Diabetes Forecast December 2005

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FOR TYPE 2

Research Profile

Blood Vessel Damage:
Seeking The Diabetes Connection
by Terri D'Arrigo

Marc K. Halushka, MD, PhD, believes certain receptors on cells prompt an immune response that damages blood vessels and contributes to diabetes-related complications.	Marc K. Halushka, MD, PhD Occupation Assistant Professor of Pathology, Department of Pathology Johns Hopkins University School of Medicine Professional Focus Pathology Outside Interests Family time, home improvement Research Funding ADA Junior Faculty Award

Almost all of the complications of diabetes involve some sort of blood vessel damage. Heart disease occurs when the blood vessels to and from your heart become clogged. Eye disease occurs when the small blood vessels in your eyes leak. Kidney disease occurs when the blood vessels in your kidneys' filters become thick and weak. Nerve damage occurs when blood vessels supplying the nerves are blocked.

With so many complications boiling down to blood vessel damage, a hot topic in research is how, precisely, diabetes causes this damage.

Marc K. Halushka, MD, PhD, assistant professor of pathology at Johns Hopkins University, is part of that research effort. Using funds from an American Diabetes Association Junior Faculty Award, Halushka and his team are studying blood vessels from different parts of the bodies of 100 deceased donors. About a third of the donors had type 2 diabetes, a third had high blood pressure, and a third had neither diabetes nor high blood pressure.

Halushka's team is interested in hypertension because high blood pressure stresses the blood vessels and is linked to diabetes-related heart, eye, and kidney disease.

Borrowing From Cancer Research

Halushka's team will collect 15 blood vessel samples from each donor for a total of 1,500 samples. The team will make slides of the tissue by using a technique called tissue microarray, which is often used in cancer research but is new to diabetes research.

To make conventional slides, tissue samples are placed in a waxy substance called paraffin. Then the slides are cut from the samples. Usually, it's one sample per slide. With tissue microarray, however, scientists use samples that are much smaller and more delicate. This enables them to lay out, or array, hundreds of tissue samples side-by-side on one slide for easy comparison. By using tissue microarray, Halushka's team will fit all 1,500 tissue samples onto just 17 slides.

Comparing Receptors

The minuscule size of the tissue samples on the slides won't affect the team's ability to make comparisons. In fact, they're looking for some rather small stuff: special receptors on cells. These receptors bind to substances in the blood and in tissues called advanced glycation end products.

"Advanced glycation end products are created when the body has high glucose levels," Halushka says. "The problem is that they muck up the body's machinery."

There are several different kinds of receptors that bind to advanced glycation end products, but Halushka says they can be divided into two basic groups: good receptors and bad receptors.

"The good receptors help the cells get rid of the advanced glycation end products," he says. "But the bad ones aren't able to do that, so they call in the cavalry. They call in macrophages and other [immune] cells to help them, and that causes inflammation. Inflammation drives atherosclerosis [hardening of the arteries] forward." Halushka suspects that wherever he finds advanced glycation end products bound to bad receptors, he will also find atherosclerosis.

Where there's atherosclerosis, there's blood vessel damage, and where there's blood vessel damage, there's a risk of a diabetes-related complication.

Halushka points out that different parts of the body are not equally susceptible to blood vessel damage. His theory is that cells in the different blood vessels have different ratios of good receptors to bad, and that this ratio may determine risk. Perhaps cells in the eyes, kidneys, heart, and other places where diabetes-related complications develop have more bad receptors than cells in organs that are not usually affected by diabetes.

Or, it might work the other way around. "If atherosclerosis never shows up in certain blood vessels, something there must be protecting them," Halushka says. Maybe those blood vessels have a higher proportion of good receptors to bad.

Tissue samples will be taken from different places on the donors' bodies, including the eyes, kidneys, heart, lungs, feet, and bowels, to see how their ratios of good to bad receptors stack up.

"You can't get such a wide range of tissue samples from one donor except at autopsy," he says. "You might get a sample from a kidney if someone has a kidney removed, but you don't know what's going on in that person's eyes or heart. This will enable us to compare different parts of the same person's body."

The next step will then be to compare the samples from various donors with each other. "If the damage is related to the presence of good versus bad receptors, how does this work in people with diabetes and people with high blood pressure compared to people with neither condition?" Halushka asks.

"This will give us an idea of why certain blood vessels develop atherosclerosis in certain states, and what the causes are," he adds. "Then we might be able to say, 'We need to target this receptor or that receptor,' in developing drugs. We could aim to inhibit the bad receptors or increase the activity of the good ones."