Protein Linked to Diabetes-Related Heart Disease

The driver between heart disease associated with diabetes has been long unknown, but the authors of a new study believe that the IRS-1 protein may be behind the link. If confirmed, this protein may offer a novel way to reduce risk of developing heart disease among patients with diabetes.

IRS-1 is critical for smooth muscle cells that veins and arteries are composed of. Findings from a study published by the Journal of Biological Chemistry suggest that low expression of the protein causes cells to become stem-cell like, which may contribute to atherosclerosis.

Atherosclerosis is characterized by plaque build-up in the heart’s arteries, and can increase the risk of experiencing a heart attack, stroke, and other events associated with heart disease.

"When diabetes is poorly managed, your blood sugar goes up and the amount of this protein goes down, so the cells become subject to abnormal proliferation," said senior study author David R. Clemmons, MD. "We need to conduct more studies, but we think this cell pathway may have significant implications for how high blood glucose leads to atherosclerosis in humans."

Vascular smooth muscle cells contract when the heart beats, and help push oxygenated blood throughout the body, but when plaque builds up, the cells do not contract as efficiently.

The study authors previously discovered that diabetes can activate an abnormal cell signaling pathway that increases vascular smooth cell proliferation, which further contributes to atherosclerosis. Interestingly, when the pathway was corrected, the problem did not disappear.

Their most recent findings suggest that IRS-1 may block the abnormal pathway, and preserve specialized vascular smooth cells. Without IRS-1, the cells were observed to revert to a stem-like state, which activates the abnormal pathway to promote proliferation, according to the study.

To examine whether IRS-1 expression can inhibit the abnormal signaling pathway, they conducted experiments in healthy mice, mice models of diabetes, and IRS-1 knock out mice. The investigators made an incision in the blood vessels of the mice models to analyze how the vascular smooth muscle cells responded to the injury.

Healthy mice were observed to heal normally with little proliferation, while mice models of diabetes and knockout mice were seen to have significantly high abnormal cellular proliferation, according to the study.

IRS-1 expression has been observed to be strongly associated with how blood glucose levels are managed, with patients who have high blood sugar showing decreased expression. This is the first study to link IRS-1 and heart disease risk.

This study could lead to the development of drugs that prevent patients with diabetes from developing heart disease. These patients are more than twice as likely to develop heart disease or experience a stroke, compared to those without diabetes. Younger patients with diabetes are also more likely to experience a major cardiac event, which highlights the importance of preventing heart disease.

In the future, the team of researchers plan to analyze different approaches to stimulate the synthesis of this protein, regardless of glucose levels, according to the study.

The investigators hypothesize that it may be possible to develop drugs to increase IRS-1 expression to limit the threat of high blood sugar. This mechanisms may also be involved with diabetes-related complications, such as eye and kidney diseases.

"The study suggests that you can't just inhibit the abnormal signaling, which we've already figured out how to do," Dr Clemmons said. "Our work suggests you probably have to restore the normal signaling pathway, at least to some extent, in order to completely restore the cells to normal cell health, differentiation, and functioning."