TYPE 2 DIABETES - INTRODUCTION

Patients with type 2 diabetes are usually overweight and have difficulty losing weight. However
diet and exercise are sometimes not enough and drugs such as gliclazide (the Greeks and Romans
called diabetes sweet urine disease) are used. Treatment of the condition only became possible in
the 1920s when Banting and Best discovered the role of the pancreas in the disease and were able to
isolate insulin. In the 1930s it was realized that there were two distinct types of diabetes, now called
type 1 and type 2 (the latter occurs in about 90% of people)
Patients with type 2 diabetes can adopt a better lifestyle to prevent the onset of the disease by
starting to lose weight and eat healthier. However, one risk factor that is not modifiable is family
history. For example, if one parent has type 2 diabetes, the risk doubles. But if two parents have it,
the risk increases sixfold. The patient is tried to maintain blood pressure values between 130 and
80, to keep the total cholesterol value below four millimoles per litre, to do at least 150 minutes of
exercise per week.
There are a number of drugs used to treat type 2 diabetes. The common ones are sulfonylureas,
metformin, and insulin.

DIABETES PHYSIOLOGY - INSULIN

Insulin is a hormone that is secreted by the pancreas, located below the liver, when blood sugar
levels are high. So the more sugar we have, the more insulin is released. The main sugar in diabetes
is glucose, there are others such as fructose and lactose, but they do not trigger the release of
insulin.
Insulin is released into the bloodstream and travels around the body to increase the amount of
glucose that enters the body's cells. Once in cells, particularly the liver, glucose is stored as
glycogen for later use. Insulin also increases the glycogen produced from glucose in cells such as
hepatocytes in the liver and muscle tissue. Insulin also reduces the breakdown of glycogen into
glucose and decreases glucose produced from other sources in the body such as fat. So, above all,
insulin reduces the amount of glucose in the blood.
In people with type 2 diabetes, not only is there less insulin released by the pancreas, but the insulin
that is released is unable to lower the amount of glucose in the blood through these mechanisms as
efficiently. The pancreatic B cell produces and secretes insulin into the bloodstream. When a person
eats a meal, glucose from the blood is taken up by B cells in an active transport mechanism,
meaning glucose is actively pumped into the cells. Glucose is broken down inside the B cell and,
after a series of steps, adenosine triphosphate, or ATP, is produced. ATP binds to and causes the
KATP channels to close, leading to an increase in potassium, which triggers the opening of the
calcium channels and calcium rushes into the cell. And this is the trigger for the release of insulin
into the bloodstream. In type 2 diabetes there is reduced insulin secretion from the pancreas.

DIABETES-CHEMISTRY
what led to the development of drugs to treat high blood glucose levels, or hyperglycemia was a
side effect of a drug. Our story begins in the 1930s, when a French research team discovered that
the newly discovered antibiotic metabolite,prontosil, was the active agent fighting bacteria. This
metabolite is known as sulfanilamide, a poorly active and poorly soluble antibiotic. The structure
comprises a benzene ring with an amino group and a sulfonamide group. Over time, attempts have
been made to find analogues of this antibiotic, for example by adding an aromatic ring to the
sulfonamide nitrogen atom. Known among these antibiotics was IPTD, which was used to treat
typhoid fever, however it led to several deaths caused by hypoglycemia. Several studies have in fact
examined the action of this antibiotic which stimulated the pancreas to release more insulin. For this
reason it was thought to use it to treat diabetes, but with poor results. After several studies, a blood
sugar-lowering effect was also found in carbutamide, which was used briefly as a medicine in the
1950s in West Germany. However for a short time, due to different fatal side effects for different
people.
The next development came with tolbutamide. The amino group on the benzene ring was replaced
with a methyl group, and this succeeded in greatly reducing the compound's toxicity. The downside
was that it was rapidly metabolized and had to be taken twice a day. Once again, chemistry has
stepped in to try and solve this problem. Since the methyl group on the benzene ring of tolbutamide
is a site of metabolism, the methyl group has been replaced with a chlorine atom in chlorpropamide.
This succeeded in reducing the metabolism considerably and the drug was no longer eliminated
quickly from the body.
The middle section of this drug is called sulfonylurea, a general class of antidiabetic agents.
Glibenclamide provided the idea that there was a possibility to vary the molecule on the left side.
For medicinal chemists, this was a great advantage. They could leave the sulfonylurea and the
benzene ring alone to get the biological activity they wanted, i.e. increased insulin release from the
pancreas, by letting them manipulate the left and right sides to get the right profile, i.e. it had to be
safe, effective and convenient for clinical use. However, the metabolism of glibenclamide varied
from person to person, leading to the use of gliclazide in the 1980s.
DIABETES – CHEMISTRY 2
If side effects are evident, where there is too much variation in the effect of a drug from one person
to another, then improvements need to be made. The history of sulfonamides, evolving towards
sulfonylurea compounds, is a classic process of continuous improvement. And all of this is geared
towards providing better medicines for better health outcomes.

From sulfanilamide, the next development was to change the right side to produce IPTD. From
there, we developed the first sulfonylurea with a short carbon chain attached to the right side. Then
there was Tolbutamide which gave us reduced toxicity and was much more specific for the
treatment of diabetes. Then there were chlorpropamide and glibenclamide, ending with glipizide.

The side effect of a drug is what led to the development of the sulfonylurea antidiuretic drugs.
Indeed, drug side effects have often been exploited to develop new drugs.

DIABETES PHARMACOLOGY
We analyze how the drug gliclazide can lead to the release of insulin. Drugs taken by mouth to
lower blood sugar are called oral hypoglycemic drugs (such as sulfonylureas). Hypoglycemia
means less glucose in the blood. In people with type 2 diabetes, the pancreas doesn't release enough
insulin, and the insulin that is released is less effective at lowering blood sugar. Therefore, glucose-
lowering drugs that cause pancreatic B cells to release more insulin are commonly prescribed for
people with type 2 diabetes. In most countries around the world, the trade name for gliclazide is
Diamicron. How does it affect blood sugar control? When gliclazide is taken in tablet form, it is
absorbed from the small intestine into the bloodstream. Gliclazide leaves the blood and binds to
KTP channels causing them to close.

This results in an increase of potassium in the cell, making it more positive. Because calcium
channels are sensitive to voltage changes, the increase of potassium in the cell triggers the opening
of the calcium channels and calcium enters the B cells. Calcium entry causes insulin-containing
vesicles to move towards the cell membrane and release their contents. And as a result, insulin is
released into the blood.

Some of the most common side effects are low blood sugar or hypoglycemia, symptoms of which
are weakness, headache, hunger and fast heartbeat. If these side effects occur, it is important to
correct the effect and raise your blood sugar by eating sugar-containing foods or drinks
immediately.

DIABETES - PHARMACEUTICS
Let's look at the pharmacokinetics of Gliclazide and how its elimination half-life affects how often
the patient needs to take the tablets. The elimination half-life of a drug is the time it takes for the
drug concentration in the elimination phase to drop to half its concentration, and this affects how
often this drug should be taken throughout the day.

The concentration of Gliclazide drops below its minimum effective concentration only after 12
hours, and this allows it to be taken twice a day or in the morning and evening or with meals.
However, as there are patients who have problems taking tablets Gliclazide is available as tablets
once a day. This new type of tablet, sometimes referred to as a slow-release or modified tablet, does
not disintegrate and releases its drug much longer than conventional tablets. Therefore, with this
type of administration, the concentration of Gliclazide drops below the minimum effective
concentration only after 24 hours, which means that it is sufficient to take only one tablet per day.

DIABETES - PATIENT SUMMARY

Now, you’ve heard about the science of gliclazide. Let’s check back with our patient Shirley.
Shirley’s been trying to keep her blood glucose under control for some time by focusing on eating
better and exercising more. She’s already been treated for her diabetes with one medicine called
metformin, but unfortunately, her blood glucose has remained high. She finally decided, with her
doctor, that it was time to start additional treatment. Shirley’s doctor started her on gliclazide, 30
milligrammes daily (gliclazide works to increase insulin in the bloodstream and, therefore, lowers
blood glucose, also the effect of gliclazide can last for 24 hours due to the combination of its
reasonably long half-life and a modified release formulation, so it only has to be taken once a day).
The pharmacist will need to explain to Shirley that gliclazide can have some side effects. The most
concerning side effect is blood sugar becoming too low. This is called hypoglycemia. If Shirley’s
blood sugar gets too low, she could become very unwell quite quickly. She could experience loss of
coordination, slurred speech, confusion, and eventually, even loss of consciousness. The first signs
of low blood glucose are weakness, trembling, shaking, sweating, and lightheadedness. Shirley
really needs to know to immediately eat some sugar to raise her blood glucose level. This could be
in the form of some jelly beans, sugar or honey, or some soft drink. There also glucose tablets and
gel available. Even after consuming sugar, the blood glucose can fall again, so Shirley also needs to
eat a meal or at least have some biscuits, fruit, or milk, to ensure her blood glucose stays high
enough. Shirley’s doctor will want to keep a close eye on her as she starts the gliclazide tablets and
will do a number of blood tests to determine how well controlled her blood glucose is. The doctor
will also check that Shirley’s diabetes is not causing other problems, such as kidney disease. Shirley
needs to make sure she tells all of her health care professionals that she has diabetes and is taking
gliclazide so they can monitor her appropriately.