Columbia University Medical Center

Columbia Doctor Finds Clue To Diabetes-Heart Disease Link

New York, NY – June 15, 2000 – An abnormality in a protein that helps clear fat from the blood may explain the greatly increased risk of heart disease people with diabetes face, according to research published by Dr. Neil S. Shachter and his colleagues at Columbia University College of Physicians & Surgeons in this month’s issue of the Journal of Clinical Investigation.
In diabetes mellitus, a person’s body can’t use sugar properly, either because he or she does not make insulin or is unable to respond to this hormone. People with diabetes are much more likely to develop atherosclerosis (hardening of the arteries) and other types of heart and blood vessel disease than people without this condition. To date, no cause for this increased risk has been identified.
When a person eats fat, a series of steps must take place in order for these fats to reach the cells where they are needed and for the liver to clear unwanted fats from the blood. Different proteins package, transport, and clear fat particles containing triglycerides through the body. Abnormalities in these proteins can lead to high levels of triglycerides in the blood, a major risk factor for heart disease.
Dr. Shachter’s research suggests that abnormalities in a class of proteins called heparan sulfate proteoglycans (HSPGs) may explain the link between diabetes and heart disease. Dr. Shachter is an assistant professor of medicine at Columbia University’s College of Physicians & Surgeons in the Division of Preventive Medicine and Nutrition and the Division of Cardiology.
Dr. Shachter and his colleagues observed the metabolic effects of giving diabetic mice a large amount of fat to eat. “They clear it extremely poorly,” says Dr. Shachter. “This is similar to what we see in diabetic humans.”
Then the Columbia researchers conducted a series of experiments to identify why this occurred. The only abnormality in fat metabolism they found was in the animals’ HSPGs. Unlike most proteins, HSPGs contain a large amount of structured sugar chains. These proteins have been shown to be abnormal in diabetic humans, but the consequences of this abnormality had not previously been determined.
“This appears to be the mechanism of why diabetics have slowed clearance of dietary fat particles,” says Dr. Shachter. “It sort of connects the dots.”
In other experiments, Dr. Shachter and his colleagues examined how HSPGs were formed in cultured cells exposed to high sugar concentrations, mimicking the environment inside a diabetic person’s body. The formation of the proteins takes three steps, and researchers found abnormalities in each of the steps. “At every step of the way, there’s less HSPG being made,” Dr. Shachter explained.
The next step for the Columbia team will be to determine why HSPGs are abnormal in people with diabetes. Finding the answer to this question could help researchers develop ways to prevent and treat the complications of diabetes, which include eye and kidney damage as well as heart disease.
“All of these major end-stage complications of diabetes have a lot to do with proteoglycan abnormalities,” Dr. Shachter says. “That could give us a direct hook into what diabetes does to you.”
Dr. Claude Lenfant, director of the National Heart, Lung, and Blood Institute, which supported the study, said: “The increased atherosclerosis experienced by patients with diabetes is not completely understood. In this intriguing study, there is evidence of a link between the disordered metabolism of glucose found in diabetes and an abnormality in lipid metabolism, together producing an effect in the blood vessel wall likely to promote plaque buildup. If this finding is replicated in humans, it may lead to the development of new targets for drug treatments to control the cardiovascular complications suffered by so many diabetics.”
This research was supported by grants from the National Heart, Lung, and Blood Institute and the Juvenile Diabetes Foundation.

Also on CUMC News: