Diabetes Forecast October 2005

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FOR TYPE 1/TYPE 2

Research Profile

Gastroparesis
An Electrical Cure?
by Laurie Meyers

	Richard McCallum, MD Occupation Professor of Internal Medicine, University of Kansas Medical Center Director, Center for Gastrointestinal Nerve and Muscle Function Professional Focus Gastroenterology Outside Interests Tennis, water skiing, boating, sports events, and going to Rolling Stones concerts Research Funding ADA Clinical Research Award

Gastroparesis is a disorder in which nerve damage interferes with the stomach's ability to digest food on its path through the digestive system. This can cause vomiting, nausea, loss of appetite, and even malnutrition. Diabetic neuropathy is the most common cause of gastroparesis—20 to 30 percent of people with diabetes have it.

Although there are drugs that can treat gastroparesis, they are often not as effective as desired, and many patients cannot tolerate their side effects. Richard McCallum, MD, hopes that his work with electrical stimulation of the stomach will provide a more effective alternative.

How Does Nerve Damage Affect Digestion?

Gastroparesis is caused by autonomic neuropathy—damage to the nerves that make up the central nervous system. These nerves regulate functions that aren't consciously controlled, such as breathing, maintaining blood pressure, and keeping the heart beating.

The vagus nerve, which is the only nerve in the body that runs from the brainstem to the abdomen, regulates digestion. Inside the stomach, the vagus branches out into a group of smaller nerves called the enteric nervous system, which directs the various digestive processes. In order to do that, it needs to send signals: electrical signals.

The stomach, like the heart, is an electrical organ. It produces natural electrical impulses—a rhythm. And special nerve cells in the stomach wall called the "interstitial cells of Cajal" initiate and regulate that rhythm. Without the rhythm, the stomach doesn't know how to handle food.

Here's how digestion normally works: When food reaches your stomach, it's first stored in the fundus, the uppermost part of that organ. The stomach then releases digestive juices and ramps up its rhythm to three electrical cycles per minute. That's the stomach's maximum rate, and the number required to digest properly. Then, the fundus gets the signal to relax its muscles and release the food to the rest of the stomach, which is called the antrum. Because the antrum is cycling at the right rhythm, its muscles are contracting and grinding, breaking down the food into small pieces and moving it down into the small intestine, where the digested food is absorbed.

At least that's how this process should work. But if you have gastroparesis, the stomach's nervous system is not getting the message. The cells of Cajal have trouble initiating impulses and may become depleted or atrophy over time. Without the steady signal, the stomach muscles don't know how to contract. The muscles in the fundus can't hold the food, so it gets released too soon. The antrum can't grind effectively because it doesn't have the power.

So the food just sits. This can cause nausea, vomiting, bloating, diarrhea, and malnutrition. Balls of leftover food may form, decreasing stomach volume and contributing to a sense of fullness. Eating is difficult, and the inconsistent absorption of food can lead to wildly fluctuating glucose levels.

Turn On The Power

Because electrical signals regulate stomach functioning, much as they do with the heart, McCallum turned to the same principle that keeps millions of hearts beating every day. "I looked at the pacemaker and thought we must be able to do something similar," he says.

In an earlier experiment, McCallum and his team came up with a device that connected a pair of electrodes to the surface of the stomach. The electrodes were attached to connecting wires that then came out through the abdominal wall and were attached to an external stimulator. This primitive pacemaker then generated the kind of energy that would trigger the stomach's natural rhythm of three cycles per minute.

McCallum and his team found that the device improved the contraction and emptying of the stomach. But it was not a permanent solution. The electrode wires could not stay in for more than a few months without exposing patients to infection. And while there was improvement, it wasn't quite the pacemaker—a device that could function like the cells of Cajal—McCallum was looking for.

In the meantime, another device called the Enterra was designed by Medtronic and approved by the U.S. Food and Drug Administration. Like a pacemaker, the device is implanted under the skin, with wires connecting to the wall of the stomach. The device has been in use for 8 years. About 70 percent of the 160 patients at McCallum's clinic who have received the Enterra have reported up to a 50 percent reduction in symptoms such as nausea. These patients were able to retain food in the uppermost parts of their stomachs better. However, their stomachs weren't actually emptying any faster.

Measure By Measure

Using what he has learned from his early experiment and his observation of patients using the Enterra, McCallum has come up with a strategy that he hopes will one day lead to a truly effective pacemaker—one which will not only make patients feel better, but actually restore function.

He believes the key is to find a way to stimulate the stomach from top to bottom. To test his theory, he has designed a new device that employs multiple electrodes that run along the stomach wall.

McCallum will test his device over the next 2 years; patients will enroll in his study on an ongoing basis. The tests will include 20 people and last 6 months. The first half of the testing will measure the effectiveness of McCallum's device; the second half will monitor how long the effects last once McCallum's device is removed and the Enterra turned on.

First, McCallum's team will measure and record how slowly the test participants' stomachs empty. The participants will eat eggs that contain a radioactive isotope so that the eggs' movement can be tracked (in a normally functioning stomach, no more than half of the eggs should remain after 2 hours). The team will also measure the electrical rhythm of participants' stomachs by using a device similar to an electro-cardiogram (EKG).

Then, participants will be implanted with both a "turned off" Enterra and four pairs of electrodes. The pairs will be evenly spread from top to bottom of their stomachs, and they will be connected to McCallum's external device.

The two uppermost electrodes will send out a signal to stimulate the stomach. McCallum thinks that starting the stimulation at the top and then reinforcing it halfway down will activate the muscles to contract. "We think that the strength of the signal will jolt the muscles to work even though the nerves don't work."

Over the course of the 6 months, the participants will first try McCallum's device. Then some will receive a "fake" device that will help the researchers explore whether there's a "placebo" effect involved simply in having a machine attached to one's body.

Halfway through the study, McCallum's devices and the "fakes" will be removed and the Enterra will be turned on. The main purpose of the Enterra will be to give participants symptom relief, but McCallum also thinks it may help sustain the effects of his device.

When it's over, the participants will be asked: Did they get any relief with McCallum's device? If so, did it last once the device was removed? Did using the Enterra help sustain the effects? McCallum also wants to make sure the devices didn't cause any twitching or discomfort and that none of the wires broke or became disconnected.

If the device works, McCallum will build a model of his digestive device for use in animals. He hopes that will lead to the development of an implantable device for humans—a true stomach pacemaker.

That's McCallum's hope. He also wonders whether his device could go beyond control. Might it actually reactivate nerves over time?

"Can we retrain the stomach?"