Diabetes

Diabetes

Contents

1. Introduction

1.1 Definition

1.2 Classification 0

1.3 Types

2. Types

2.1 Type 1

2.2 Type 2

* Prediabetes

2.3 Gestational

2.4 MODY

2.5 Diabetes due to mutant insulin’s

2.6 Diabetes due to mutant insulin receptors

2.7 Diabetes due to mutation of mitochondrial DNA

2.8 Wolfram’s syndrome

2.9 DIDMOAD

3. Causes

3.1 General

3.2 Type 1

3.3 Type 2

3.4 Gestational

3.5 Other

4. What is Insulin?

5. Symptoms of Diabetes.

6. Diagnosis

6.1 The A1C test

6.2 The FPG (Fasting Plasma Glucose) test

6.3 The OGTT (Oral Glucose Tolerance Test)

6.4 Benedict’s test

6.5 Dipstick method

6.6 Fructosamine test

7. Treatment

7.1 Treatment of hypoglycemia

7.2 Treatment of hyperglycemia

7.3 Intake of insulin

a. Rapid acting insulin

b. Short acting insulin

c. Intermediate acting insulin

d. Long acting insulin

e. Pre-mixed insulin

Diabetes

1. Introduction

1.1 Definition

”Diabetes mellitus is a syndrome with disordered metabolism and inappropriate hyperglycemia due to either

a deficiency of insulin secretion or to a combination of insulin resistance and inadequate insulin secretion to

compensate.” (Mushtaq Ahmad, 2008) (1)

“Diabetes, often referred to by doctors as diabetes mellitus, describes a group of metabolic diseases in which

the person has high blood glucose or low blood glucose (blood sugar), either because insulin production is

inadequate, or because the body's cells do not respond properly to insulin, or

both.”(www.medicalnewstoday.com) (3)

1.2 Classification

Diabetes can be classified into following classes:

a. Hypoglycemia

Hypoglycemia is sometimes called insulin reaction. It is when your blood glucose is too low.

b. Hyperglycemia

Hyperglycemia is when your blood glucose is too high; it is the opposite of hypoglycemia. Hyperglycemia

needs to be treated immediately as it is a major cause of complications among people with diabetes.

Hyperglycemia happens when there is no insulin in the blood, not enough insulin in the blood, or the insulin

in the blood is not working properly

1.3 Types

Diabetes has been categorized into the following types

a. Type 1 Diabetes

The body does not produce insulin. Some people may refer to this type as insulin-dependent diabetes,

juvenile diabetes, or early-onset diabetes. People usually develop type 1 diabetes before their 40th year, often

in early adulthood or teenage years.

Type 1 diabetes is nowhere near as common as type 2 diabetes. Approximately 10% of all diabetes cases are

type 1.

Patients with type 1 diabetes will need to take insulin injections for the rest of their life. They must also

ensure proper blood-glucose levels by carrying out regular blood tests and following a special diet.

(www.medicalnewstoday.com) (3)

b. Type 2 Diabetes

This type was called in the past as not insulin dependent diabetes mellitus because in these patients sufficient

insulin is produced which can prevent ketosis; however hyperglycemia is not prevented as tissue need more

insulin to overcome insulin resistance.

Type 2 diabetes has further been classified into two types

a. Non-obese type 2 diabetes

b. Obese type 2 diabetes (Mushtaq Ahmad, 2008) (1)

c. Gestational

This occurs during pregnancy as a result of hormonal influences causing insulin resistance

(www.slideshare.com/diabetes) (4 & 5)

This type affects females during pregnancy. Some women have very high levels of glucose in their blood,

and their bodies are unable to produce enough insulin to transport all of the glucose into their cells, resulting

in progressively rising levels of glucose. (www.medicalnewstoday.com) (3)

d.Other: other types includes MODY, Diabetes due to mutant insulin, Diabetes due to mutant insulin receptor.

2. Types

Following are the different types of diabetes.

2.1 Type 1 Diabetes

This is the severe form of diabetes mellitus and occurs most commonly in juveniles. It is a catabolic disorder

in which circulating insulin is virtually absent, plasma glucagon is elevated and the pancreatic B-cells fails to

produce any insulin in response to all insulinogenic stimuli. It is usually associated with ketosis. Exogenous

insulin is therefore required to reverse the catabolic state, prevent ketosis, and reduce the hyperglucagonemia

and lower plasma glucose. For this reason this type of the disease has been called in the past insulin-

dependent diabetes mellitus, i.e. IDDM- now an obsolete term; other names were ketoacidosis-prone,

immune mediated diabetes mellitus. Its incidence varies gently in different countries. For example in

Scandinavia it comprises 20% of total cases of diabetes, while in China and Japan less than 1 % of diabetics

have type 1.

Type 1 diabetes seems to have an immunologic basis. Certain human leukocyte antigens (HLA) are

strongly associated with its development. Moreover circulating islet cell antibodies and anti-insulin

antibodies can be demonstrated in most cases.

This auto immune basis of type 1 diabetes mellitus is supported by the observation that administration of

cyclosporine (immunosuppressant drug) decreases hyperglycemia. It is believed that autoimmune response

is genetically predisposed persons may be triggered by some virus (mumps), toxic chemical agents, etc.

(Mushtaq Ahmad, 2008) (1)

Type 1 diabetes is also known as juvenile diabetes or childhood diabetes. Although a large number of

diabetes Type 1 patients become so during childhood, it can also develop after the age of 18. Developing

Type 1 after the age of 40 is extremely rare.

Type 1, unlike Type 2, is not preventable. The majority of people who develop Type 1 are of normal weight

and are otherwise healthy during onset. Exercise and diet cannot reverse Type 1. Quite simply, the person

has lost his/her insulin-producing beta cells. Several clinical trials have attempted to find ways of preventing

or slowing down the progress of Type 1, but so far with no proven success.

A C-peptide assay is a lab test that can tell whether somebody has Type 1 or Type 2. As external insulin has

no C-peptide a lack of it would indicate Type 1. The test is only effective when ALL the endogenous insulin

has left the body - this can take several months. (www.medicalnewstoday.com) (3)

Type 1 diabetes has further been classified into 2 types

a. Immune mediated type 1 diabetes mellitus

Approximately one-third of the disease susceptibility is due to genes and two-thirds to environmental

factors.

Genes that are related to the HLA locus contribute about 40% of the genetic risk.

About 95% of patients with type 1 diabetes possess either HLA-DR3 or HLA-DR4, compared with 45–

50% of white controls.

Most patients with type 1 diabetes mellitus have circulating antibodies to islet cells (ICA), insulin (IAA),

glutamic acid decarboxylase (GAD65), and tyrosine phosphatases (IA-2 and IA2-β ) at the time the

diagnosis is made.

b. Idiopathic type 1 diabetes mellitus

Less than 10% of subjects have no evidence of pancreatic β cell autoimmunity to explain their insulinopenia

and ketoacidosis.

It was recently reported that about 4% of the West Africans with ketosis-prone diabetes are homozygous for

a mutation in PAX-4 (Arg133Trp)—a gene that is essential for the development of pancreatic islets.

(www.slideshare.com/diabetes) (4 & 5)

2.2 Type 2 diabetes

This type was called in the past as non-insulin-dependent diabetes mellitus (NIDDM) because in these

patients sufficient insulin is produced which can prevent ketosis; however hyperglycemia is not prevented as

tissues need more insulin to overcome insulin resistance. Still other names were ketoacidosis-resistant and

non-immune mediated diabetes mellitus. In addition to this insulin resistance, the pancreatic B-cells also

show a decreased response to raised plasma glucose. Both these defects are aggravated by hyperglycemia

and a decrease in plasma glucose decreases their intensity. (Mushtaq Ahmad, 2008) (1)

A person with diabetes type 2 either:

1. Does not produce enough insulin. Or

2. Suffers from 'insulin resistance'. This means that the insulin is not working properly.

The majority of people with Type 2 have developed the condition because they are overweight. Type 2

generally appears later on in life, compared to Type 1. Type 2 is the most common form of diabetes.

In the case of insulin resistance, the body is producing the insulin, but insulin sensitivity is reduced and it

does not do the job as well as it should do. The glucose is not entering the body's cells properly, causing two

problems:

1. A build-up of glucose in the blood.

2. The cells are not getting the glucose they need for energy and growth.

In the early stages of Type 2 insulin sensitivity is the main abnormality - also there are elevated levels of

insulin in the blood. There are medications which can improve insulin sensitivity and reduce glucose

production by the liver.

As the disease progresses the production of insulin is undermined, and the patient will often need to be given

replacement insulin.

Excess abdominal fat is much more likely to bring on Type 2 Diabetes than excess fat under your skin

(www.medicalnewstoday.com) (3)

Type 2 diabetes is further classified into:

a. Non-obese type 2 patients

These patients generally do not show the early phase of insulin release in response to the raised plasma

glucose; however B-cells do respond to other insulinogenic stimuli such as sulfonylures, glucagon or

secretin. They may show insulin resistance but their disease is easily controlled by appropriate doses of

insulin or oral hypoglycemic agents.

Most cases of this type are idiopathic but in some cases chromosomal monogenic defects have been

demonstrated.

b. Obese type 2 patients

These patients show insulin resistance. In early stages there is hyperplacia or B-cells associated with

hyperinsulinism; later B-cells stop functioning. The defect appears to be post-receptor one. Lack of insulin

action despite hyperinulinemia further decreases the sensitivity of insulin receptors (down regulation effect).

Obesity in these cases is generally of the abdominal type (apple liken truncal), producing an abnormally high

waist-hip ratio. The metabolites from viscera on reaching the liver via portal vein alter liver metabolism and

increase hepatic glucose output more then peripheral fat mobilization into systemic veins. It has been found

that obesity due to excessive fat in the sub cutaneous tissue (e.g. in summon wrestlers of japan) does not

exert these harmful effects. This type of diabetes is treated by decreased caloric intake to decrease obesity

and by muscular excerise to increase muscle mass as well as increased entery of glucose into muscle cells.

These measures decrease insulin insensitivity and decrease hyperglycemia and hyperinsulinism. (A.F.

Smith/ G.J. Beckett/ S.W. Walker/ P.W.H. Rae.

, 6th edition) (2)

2.3 Gestational diabetes

This type affects females during pregnancy. Some women have very high levels of glucose in their blood,

and their bodies are unable to produce enough insulin to transport all of the glucose into their cells, resulting

in progressively rising levels of glucose.

Diagnosis of gestational diabetes is made during pregnancy.

The majority of gestational diabetes patients can control their diabetes with exercise and diet. Between 10%

to 20% of them will need to take some kind of blood-glucose-controlling medications. Undiagnosed or

uncontrolled gestational diabetes can raise the risk of complications during childbirth. The baby may be

bigger than he/she should be.

Scientists from the National Institutes of Health and Harvard University found that women whose diets

before becoming pregnant were high in animal fat and cholesterol had a higher risk for gestational diabetes,

compared to their counterparts whose diets were low in cholesterol and animal fats.

(www.medicalnewstoday.com) (3)

2.4 Maturity-onset diabetes of the young (MODY)

This type is relatively rare and shows autosomal dominant inheritance; the disease starts at 25 years of age or

less. Five different types of MODY have been descried, called MODY 1, 2, 3, 4 & 5 caused by mutations at

different chromosomes.

No obese and impaired glucose-induced secretion of insulin.

2.5 Diabetes due to mutant insulin

This is a very rare subtype of no obese type 2 diabetes, with no more than ten families having been

described.In this case chromosome 11 is affected.

2.6 Diabetes due to mutant insulin receptors

Defects in one of their insulin receptor genes have been found in more than 40 people with diabetes, and

most have extreme insulin resistance associated with acanthosis Nigerians.In this case chromosome 19 is

affected

2.7 Diabetes due to mutation of mitochondrial DNA

Only mothers transmit this type of diabetes because mitochondrial DNA is 100 % derived from the ovum

and not at all from the sperm whose head lacks mitochondria and therefore does not have any mitochondrial

DNA (Mushtaq Ahmad, 2008) (1)

2.8 Wolfram’s syndrome

An autosomal recessive neurodegenerative disorder first evident in childhood.

2.9 DIDMOAD

It is due to mutations in a gene WFS1, which encodes a 100.3 KDa trans membrane protein localized in the

ER. (www.slideshare.com/diabetes) (4 & 5)

3. Causes

Diabetes (diabetes mellitus) is classed as a metabolism disorder. Metabolism refers to the way our bodies use

digested food for energy and growth. Most of what we eat is broken down into glucose. Glucose is a form of

sugar in the blood - it is the principal source of fuel for our bodies.

When our food is digested, the glucose makes its way into our bloodstream. Our cells use the glucose for

energy and growth. However, glucose cannot enter our cells without insulin being present - insulin makes it

possible for our cells to take in the glucose.

Insulin is a hormone that is produced by the pancreas. After eating, the pancreas automatically releases an

adequate quantity of insulin to move the glucose present in our blood into the cells, as soon as glucose enters

the cells blood-glucose levels drop.

A person with diabetes has a condition in which the quantity of glucose in the blood is too elevated

(hyperglycemia). This is because the body either does not produce enough insulin, produces no insulin, or

has cells that do not respond properly to the insulin the pancreas produces. This results in too much glucose

building up in the blood. This excess blood glucose eventually passes out of the body in urine. So, even

though the blood has plenty of glucose, the cells are not getting it for their essential energy and growth

requirements.(www.medicalnewstoday.com) (3)

4. What is Insulin?

Insulin is a hormone. It makes our body's cells 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.

When there is very little insulin in the blood, or none at all, glucose is not taken up by most body cells. When

this happens our body uses fat as a source of energy. Insulin is also a control signal to other body systems,

such as amino acid uptake by body cells. Insulin is not identical in all animals - their levels of strength vary.

Porcine insulin, insulin from a pig, is the most similar to human insulin. Humans can receive animal insulin.

However, genetic engineering has allowed us to synthetically produce 'human' insulin.

(www.medicalnewstoday.com) (3)

5. Symptoms of diabetes

Most common diabetes symptoms:

1. Frequent urination

Have you been going to the bathroom to urinate more often recently? Do you notice that you spend most of

the day going to the toilet? When there is too much glucose (sugar) in your blood you will urinate more

often. If your insulin is ineffective, or not there at all, your kidneys cannot filter the glucose back into the

blood. The kidneys will take water from your blood in order to dilute the glucose - which in turn fills up your

bladder.

2. Disproportionate thirst

If you are urinating more than usual, you will need to replace that lost liquid. You will be drinking more than

usual. Have you been drinking more than usual lately?

3. Intense hunger

As the insulin in your blood is not working properly, or is not there at all, and your cells are not getting their

energy, your body may react by trying to find more energy - food. You will become hungry.

4. Weight gain

This might be the result of the above symptom (intense hunger).

5. Unusual weight loss

This is more common among people with Diabetes Type 1. As your body is not making insulin it will seek

out another energy source (the cells aren't getting glucose). Muscle tissue and fat will be broken down for

energy. As Type 1 is of a more sudden onset and Type 2 is much more gradual, weight loss is more

noticeable with Type 1.

6. Increased fatigue

If your insulin is not working properly, or is not there at all, glucose will not be entering your cells and

providing them with energy. This will make you feel tired and listless.

7. Irritability

Irritability can be due to your lack of energy

8. Blurred vision

This can be caused by tissue being pulled from your eye lenses. This affects your eyes' ability to focus. With

proper treatment this can be treated. There are severe cases where blindness or prolonged vision problems

can occur.

9. Cuts and bruises don't heal properly or quickly

Do you find cuts and bruises take a much longer time than usual to heal? When there is more sugar

(glucose) in your body, its ability to heal can be undermined.

10. More skin and/or yeast infections

When there is more sugar in your body, its ability to recover from infections is affected. Women with

diabetes find it especially difficult to recover from bladder and vaginal infections.

11. Itchy skin

A feeling of itchiness on your skin is sometimes a symptom of diabetes.

12. Gums are red and/or swollen - Gums pull away from teeth

If your gums are tender, red and/or swollen this could be a sign of diabetes. Your teeth could become loose

as the gums pull away from them.

13. Frequent gum disease/infection

As well as the previous gum symptoms, you may experience more frequent gum disease and/or gum

infections.

14. Sexual dysfunction among men

If you are over 50 and experience frequent or constant sexual dysfunction (erectile dysfunction), it could be a

symptom of diabetes.

15. Numbness or tingling, especially in your feet and hands

If there is too much sugar in your body your nerves could become damaged, as could the tiny blood vessels

that feed those nerves. You may experience tingling and/or numbness in your hands and feet.

(www.medicalnewstoday.com) (3)

6. Diagnosis

Diabetes can often be detected by carrying out a urine test, which finds out whether excess glucose is

present. This is normally backed up by a blood test, which measures blood glucose levels and can confirm if

the cause of your symptoms is diabetes.

Following are some of the tests used to diagnose diabetes.

6.1 The A1C test

- At least 6.5% means diabetes

- Between 5.7% and 5.99% means prediabetes

- Less than 5.7% means normal

6.2 The FPG (Fasting Plasma Glucose) test

Usually it is quite high, but in some cases it may be within normal limits. Blood is obtained after an

overnight fast

6.3 The OGTT (Oral Glucose Tolerance Test)

The standard oral glucose tolerance test is described below

In a normal person an excessive intake of glucose does not raise the blood glucose level to an abnormally

high level. This is due to the fact that a raise plasma glucose level stimulates the secretion of more insulin

which increases the rate of utilization of glucose by many different mechanisms. But a diabetic patient lacks

this homeostatic mechanism and when a large amount of glucose is administered to such a person, his

plasma glucose level rises markedly; when the renal threshold of 160 to 180 mg glucose/dL of plasma is

exceeded, glucose starts appearing in the urine. This abnormal sensitivity of the diabetic patient of glucose

intake is the basis of the glucose tolerance test. There are many different methods of doing this test, one of

which (standard oral) is described below.

The patient is asked to come to the laboratory in the morning without having eaten his breakfast. The fasting

blood sample and urine are collected. He is given plenty of water containing 75 grams of glucose. His blood

samples are taken at half or intervals up to 2 or 3 hours after glucose administration. Any urine voided may

also be collected for testing for glucose. The plasma concentration of glucose in the blood samples is then

measured.

6.4 Intravenous tolerance test

Instead of giving glucose orally, it can be given by intravenous injection; this is called intravenous glucose

tolerance test. It is done when it is desired to avoid variations in glucose absorption that may occur with the

oral test, e.g. in small bowel disease and hyperthyroidism.

6.5 Cortisone glucose tolerance test

Another modification is cortisone glucose tolerance test in which the oral test is preceded by administering

cortisone or prednisolone; this test is more sensitive than the standard oral test

6.6 HbA1c test

The long term control of diabetes can be assessed by the measurement of HbA1c in the blood. HbA1c is a

minor component of Hb A and is normally present in small amounts only, i.e. up to about 6 % of total Hb A.

but in the presence of long standing hyperglycemia its concentration rises. It is produced by the non

enzymatic glycosylation (i.e. glycation) of the amino acids valine and lysine present in Hb A molecule. The

HbA1 includes HbA1c and two other glycohaemoglobins HbA1a and HbA1b; the latter contain

phosphorylated glucose or fructose. (Mushtaq Ahmad, 2008) (1)

6.7 Benedict’s test

To assess urine sugar level

To 5 ml Benedict’s solution add 8-10 urine drops

Boil and allow to cool. Then observe color change

COLOR CHANGE % OF SUGAR

Blue Nil

Clear green 0.1

Turbid green 0.3

Green and yellow 0.5-1.0

Yellow 1.0

Orange 2.0

Brick red >2.0

I. Maltose, galactose, sucrose and drops which contain aldehyde group such as aspirin, penicillin, vitamin C,

antibiotics positive results.

II. Detect only blood sugar level >180 mg/dL

6.8 Dipstick method

i. A plastic strip coated with reagents

ii. Reagent strip measure glucose level using glucose oxidase method

Glucose H2O2 (change the color of indicates)

6.9 Fructose amine test

Ructosamine = Glycosylated Plasma protein, mainly albumin

Indicate previous 2-3 week glycaemic control

Impaired in patient with anemia, haemoglobinopathies & pregnancy

(www.slideshare.com/diabetes) (4 & 5)

7. Treatment

A long time ago

Before insulin was discovered in 1921 Diabetes Type 1 was a fatal disease - most patients

would die within a few years of onset. Things have changed a great deal since then.

7.1 Treatment Of Hypoglycemia

Hypoglycemia is sometimes called insulin reaction. It is when your blood glucose is too

low. Even though you may do all you can to manage your diabetes, hypoglycemia can

happen, and it can and must be treated before it gets worse.

You need to raise your blood glucose. The fastest way to do this is to eat some form of

sugar. The ADA advises:

Take 3 glucose tablets (easily bought)

1/2 a cup of fruit juice

5 to 6 pieces of hard candy (UK 'sweets')

You should ask your dietitian or health care professional for more advice on what you

could eat to treat hypoglycemia.

Make sure you always carry at least one type of sugar with you so that you are prepared.

7.2 Treatment of Hyperglycemia

The American Diabetes Association says exercising can help lower blood glucose levels.

If your blood glucose is above 240mg/dl. Check your urine for ketones and do not

exercise if there are ketones present as this will raise your blood glucose levels even

more!

Reducing your food intake will also help lower your blood glucose. It is important that

you stick to your meal plan, which should be worked out with a dietitian or health care

professional.

7.3 Intake of Insulin

You cannot take insulin as a pill. If you did, the moment it got to your stomach it would

be digested and would never get into your bloodstream.

You have to inject insulin into the fat just under your skin - from there it will get to your

bloodstream.

There are many types of insulin. According to the American Diabetes Association (ADA)

there are over 20 types of insulin in the American market. They work in different ways,

they are made differently, and they vary in price.

Insulin is most commonly made in laboratories today. It can also come from animals,

mainly pigs.

a. Rapid-acting insulin

This type of human insulin starts to work within five minutes of being injected and peaks

after about one hour. It continues to be active for 2 to 4 hours. Examples of rapid-acting

insulin are lispro marketed by Eli Lilly, insulin aspart marketed by Novo Nordisk, or

insulin glulisine marketed by sanofi-aventis.

b. Short-acting insulin

Also known as Regular (acting) insulin. This type of human insulin reaches your

bloodstream approximately 30 minutes after you inject it, and peaks from 2 to 3 hours

after injection. It is effective for 3 to 6 hours.

c. Intermediate-acting insulin

This human insulin takes from 2 to 4 hours to reach the bloodstream after injection. It

peaks at 4 to 12 hours. It is effective for approximately 12 to 18 hours.

d. Long-acting insulin

This insulin gets into your bloodstream about 6 to 10 hours after you inject it. It is

effective for 20 to 24 hours. This type of insulin is also known as ultralente.

e. Pre-mixed insulin

Some patients have to mix two different types of insulin. If they find that difficult they

can have the insulin pre-mixed. This is especially useful for people who are visually

impaired. (www.medicalnewstoday.com) (3)

References

1. Essentials of medical biochemistry by MUSHTAQ AHMAD, volume 11, published by merit publishers, new

edition 2008, page 308-312

2. Lecture notes on clinical biochemistry by A.F. Smith/ G.J. Beckett, S.W. Walker/ P.W.H Rae, sixth edition,

Blackwell publishing, page 151-156

3. What is Diabetes? What causes Diabetes? On http://www.medicalnewstoday.com/info/diabetes/

4. Recent advance in diabetes mellitus ppt BIOCHEMISTRY on http://www.slideshare.net/biochem/recent-

advance-in-diabetes-mellitus-ppt-biochemistry#

5. www.slideshare.com/diabetes