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Managing Diabetes Magazine - diabetes

Incredible Incretins
A hormone-based treatment for type 2 diabetes

Incretins are a small but important part of the complex way your body processes food. When you eat, your intestine releases these hormones. The word incretin comes from intestinal secretion of insulin. Incretins are an essential part of the body’s blood glucose control system. Although first discovered in the early 1900s, nobody knew then how to use incretins. In those with type 2 diabetes incretins do not work well. However, we have recently found ways to involve incretins in treating this condition.

Incretins boost the amount of insulin released in response to glucose (sugar) in the blood stream. They are responsible for more than half of the body’s insulin response. As well, they have many effects which work together to lower blood glucose levels.

In the brain, incretins increase the sense of fullness and reduce appetite.
In the stomach, they slow the passing of food from the stomach into the intestines.
In the pancreas, they help with insulin secretion. They also lower the amount of glucagon, a hormone released after meals.
In the liver, they stop glucagon and reduce the amount of glucose released.

Scientists have found that the pancreas makes more insulin when glucose is taken orally (by mouth) rather than intravenously (by a needle into a vein). This is called the ‘incretin effect.’ In someone without diabetes, taking glucose orally increases the amount of insulin made by the pancreas by 50 to 70 per cent.

Digestion details

When someone eats, the stomach and intestines break food down into glucose. Once glucose is created, the body reacts to it. The pancreas, sensing more glucose in the bloodstream, releases insulin. Insulin is like a key – it unlocks the body’s cells, allowing glucose to enter them and be used as energy.

The pancreas makes another hormone called glucagon. Glucagon works in the opposite way to insulin. It increases the amount of glucose in the bloodstream by stimulating the liver to produce glucose. This keeps blood glucose levels stable, since parts of the body (like the brain) are unable to store glucose. Glucose must be on hand 24 hours a day. Even when sleeping, the body still needs glucose.
The intestine reacts to food intake by releasing incretins. These hormones help the pancreas release more insulin and lower the release of glucagon. Both actions lower blood glucose.

The brain, pancreas, stomach and different hormones in the body all interact to control glucose. Insulin is released by the beta cells of the pancreas to lower blood glucose. Glucagon released by alpha cells of the pancreas increases blood glucose.

Digesting with diabetes

When someone with type 2 diabetes eats, several things may happen.

The pancreas may not produce enough insulin. Without this key, glucose stays in the blood and cannot move into the cells.
If the pancreas is making enough insulin, the cells may not recognize it. The insulin is unable to help get glucose into the cells. This is called insulin resistance. The key (insulin) is still there, but someone has changed the lock. If the insulin cannot open the cells, glucose stays in the blood and blood glucose levels remain high.
The liver may also make too much glucose, keeping blood glucose levels high.

Incretins and diabetes

Two kinds of incretins exist:

GLP-1 (glucagon-like peptide 1)
GIP (glucose dependent insulinotropic peptide or gastric inhibitory polypeptide).

Incretin hormones appear in response to food. The body uses the enzyme DPP-4 (dipeptidyl peptidase 4) to quickly break down incretins into inactive substances. More than half of GLP-1 breaks down in a minute or two. Likewise, over half of GIP disintegrates in seven minutes.

In those living with type 2 diabetes, incretins do not work as well. The release of GLP-1 after meals is lower, while GIP loses its ability to help the pancreas release insulin. However, the action of GLP-1 continues to work in people with type 2 diabetes. For this reason, the GLP-1 molecule has been of more interest to the scientific community.Beta cells in the pancreas make insulin. In type 2 diabetes, beta cells work poorly, this continues to decline with age. Studies done in animals show GLP-1 can significantly affect beta cell growth and survival. These studies have not been done in humans. The hope is that therapy using incretins in people with type 2 may protect the beta cells. This has not yet been proven.

Medication

Currently, two kinds of medications either copy GLP-1 or extend the action of the body’s natural occurring incretins. Versions that copy GLP-1 action are not available in Canada. However, one called Byetta™ (exenatide) is currently available in the United States. Many more are waiting for approval from the FDA. Byetta™ is available as an injection and is given twice a day. It is able to reduce A1c levels by 0.8 to two per cent.

The medications that extend the action of the body’s natural incretins are called the DPP-4 inhibitors. Januvia™ (sitagliptin) is one first introduced in Canada in January 2008. Others are currently awaiting approval by Health Canada.

Januvia™ stops the DPP-4 enzyme from breaking down the body’s natural incretins. This allows those hormones to work more effectively. It comes as a 100 mg tablet, taken once a day with or without food. In Canada, Januvia™ is approved for use with metformin. Together, they have greater effect on A1c, partly because they each work on different areas of the body.

Januvia™ is unique because it has several effects. Its action in the pancreas results in increased insulin secretion and lowered glucagon secretions. Together, these two actions reduce blood glucose levels.

There are benefits to this new class of medication:

There is little to no risk of low blood glucose when used with metformin, as recommended.
It does not cause weight gain.
It helps with blood glucose after meals.

Using Januvia™ with medications known to cause hypoglycemia (low blood glucose levels), such as sulfonylureas (glyburide and gliclazide) or insulin, has not been adequately studied. This combination is not recommended. Studies of those using Januvia™ alone or with metformin show a reduction of A1c by 0.5 to 0.8 per cent. Most people experience no side effects with this medication.

However, side effects include upper respiratory infection, headache and stuffy nose.

Since incretins appear in response to food, they do not stimulate insulin secretion when blood glucose levels are normal. The chance of experiencing a low blood glucose reaction is low. It does not cause nausea or weight gain. People who have congestive heart failure, or decreased kidney or liver function should not use it.

Keep in mind that as Januvia™ is a newer medication, so long term safety data is lacking. As it is new, it costs more than older medications.

Who should consider Januvia™?

2008 guidelines recommend that metformin should be the first drug used, both in overweight and non-overweight people. For those currently on metformin whose A1c is not at target, Januvia™ may be an option.

Deciding on a medication depends on:

blood glucose levels
length of diabetes diagnosis
side effects of medications
expected effect of lowering blood glucose
and personal preferences.

Talk with your doctor about all of your choices.

The body’s incretin hormones play an important role in glucose control. Medications that copy GLP’s action and those that stop the breakdown of the body’s natural incretins offer new treatment options. They may prove to have a significant role in controlling type 2 diabetes.