the increasing incidences of diabetes, the substantial cost and
the decreased quality of life associated with the disease a cure
and/or prevention of the disease are required as soon as
possible. A systems biology approach to researching NIDDM
would allow study of the disease to be undertaken with a
holistic approach. Factors such as heredity, insulin resistance,
insulin secretion dysfunction and environmental influences
could be studied together and their interrelations on each other
observed. For a systems biological approach to be successful
in the field of NIDDM a study of the genetic and non-genetic
factors would have to be studied in parallel.
II. NIDDM
NIDDM prevalence rates vary markedly between
populations. The prevalence increases with age, with approx.
20% of people over 65 affected [4]. This form of diabetes
accounts for the majority of cases in developing countries.
The highest prevalence rates have occurred in populations that
have undergone radical changes from traditional to
‘Westernized’ lifestyles (i.e. North American Indian,
Australian Aborigines and Pacific Islanders. The Prima
Indians of Arizona have the highest recorded prevalence with
over 50% of adults 35 or over acquiring the disease [2]. The
‘Thrifty Genotype’ hypothesis proposed by Neel states that to
ensure survival during periods of famine, certain genes
evolved to regulate efficient input and utilization of glycogen
during physical exertion [7]. Evidence has shown that this
thrifty genotype has not changed for the past 10 000 years [7].
This thrifty genotype is hypothesized to be present in several
isolated populations of Indian groups throughout the world for
whom food availability was not stable. The combination of
continuous food abundance and inactivity have resulted in a
metabolic disturbance which eliminates the evolutionarily
programmed biochemical cycles that were selected to support
interchanges of feast and famine and physical activity These
above notions support the evolutionarily hypothesized need to
undertake regular physical activity [7]. NIDDM has a strong
genetic influence however phenotypic expression of genetic
defects may change depending on presence or absence of
various environmental factors [8]. Clearly, the prevalence of
type 2 diabetes in a population depends not only on genetic
predisposition but is also largely influence by the lifestyle
which seems to inevitably result from urbanization and
2
industrialization. A strong backing for a genetic link has been
demonstrated through twin studies and family studies showing
a correlation between genotype and diabetes. To control
NIDDM a balanced diet followed by exercise and weight loss
may help to eliminate the disease. However, sometimes an
anti-diabetic drug such as glyburide (DiaBeta) is needed.
DiaBeta stimulates secretion of insulin by beta cells of the
pancreas [1].
Fig. 2. A systems biology illustration of the individual disciplines needed for
an interdisciplinary approach for understanding the structure of a biological
organism at the systems level [6].
IV. INSULIN RESISTANCE AND INSULIN SECRETION
Fig. 1 “Thrifty Gene Hypothesis “ Schematic of hypothesized interaction
of cycles of physical activity and metabolic processes between 50 000 and
10000 BC [7]
III. SYSTEMS BIOLOGY
Systems Biology refers to the study of biological systems
by systematically perturbing them chemically, genetically and
biologically while monitoring the gene, protein and
informational pathway response. This data is integrated and
eventually formulated into a working mathematical model that
describes the structure and response to individual
perturbations of the system [9]. The first step in systems
biology research is to identify all of the elements within the
system and to create a database containing this information
[9]. This initial approach is referred to as discovery science.
The second step of systems biology is to use hypothesis driven
science. Hypotheses are made in an attempt to distinguish
among the different elements discovered. Once information is
collected at each of the levels for a biological system the data
may be integrated to generate analytical mathematical models
of the system [9]. Systems biology is an integration of
discovery and hypothesis driven science [6]. For a systems
biological approach of research to be successful a crossdisciplinary faculty of biologists, computer scientists,
engineers, mathematicians, and physicists who speak and
understand the language of the different disciplines is needed
to develop a working computational mathematical model that
will predict the outcome on the biological system of several
changes in external and internal stimuli [9].
NIDDM occurs when insulin resistance and insulin
secretion both occur in the biological organism [4]. These two
fundamental defects disrupt the delicate balance by which
insulin-targeted tissues communicate with Beta cells and visa
versa [4]. Beta cells are located in the pancreas and secrete
the hormone insulin, which acts to lower blood sugar level [1].
Insulin resistance is a progressive metabolic disorder
associated with inactivity, aging and genetic predisposition
and environmental factors. The primary defect in the
development of whole body insulin resistance remains
unclear. In the past decade major advances have been made in
the understanding of molecular and cellular mechanisms
regulating entry of glucose into insulin-sensitive tissue.
However, a further understanding of the crucial glucoregulatory biochemical/molecular sites that can be targeted by
treatment strategies (i.e. exercise training) still has not
understood [10].
Insulin resistance results from complex
sequences of extracellular and intracellular events resulting in
the possibility of prereceptor, receptor and postreceptor
defects all potentially contributing to the disease [4]. Insulin
resistance is gated not only by the number and affinity of
insulin receptors but also by the functional state of
intracellular signaling pathways that transduce insulin binding
to various effectors. Cellular resistance of the glucose
pathway is caused by a malfunction of signal transduction
machinery [11]. Insulin receptor tyrosine-kinase activity has
been demonstrated to be decreased in skeletal muscle and
adipose tissue of patients with NIDDM [12]. In early stages
of NIDDM insulin resistance is greatest in the skeletal muscle
(the tissue responsible for approximately 80% of glucose
disposal under insulin-stimulated conditions). The insulin
resistance causes an increase of glucose in the blood plasma.
This increase in plasma glucose causes -cells to secrete an
increase of insulin into the blood. Unfortunately, the -cells
cannot continue to respond appropriately to the glucose load
3
and a rapid deterioration of the glucose homeostasis results
[10]. As skeletal tissue insulin resistance increases adipose
tissue generates more fatty acid, liver production of glucose
begins to go awry and Beta cells may undergo complete
failure. The Beta cells function in NIDDM has been studied
for years however there has been much progress in the
physiology and pathophysicology of insulin secretion made in
the last few years [4]. Pinpointing the number of variables
that could potentially contribute to disorder of insulin
secretory response and the precise definition of the sequence
of vents that leads to this disorder in a given patient with
NIDDM remains an elusive goal. A systems biology approach
would enable the various sequence of events leading to the
disorder of insulin secretory response to be reviewed in
parallel. Perturbing the system chemically, genetically and
biologically while using current technology developed from
the human genome projects for acquiring data, a solution for
NIDDM could be tangible in the near future.
free fatty acid release. This in turn triggers reduction in
insulin sensitivity at the hepatic and muscular levels [4]. In
normal glucose metabolism the liver removes 40% of insulin
secreted by the pancreas. Insulin reduces free fatty acid
levels. With rising free fatty acid levels further impairment of
insulin resistance results and an increase in plasma glucose in
the blood results in a vicious cycle between obesity and
NIDDM [11]. Several recent studies have provided new
evidence that weight loss and increased physical activity may
help prevent or delay development of NIDDM [13]. A
molecular mechanism, which enhances glucose uptake and
insulin sensitivity with exercise training, is related to an
increase in expression and/or activity of key signaling proteins
involved in skeletal muscle glucose metabolism [10]. One of
these proteins glucose-transporter 4 (GLUT-4) has increased
expression with exercise. The increase signaling of protein
GLUT-4 has been shown to be strongly associated with
improved insulin resistance on glucose metabolism [4]. An
additional factor that may contribute to the natural history of
obese patients developing NIDDM is the “overworked beta
cell hypothesis”. This hypothesis states that a prolonged
phase of compensatory hyperinsulinism may cause the beta
cells to become overworked and dysfunction occurs with the
progression of time [4]. With increasing work demands
towards a more sedentary lifestyle it becomes more difficult to
exercise and lose weight. With the availability of food and
portion sizes increasing every year it becomes harder to
consume less calories. Fewer calories consumed and an
increase in physical activity would greatly reduce the
occurrence of diabetes.
Fig. 3. A schematic illustrating the progression of NIDDM [7].
Fig. 4 A chart showing an increase in the risk of Type II diabetes with an
increase in waist circumference (cm) [14]
V. ENVIRONMENTAL FACTORS
Obesity, aging, sedentary lifestyle and an increase in fat
consumption are significant environmental factors affecting
the annual increase in NIDDM [10]. Since prevalence of
NIDDM increases with age the changing population
demographics will significantly affect the worldwide burden
of NIDDM in the future. Of all the environmental factors
listed above obesity is by far the most abundant in NIDDM
cases. Obesity accounts for 50-80% of all NIDDM
occurrences [10]. Obesity increases the fat mass (especially
visceral adiposity), which is associated with an increase in the
VI. CONCLUSION
NIDDM is a serious form of diabetes affecting several million
people worldwide. Although diabetes has been studied
extensively for the past 75 years there are still many
unknowns. These unknowns reduce the potential for a cure in
the near future. In the past, NIDDM has been researched
through its individual components (ie. genes, proteins, insulin
resistance, insulin secretion dysfunction, etc.) however there
are always stalls in these studies because several factors
contribute to the onset of NIDDM are not taken into account
4
sequentially. For example it is not clearly understood whether
or not insulin resistance is a result of genetics or merely a
secondary effect to obesity. Currently research in the area of
NIDDM has not developed a genetic model that may help to
explain the genetic aspect of diabetes. Another area of
research that is not yet understood is how the genetic and
environmental factors work in unison to develop diabetes.
Systems biology has been used to study many fields (i.e.
dementia, aging, cancer, autoimmunity, etc.) and has helped
the advancement towards a cure for several diseases. .
NIDDM however is not yet being studied with a systemic
view. A systems biological approach would allow an
understanding of the genetic, and non-genetic attributes of the
disease. The interrelation and interdependencies of each
element of the diabetic system need to be demonstrated to
understand the disease as a whole. There is still much need
for the study of diabetes at the discovery and hypothesis
driven levels of systems biology before a cure and/or
prevention will be possible. A cure for diabetes would
improve the lifestyle of many millions of people with the
disease as well as alleviate the emotional strain of those
watching loved ones suffer through the disease. Many new
methods of computational modeling have been developed
through the human genome project. It is hopeful that these
methods will one day help to cure NIDDM and make it a thing
of the past.
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