Animal Model Developed To Study Accelerated Atherosclerosis In Diabetics

"Diabetics don't die of diabetes; they die from the complications of diabetes and the most common cause of death in adult diabetics is coronary artery disease," said Dr. Ross G. Gerrity, experimental pathologist at MCG and lead author on the article published in the July issue of Diabetes. "We don't know why it is that diabetics have accelerated rates of coronary disease and resultant death; one of the reasons we know so little about it is that, until now, there has not been a good animal model for study."

Coronary artery disease occurs at an accelerated rate in both insulin-dependent and non-insulin dependent diabetics; it also appears earlier in life, affects women as often as men and is often fatal, Dr. Gerrity said.

By giving young swine streptozotocin, a cytotoxic compound that destroys insulin-producing beta cells in the pancreas, researchers have created diabetes in these animals and shown repeatedly that, within as little as 20 weeks, the combination of a high-fat diet and diabetes can produce severe occlusive coronary artery disease eerily similar to that found in humans, Dr Gerrity said.

He has reproduced the model in about 250 swine, comparing diabetic swine on both high-fat diets or regular diets to non-diabetic swine on high-fat and normal diets for periods up to 48 weeks. In all cases, histological and biochemical studies showed that diabetic swine with high lipid, or fat, levels had double the amount of blood vessel disease that was seen in their non-diabetic, high-lipid counterparts. Not only were there more lesions, but the diabetic lesions were more severe and occlusive, Dr. Gerrity said. The swine even tend to develop lesions where humans do: in the first one to three centimeters of the coronary arteries and at branch points in the aorta and iliac arteries. "When you compare the structure of these plaques in humans and swine, they are remarkably similar, particularly in the diabetic, as diabetic swine plaques develop the severe calcification and other complications seen in humans," he said.

Diabetes occurs spontaneously in at least one strain of swine and the animals are known to be a good model for studying atherosclerosis, Dr. Gerrity said. Swine, like humans, also develop atherosclerosis spontaneously in old age or if they eat a high-fat diet.

Dr. Gerrity has worked with the swine model for atherosclerosis since 1973; among his findings is the fact that scavenger blood cells called monocytes, which migrate into artery walls and ingest excess fat with the idea of removing it, apparently become overburdened in the face of a prolonged high-fat diet. So instead of removing fat from the walls, they over-ingest, becoming lipid-laden foam cells – the hallmark of atherosclerosis – and eventually die in the vessel wall. "Subsequently it's been demonstrated that the same type of thing occurs in the human," he said. "So it's a classic example where an animal model has been very useful in elucidating what happens in human disease."

He believes this new diabetic swine model will do the same for helping understand the vascular devastation that occurs in human diabetics.

He has already put the model to work, looking at whether insulin and other anti-diabetic drugs reduce atherosclerosis; data suggests that in humans, even tight control of insulin levels doesn't help in Type 1 diabetes but may be protective in Type 2.

In collaborative studies with Drs. Jerry Nadler and Ian Sarembock at the University of Virginia Health Sciences Center, Dr.Gerrity also is looking at why stents – tiny, flexible tubes placed inside coronary arteries to help keep them open after angioplasty – close prematurely in diabetics. The researchers have found premature closure in the diabetic animal model and now are looking at varying levels of lipids and lipoproteins, a combination of fat and proteins which also are a risk factor for atherosclerosis. "The levels do go up in the diabetic swine. But when we maintained cholesterol levels so that they were not significantly different in the diabetic and non-diabetic swine, you still get accelerated plaque formation in the diabetic animal. So there has to be something else," Dr. Gerrity said.

He's also looking at lipoxogenase, enzymes produced by various cells that may play a role in accelerated atherosclerosis. In collaboration with researchers at the University of Washington in Seattle, he's looking at whether these enzymes are giving lipoproteins a lethal dose of oxygen, thereby accelerating their contribution to vessel-clogging plaque.

The research was funded primarily by the National Institutes of Health and the Juvenile Diabetes Foundation.

In collaborative studies with Drs. Jerry Nadler and Ian Sarembock at the University of Virginia Health Sciences Center, Dr.Gerrity also is looking at why stents – tiny, flexible tubes placed inside coronary arteries to help keep them open after angioplasty – close prematurely in diabetics. The researchers have found premature closure in the diabetic animal model and now are looking at varying levels of lipids and lipoproteins, a combination of fat and proteins which also are a risk factor for atherosclerosis. "The levels do go up in the diabetic swine. But when we maintained cholesterol levels so that they were not significantly different in the diabetic and non-diabetic swine, you still get accelerated plaque formation in the diabetic animal. So there has to be something else," Dr. Gerrity said.

He's also looking at lipoxogenase, enzymes produced by various cells that may play a role in accelerated atherosclerosis. In collaboration with researchers at the University of Washington in Seattle, he's looking at whether these enzymes are giving lipoproteins a lethal dose of oxygen, thereby accelerating their contribution to vessel-clogging plaque.

The research was funded primarily by the National Institutes of Health and the Juvenile Diabetes Foundation.