ASSIGNMENT

DIABETES MELLITUS

SUBMITTED TO: SUBMITTED BY:

ASHIM BORAH SIR NITASHA (Group-3)

RAJAT

PEEYUSH

ASHISH

VIVEK

INTRODUCTION

In 2013, it was established that over 382 million people throughout the world had diabetes.

It is a metabolic disease in which the person has high blood glucose, either because insulin production is inadequate or because the body’s cells do not respond properly or both.

INSULIN

Insulin is a hormone. It makes our body’s cell absorb glucose from the blood. The glucose is stored in the liver and muscle as glycogen and stops the body from using fat as a source of energy.

Glucose level is maintained in the body by the appropriate levels of insulin and glucagon. The pancreas releases glucagon when the concentration of glucose in the bloodstream falls too low. Glucagon causes the liver to convert stored glycogen into glucose to be taken up and used by the insulin dependent tissues.

Diagram showing balance between insulin and glucagon

TYPES OF DIABETES

1. TYPE 1

Pancreas does not produce insulin. This type of diabetes also referred to as insulin dependent diabetes or early onset diabetes. People usually develop type 1 diabetes before adulthood or teenage years. Approximately 10 percent of cases are type1.

CAUSE AND RISK FACTORS

Type1 diabetes is caused by a lack of insulin due to the destruction of insulin producing beta cells in the pancreas i.e. it is an autoimmune disease. Beta cell destruction may take place over several years, but the symptoms of the disease usually develop over a short period of time.

GENETIC SUSCEPTIBILITYCertain gene variants that carry instructions for making proteins called human leukocyte antigens (HLA) on the white blood cells (WBC’S) are linked to the risk of developing type 1 diabetes.

The proteins produced by HLA genes help determine whether the immune system recognise a cell as a part of the body or as foreign material. Some combinations of HLA gene variants predict that a person will be at higher risk for type 1 diabetes. Many additional gene regions have been found which help identify people at risk type1.

Genetic testing can show what types of HLA genes a person carries and can reveal other genes related to diabetes.

ENVIRONMENTAL FACTORS Environmental factors such as food, viruses and toxins may play a role in the development of the type 1 diabetes, but the exact nature of their role has not been determined.

2.TYPE 2

The body does not produce enough insulin for proper function or the cells do not interact with the insulin in comprehensive manner (insulin resistance).

Approximately 90 percent of the cases worldwide are of this type 2. It a progressive disease.

CAUSE AND RISK FACTORS

Overweight and obese people have much higher risk of developing type2 diabetes. Being obese causes the body to release chemicals that can destabilise the body’s cardiovascular and metabolic systems.

Physical inactivity and age GENETIC SUSCEPTIBILITY

The role of genes is suggested by the high rate of type2 diabetes in families and identical twins and wide variations in diabetes prevalence by ethnicity. Type2 occurs more frequently in African Americans, Alaska natives, American Indians etc.

Studies have shown that variants of the TCF7L2 gene increases susceptibility of type2 diabetes. For people who inherit two copies of the variants, the risk of developing type2 diabetes is about 80 percent higher than for those who do not carry the gene variant.

3. GESTATIONAL DIABETESThis type affects females during pregnancy. Some women have very high levels of glucose in their bodies as they are unable to produce enough insulin to transport all of the glucose into their cells, resulting in the progressively rising levels of glucose.

CAUSE AND RISK FACTORS

It is caused by the hormonal changes and metabolic demands of pregnancy together with genetic and environmental factors.

Insulin resistance and beta cell dysfunction hormones produced by the placenta and other pregnancy related factors contribute to insulin resistance which occurs in most of pregnancy cases during late pregnancy.

Common symptoms of diabetes include:

Excessive thirst and appetite

Increased urination (sometimes as often as every hour) Unusual weight loss or gain Fatigue Nausea, perhaps vomiting Blurred vision In women, frequent vaginal infections In men and women, yeast infections Dry mouth Slow-healing sores or cuts Itching skin, especially in the groin or vaginal area

Sexual and urological problems of diabetes facts

Sexual and urologic complications of diabetes occur because of the damage diabetes can cause to blood vessels and nerves.

People with diabetes may experience bladder problems such as overactive bladder, poor control of sphincter muscles that surround the urethra, urine retention, and urinary tract infections.

Those people with diabetes who are at risk of sexual or urologic problems include people who have poor glucose and blood pressure control; have high levels of cholesterol; are overweight, are over the age of 40 years, those that smoke, and lack of physical activity.

Bladder Problems

Many events or conditions can damage nerves that control bladder function, including diabetes and other diseases, injuries, and infections. More than half of men and women with diabetes have bladder dysfunction because of damage to nerves that control bladder function. Bladder dysfunction can have a profound effect on a person's quality of life. Common bladder problems in men and women with diabetes include the following:

Overactive bladder: Damaged nerves may send signals to the bladder at the wrong time, causing its muscles to squeeze without warning. The symptoms of overactive bladder include

urinary frequency-urination eight or more times a day or two or more times a night urinary urgency-the sudden, strong need to urinate immediately

urge incontinence-leakage of urine that follows a sudden, strong urge to urinate

Poor control of sphincter muscles Sphincter muscles surround the urethra-the tube that carries urine from the bladder to the outside of the body-and keep it closed to hold urine in the bladder. If the nerves to the sphincter muscles are damaged, the muscles may become loose and allow leakage or stay tight when a person is trying to release urine.

Urine retention: For some people, nerve damage keeps their bladder muscles from getting the message that it is time to urinate or makes the muscles too weak to completely empty the bladder. If the bladder becomes too full, urine may back up and the increasing pressure may damage the kidneys. If urine remains in the body too long, an infection can develop in the kidneys or bladder. Urine retention may also lead to overflow incontinence-leakage of urine when the bladder is full and does not empty properly.

Tests to Diagnose Diabetes

1. Fasting plasma Glucose test (FPG)2. Oral Glucose tolerance test (OGTT)

In FPG amount of glucose in the blood is taken after overnight fast (not eating for at least 8 hours).

In OGTT a person glucose level is measured after fasting and 2 hours drinking glucose rich beverage than check blood glucose level.

After confirmation of Diabetes there are two tests which will check regular for controlling diabetes

1. A1C Test: The A1C test can be used to diagnose type 2 diabetes and pre diabetes alone or in combination with other diabetes tests. When the A1C test is used for diagnosis, the blood sample must be sent to a laboratory that uses an NGSP-certified method for analysis to ensure the results are standardized. Blood samples analyzed in a health care provider’s office, known as point-of-care (POC) tests, are not standardized for diagnosing diabetes. The following table provides the percentages that indicate diagnoses of normal, diabetes, and pre diabetes according to A1C levels.

Having pre diabetes is a risk factor for getting type 2 diabetes. People with pre diabetes may be retested each year. Within the pre-diabetes A1C range of 5.7 to 6.4 percent, the higher the A1C, the greater the risk of diabetes. Those with pre diabetes are likely to develop type2 diabetes within 10 years, but they can take steps to prevent or delay diabetes.

2. Self-Monitoring of Blood Glucose (SMBG)

Self-monitoring of blood glucose or SMBG refers to home blood glucose testing for people with diabetes. Self-monitoring is the use of regular blood testing to understand one’s diabetes control and inform changes to improve one’s control or wider regime. Self-monitoring of blood glucose

levels has been a hotly disputed issue for a number of years, particularly with regards to people with type 2 diabetes who are not on insulin.

Treatment and Drug:

Diabetes is a group of metabolic disease in which a person has high blood glucose .there are three types of diabetes Type 1, Type2 & Gestational.

Type 1- There is no production of insulin.

Type 2- There is not enough production of insulin for proper function or the cells in the body do not react to insulin (insulin resistance)

Gestational -This type of diabetes, which causes high blood sugar, develops during pregnancy (gestation) and is caused by increased production of hormones that make the body less able to use insulin as well as it should. Most gestational diabetes goes away after birth but it does put you at higher risk of developing type2 diabetes later. Healthy eating and being active may decrease the risk of developing subsequent type 2 diabetes.

Treatment for type 1 diabetes includes:

Taking insulin Carbohydrate counting

Frequent blood sugar monitoring Eating healthy foods Exercising regularly and maintaining a healthy weight

Management of type 2 diabetes includes:

Healthy eating Regular exercise Possibly, diabetes medication or insulin therapy Blood sugar monitoring

These steps will help keep your blood sugar level closer to normal, which can delay or prevent complications.

DRUGS

Drug Name Working mechanism Possible side effectMetformin Improving the sensitivity your It does not lower the

body to insulin so that body uses insulin more effectively

blood sugar itself. Nausea Diarrhea

Sulfonylurease Glyburide Glipizide

Help your body to secrete more insulin

Low blood sugar Weight gain

Thaizolidines * Like metformin more sensitive to insulin

Heart failure Fractures

* Because of the side effect of Thaizolidines, generally are not first choice of treatment.

Insulin therapy:

Some people who have Type 2 diabetes need insulin therapy as well .In past insulin therapy was used as last resort but most prescribed because of its benefit.

Types of insulin are many and include:

Rapid-acting insulin Long-acting insulin Intermediate options

Insulin administration:

Injections. You can use a fine needle and syringe or an insulin pen to inject insulin under your skin. Insulin pens look similar to ink pens, and are available in disposable or refillable varieties. Needles are available in a variety of sizes, so you can find one that's most comfortable for you.

An insulin pump — a device about the size of a cellphone worn on the outside of your body. A tube connects a reservoir of insulin to a catheter that's inserted under the skin of your abdomen. This type of pump can be worn in a variety of ways, such as on your waistband, in your pocket, or with specially designed pump belts.

Role of Stem Cell in Diabetes treatment

1. Stem cells and their therapeutic potential:

Stem cell has exceptional ability to proliferate and differentiate into specialized cell types under appropriate microenvironment. The stem cells have the potential to become any type of specialized cell such as a myocyte, blood cell, hepatocyte and brain cell (Fig. 1).

Fig 1 Self renewal and differentiation potential of the stem cells

Fig 2 Different types of stem cell resources with a potential to be developed into insulin secreting cells

2. Adult stem cells and diabetes2.1 Pancreatic stem cells

The pancreas is an organ of first choice to be looking for the potential stem cells. Animal studies have shown that the availability of small amounts of pancreatic tissue would restore the maximum pancreatic b-cell mass (Bonner-Weir et al., 1993).

Studies have shown that the islets of both rodent and human contains multi potent stem cells (Eberhardt et al., 2006; Zulewski et al., 2001)

Research proves two facts, first the existence of pancreatic stem cell and second the b-cells can be formed from non-b-cells.

2.2 Haemopoietic progenitor cells For HSC transplant, we mobilize the patient's hematopoietic SC from bone

marrow to the blood with the use of low dose cyclophosphamide and granulocyte colony-stimulating factor. Then the hematopoietic SC are collected from peripheral blood by leukapheresis and cryopreserved. The cells are re-injected intravenously. This is a lymphoablative scheme, as we destroy most of the patient's lymphocyte clones, which include both autoreactive and non-autoreactive, and we recover the immunologic system with AHSCT. This phenomenon is called immunologic reset.

2.3 Other adult stem cells Liver and small intestine can also act as a source of beta-cells. Production of insulin secreting beta cells from the stem cells of the small

intestine (Suzuki et al., 2003; Yoshida et al., 2002), salivary glands (Okumura et al., 2003) and adipose tissue (Timper et al., 2006).

3. ESCs and diabetesA five-step protocol for differentiation of hES (human embryonic stem) cells toPancreatic hormone expressing cell. First focused on generating DE, followed by PDX1-expressing cells and, finally, insulin-expressing cells (http://www.med.upenn.edu/timm/documents/Klaus_DAmour.pdf)

4. Induced pluripotent stem cells and diabetes The production of pluripotent stem cells from non-pluripotent resource is referred

as induced pluripotency. Somatic cells can be reprogrammed to produce

pluripotent stem cell under specific conditions and such cell is known as induced pluripotent stem cell (iPSC). Induced pluripotency is achieved by directed expression of specific transcription factors (Yamanaka, 2008).

In vitro differentiation protocol that guaides the differentiation of induced pluripotent stem (iPS) cells into insulin-producing β cells.(A) Stepwise differentiation of iPs cells onto insulin-producing cells.(B) combination of factors used to guide the differentiation, (C) specific markes used to evaluate the corresponding stage of differentiation.

(http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3474639/ )5. Safety concerns

Safety aspects: Safe administration and potential risk of teratoma formation.

Transplantation issues: Transplantation complications and acclimatization in the tissue microenvironment.

Scale up issues: Scale up potential of stem cells. Ethical issues: Ethical issues concerned with the use of ESCs. Side effects