**2. Diabetes**

#### **2.1 What is diabetes?**

Diabetes is a global problem with devastating human, social and economic impact. Diabetes is a growing epidemic threatening to overwhelm global healthcare services, wipe out some indigenous populations and undermine economies worldwide, especially in developing countries. Today more than 250 million people worldwide are living with diabetes and by 2025, this total is expected to increase to over 380 million people. Approximately 24 million people are diabetics in United States which is about 8 percent of the total population. The number of people with diabetes is increasing due to population growth, aging, urbanization, and increasing prevalence of obesity and physical inactivity. Diabetes is a highly prevalent disease in India where more than 35 million people suffer from diabetes. Alarmingly, as much as 13 million cases remains undiagnosed which leads to long term complications. The prevalence of diabetes is greater amongst the urban South Asian population (12-15%) compared to urban population in the West (6%).[9] That is why Diabetes has been one of the most important subjects for biomedical research for many years.

Diabetes Mellitus, commonly referred to as Diabetes, means sweet urine. Consistently elevated levels of blood glucose lead to spillage to glucose into urine, hence the term sweet urine. When the blood sugar level consistently runs too high in our blood stream, the condition is named as Diabetes. In patients with Diabetes Mellitus, the absence or insufficient production of insulin by the liver causes hyperglycemia. Diabetes Mellitus is a syndrome characterized by chronic hyperglycemia resulting from absence or relative impairment in insulin secretion and/or insulin action. It can also be referred to as a condition characterized by the disturbances of carbohydrate, protein and fat metabolism, the way our bodies use digested food for growth and energy. The chronic hyperglycemia of diabetes is associated with long term damage, dysfunction and failure of various organs, especially the eyes, kidneys, nerves, heart and blood vessels.[7] Diabetes is the most common endocrine disorder. It is a chronic medical condition meaning it can last a lifetime which can be controlled but can not be cured completely.

these studies for management of diabetes, and attempt to lay out a framework for further development of these models to include pump therapy. These models are often formulated as a system of differential equations that describes the profile of insulin release and the dynamics of glucose concentration over specified period of time. In addition to providing background on existing modelling frameworks, the practical implications of their outputs

The main goals are (a) formulation of the model using the pump mechanism (b) defining the parameters (c) profiling the insulin release (d) simulating using estimated parameter values and (e) modelling extensions to include obesity as it had been well established that obesity promotes insulin resistance through the inappropriate inactivation of a process called gluconeogenesis, where the liver creates glucose for fuel. The model consists of blood glucose concentration, remote insulin action and amount of insulin. The model predictions include insulin secreted, if any, in pancreas, role of other organs, tissue uptake etc. This chapter closes with future direction in mathematical modelling of type 1 diabetes for optimal usage of external insulin and measuring insulin dependency with an insight into

Diabetes is a global problem with devastating human, social and economic impact. Diabetes is a growing epidemic threatening to overwhelm global healthcare services, wipe out some indigenous populations and undermine economies worldwide, especially in developing countries. Today more than 250 million people worldwide are living with diabetes and by 2025, this total is expected to increase to over 380 million people. Approximately 24 million people are diabetics in United States which is about 8 percent of the total population. The number of people with diabetes is increasing due to population growth, aging, urbanization, and increasing prevalence of obesity and physical inactivity. Diabetes is a highly prevalent disease in India where more than 35 million people suffer from diabetes. Alarmingly, as much as 13 million cases remains undiagnosed which leads to long term complications. The prevalence of diabetes is greater amongst the urban South Asian population (12-15%) compared to urban population in the West (6%).[9] That is why Diabetes has been one of the

Diabetes Mellitus, commonly referred to as Diabetes, means sweet urine. Consistently elevated levels of blood glucose lead to spillage to glucose into urine, hence the term sweet urine. When the blood sugar level consistently runs too high in our blood stream, the condition is named as Diabetes. In patients with Diabetes Mellitus, the absence or insufficient production of insulin by the liver causes hyperglycemia. Diabetes Mellitus is a syndrome characterized by chronic hyperglycemia resulting from absence or relative impairment in insulin secretion and/or insulin action. It can also be referred to as a condition characterized by the disturbances of carbohydrate, protein and fat metabolism, the way our bodies use digested food for growth and energy. The chronic hyperglycemia of diabetes is associated with long term damage, dysfunction and failure of various organs, especially the eyes, kidneys, nerves, heart and blood vessels.[7] Diabetes is the most common endocrine disorder. It is a chronic medical condition meaning it can last a lifetime

are discussed.

**2. Diabetes** 

**2.1 What is diabetes?** 

the role of obesity in developing diabetes.

most important subjects for biomedical research for many years.

which can be controlled but can not be cured completely.

Human body functions best at a certain level of sugar in the blood stream. Blood sugar levels are tightly controlled by insulin, the principal hormone that makes it possible for many cells (primarily muscle and fat cells) to use glucose from the blood. It is manufactured by the beta cells of the pancreatic islets of Langerhans, a small section of the pancreas. Secretion of insulin primarily occurs in response to increased concentration of glucose in the blood. Insulin helps the glucose from food get into the body cells. If body does not make enough insulin or if the insulin does not work the way it should, glucose can not get into the cells. It stays in the blood instead and blood glucose level gets too high causing to have Diabetes. Deficiency of insulin or its action plays a central role in all forms of diabetes. There are three major forms of diabetes:[18]

#### **2.1.1 Type 1 diabetes**

Type 1 diabetes is one of the most challenging medical disorder because of the demands it imposes on day-to-day life. It was formerly known as insulin dependent diabetes mellitus (IDDM) or juvenile onset diabetes mellitus.

In this type of diabetes, the pancreas undergoes an autoimmune attack by the body itself and is rendered incapable of making insulin. It is an autoimmune disorder, in which body's own immune system attacks the beta cells in the islets of Langerhans of the pancreas destroying them or damaging them sufficiently to reduce insulin production. The pancreas then produces little or no insulin. At present, scientists do not know exactly what causes the body's immune system to attack the beta cells, but it is believed that autoimmune, genetic, and environmental factors, possibly viruses, are involved. It develops most often in children and young adults, but can appear at any age.Type 1 diabetes, which predominately affects youth, is rising alarmingly worldwide, at a rate of 3% per year. Some 70,000 children worldwide are expected to develop type 1 diabetes annually. If not diagnosed and treated with insulin, a person with type 1 diabetes can lapse into a life-threatening diabetic coma, also known as diabetic ketoacidosis.

#### **2.1.2 Type 2 diabetes**

Type 2 diabetes, formerly called adult-onset diabetes or non-insulin- dependent diabetes mellitus (NIDDM), is the most common form of diabetes. Type 2 diabetes is responsible for 90 -95% of diabetes cases and is increasing at alarming rates globally as a result of increased urbanization, high rates of obesity, sedentary lifestyles and stress. Type 2 diabetes is increasingly being diagnosed in children and adolescents though it can occur at any age. Millions of people don't even know they have it because it can arise with minimal outward signs or symptoms. It is diagnosed with insulin resistance in which the pancreas is producing enough insulin but for unknown reasons, the body can not use the insulin effectively. This leads to a situation similar to type 1 diabetes in which the pancreas can't secrete enough insulin because of which glucose builds up in the blood and the body cannot make efficient use of its main source of fuel. This form of diabetes is associated with obesity, older age, a family history of diabetes, a history of gestational diabetes, certain medications, impaired glucose metabolism, psychological factors, and physical inactivity. Type 2 diabetes can be controlled with exercise, diet and lifestyle modifications.[6] This type of diabetes may develop microvascular complications, which may lead to retinopathy, nephropathy and peripheral and autonomic nephropathies, and macrovascular complications include atherosclerotic coronary and peripheral arterial disease.

Therapeutic Modelling of Type 1 Diabetes 465

Hispanic, Native American, African American, Asian American or Pacific Islander

Hypertension (>140/90 mm Hg) or dyslipidemia (high-density lipoprotein HDL

Diabetes mellitus (DM) has diverse intial presentations. The early symptoms of diabetes are related to elevated blood sugar levels in the body and loss of glucose in the urine. It usually presents with symptomatic hyperglycemia. Common sign and symptoms may include any

**Insulin:** An anabolic hormone, produced by the beta cells of the islets of Langerhans of pancreas in response of elevated blood sugar level in the body. It helps to control the blood

**Glucose:** Glucose is a simple sugar present in everyone's body. It is an essential nutrient that provides energy for the proper functioning of the body cells. After meals, food is digested in the stomach and intestines. The glucose in digested food is absorbed by the intestinal cells into the blood stream and is carried by the blood to all the cells in the body.

**Glucagon:** Glucagon is a hormone synthesized and secreted from alpha cells of the pancreatic islets used for carbohydrate metabolism. Its secretion increases rapidly when the sugar level is too low in the body. It maintains the level of glucose in the blood by binding to specific receptors on hepatocytes causing the liver to release its intracellular stores of glucose. As these stores become depleted, glucagon then encourages the liver to synthesize glucose by gluconeogenesis which will be released to prevent the development of

**Insulin Resistance**: Sometimes the cells throughout the body become resistant to the insulin produced by the pancreas due to which it becomes difficult for the sugar to enter the cells.

**Diabetic Ketoacidosis:** It is a condition in which the cells of muscle, liver and other body parts are unable to take up glucose for producing energy due to the absence of insulin. It is a

Glucose needs insulin to enter into the body as it can not get into the cells alone.

Family history of diabetes in a first degree relative (parent or sibling)

cholesterol <35mg/dl or triglyceride level >250mg/dl)

**2.3 Symptoms and diagnosis of diabetes mellitus** 

Tingling or loss of feeling in the hands or feet

**2.4 Biological terms commonly used in diabetes** 

Age-older than 45 years

History with gestational diabetes mellitus

Obesity

descent

of the following: Being very thirsty Urinating often

 Feeling very hungry or tired Losing weight without trying Repeated or slow healing infections

sugar level in the desirable range.

hypoglycemia, low sugar level.

This condition is known as insulin resistance.

 Having dry, itchy skin Extreme fatigue Blurred vision

#### **2.1.3 Gestational diabetes**

This type of diabetes develops just before or during the pregnancy. Though the patient may have diabetes before the onset of the pregnancy, it is termed gestational only if it is first identified after the pregnancy has occurred. Gestational diabetes is caused by the hormones of pregnancy which is produced when the placenta supports the growing fetus. These hormones may interfere with the mother's ability to produce and use her own insulin. Usually this form of diabetes goes away after the delivery but women who have had gestational diabetes have a 20 to 50 percent chance of developing type 2 diabetes within 5 to 10 years especially those who require insulin during pregnancy and those who are overweight. Untreated Gestational Diabetes Mellitus (GDM) can lead to fetal macrosomia, hypoglycemia, hypocalcemia and hyperbilirubinemia. Also chances of cesarean delivery and chronic hypertension increases in women with GDM.

#### **2.2 History and causes of diabetes**

Diabetes is not a newly born disease, it has been with human race from long back but, we came to knew about it in 1552 B.C. Since after than, many of Greek as well French **physicians** had worked on it and threw some light on the nature of disease, organs responsible for it etc. Diabetes was recognized and categorized with complete details and its types, Type 1and Type 2 in 1959. In 1870s, a French physician had discovered a link between Diabetes and diet intake, and then diabetic diet was formulated with inclusion of milk, oats and other fiber containing foods in 1900-1915. Dr. Frederick Banting, Prof. Macleod and Dr. Collip discovered the function of **insulin**, its nature, along with its use started at the University of Toronto from 1920 -1923, who were awarded a Noble prize. In 1922, 14 year old Leonard Thompson becomes the first human to receive insulin. In the decade of 1940, it has been discovered that different organs like kidney and skin are also affected if diabetes is creeping from a long term. A major turn in this **research** was in 1955, when the oral hypogycemic drugs had been manufactured. Paul E. Lacy, a JDRF – funded researcher at Washington University School of Medicine performs the first successful islets transplantation in diabetic animal models in 1976. The first experimental insulin pump was developed in 1979 which leads to further refined pumps to provide the infusion of insulin in a way which closely mimics the glucose response of human islets. Since then, scientists are trying their best to produce results with the most impact.

Diabetes and its complications occur among Americans of all ages and ethnicities but the elderly and certain racial/ethnic groups are more commonly affected. In comparison of non – Hispanic whites, African Americans and Hispanics/Latino Americans are about two times more likely to be affected by the disease. It has been found that one tribe in Arizona has the highest rate of diabetes in the world, with about 50 percent of the adults between the ages of 30 and 64 with the disease. Population of type 2 diabetes sufferers has officially reached epidemic proportions.

Diabetes mellitus is developed when pancreatic tissue responsible for the production of insulin is absent because it is destroyed by disease such as chronic pancreatitis, trauma or surgical removal of pancreas. It can also result from other hormonal disturbances such as excessive growth hormone production (acromegaly, in which a pituitary gland tumor at the base of the brain causes excessive production of growth hormone leading to hyperglycemia) and Cushing's syndrome, in which the adrenal glands produce an excess of cortisol which promotes blood sugar elevation. Several other factors that make it more likely that a person develop diabetes are as follows:


This type of diabetes develops just before or during the pregnancy. Though the patient may have diabetes before the onset of the pregnancy, it is termed gestational only if it is first identified after the pregnancy has occurred. Gestational diabetes is caused by the hormones of pregnancy which is produced when the placenta supports the growing fetus. These hormones may interfere with the mother's ability to produce and use her own insulin. Usually this form of diabetes goes away after the delivery but women who have had gestational diabetes have a 20 to 50 percent chance of developing type 2 diabetes within 5 to 10 years especially those who require insulin during pregnancy and those who are overweight. Untreated Gestational Diabetes Mellitus (GDM) can lead to fetal macrosomia, hypoglycemia, hypocalcemia and hyperbilirubinemia. Also chances of cesarean delivery

Diabetes is not a newly born disease, it has been with human race from long back but, we came to knew about it in 1552 B.C. Since after than, many of Greek as well French **physicians** had worked on it and threw some light on the nature of disease, organs responsible for it etc. Diabetes was recognized and categorized with complete details and its types, Type 1and Type 2 in 1959. In 1870s, a French physician had discovered a link between Diabetes and diet intake, and then diabetic diet was formulated with inclusion of milk, oats and other fiber containing foods in 1900-1915. Dr. Frederick Banting, Prof. Macleod and Dr. Collip discovered the function of **insulin**, its nature, along with its use started at the University of Toronto from 1920 -1923, who were awarded a Noble prize. In 1922, 14 year old Leonard Thompson becomes the first human to receive insulin. In the decade of 1940, it has been discovered that different organs like kidney and skin are also affected if diabetes is creeping from a long term. A major turn in this **research** was in 1955, when the oral hypogycemic drugs had been manufactured. Paul E. Lacy, a JDRF – funded researcher at Washington University School of Medicine performs the first successful islets transplantation in diabetic animal models in 1976. The first experimental insulin pump was developed in 1979 which leads to further refined pumps to provide the infusion of insulin in a way which closely mimics the glucose response of human islets. Since then, scientists are

Diabetes and its complications occur among Americans of all ages and ethnicities but the elderly and certain racial/ethnic groups are more commonly affected. In comparison of non – Hispanic whites, African Americans and Hispanics/Latino Americans are about two times more likely to be affected by the disease. It has been found that one tribe in Arizona has the highest rate of diabetes in the world, with about 50 percent of the adults between the ages of 30 and 64 with the disease. Population of type 2 diabetes sufferers has officially reached

Diabetes mellitus is developed when pancreatic tissue responsible for the production of insulin is absent because it is destroyed by disease such as chronic pancreatitis, trauma or surgical removal of pancreas. It can also result from other hormonal disturbances such as excessive growth hormone production (acromegaly, in which a pituitary gland tumor at the base of the brain causes excessive production of growth hormone leading to hyperglycemia) and Cushing's syndrome, in which the adrenal glands produce an excess of cortisol which promotes blood sugar elevation. Several other factors that make it more likely that a person

**2.1.3 Gestational diabetes** 

and chronic hypertension increases in women with GDM.

trying their best to produce results with the most impact.

epidemic proportions.

develop diabetes are as follows:

**2.2 History and causes of diabetes** 


#### **2.3 Symptoms and diagnosis of diabetes mellitus**

Diabetes mellitus (DM) has diverse intial presentations. The early symptoms of diabetes are related to elevated blood sugar levels in the body and loss of glucose in the urine. It usually presents with symptomatic hyperglycemia. Common sign and symptoms may include any of the following:

