BOSTON – (October 1, 2019) – People with diabetes are much more likely to develop heart disease than those without the condition. They also are several times more likely to develop complications after their coronary disease is treated via angioplasty—a minimally invasive procedure that can open up constricted arteries and hold them open with a tube-shaped device called a stent.

Using mice models, investigators at Joslin Diabetes Center have examined the mechanisms that drive a complication of angioplasty known as restenosis, in which the vessel clogs up again. The scientists discovered, to their surprise, that insulin plays an important role in this process.

Their finding suggests an approach to minimize restenosis among people with diabetes by coating the stent with an agent that defends against the clogging process, says George L. King, MD, Joslin Senior Vice President, and Chief Scientific Officer, and senior author on a paper presenting the work in Nature Communications.

Scientists have known that one main culprit for restenosis is the vascular smooth muscle cell (VSMC), the main component of the wall of blood vessels. After angioplasty, these cells migrate into the affected part of the artery, explains King, who is also a professor of medicine at Harvard Medical School.

Both insulin and insulin-like growth factor (IGF, a very similar hormone) have been shown to stimulate the growth and migration of VSMCs. Previously, IGF and its signaling pathways were seen as the main driver of restenosis in people with diabetes and insulin resistance.

King and their colleagues began their work with a mouse model of type 2 diabetes that was then genetically engineered so that its VSMCs lacked either an insulin receptor (a protein that allows insulin to enter the cell) or an IGF receptor (a protein that allows that hormone to enter).

“Surprisingly, when you delete the insulin receptor in this muscle cell, the restenosis process got better, suggesting the insulin receptor plays a role in causing the restenosis,” says Joslin research associate Qian Li, MD, PhD, first author on the paper. “When we removed the IGF receptor, the restenosis got worse. So both pieces of the data support the idea that in diabetes, the insulin receptor is playing an important role in restenosis, which is a major reason for the failure of stents.”

To complicate the research, the insulin receptor and IGF receptor are very similar in structure, each made up of two main arms, and VSMCs often present a “hybrid receptor” that combines one insulin and one IGF arm. “It took us two or three years to figure out that the reason these cells proliferate so much and migrate to cause the restenosis is the pure insulin receptor,” King notes.

Looking further into the molecular mechanisms at work, the Joslin scientists found that insulin was linked to the stimulation of an enzyme called Has2.  This enzyme makes a protein called hyaluronan, which helps cells to proliferate and migrate. Hyaluronan is also known to be important in atherosclerosis, (hardening of the arteries).

“Our results suggest that inhibiting the pure insulin receptor at the stent site could be a potential clinical target for treatment to reverse the risk of restenosis after stents and angioplasty in people with diabetes and insulin resistance,” King says. “Stent failures commonly occur within three to six months, so if such stents were effective for that period, stent failure could be reduced significantly for people with diabetes or insulin resistance.”

The Joslin team is now moving ahead with similar inquiries on the roles of insulin and insulin-like factor in atherosclerosis among people with diabetes.

Joslin co-authors included Jialin Fu, Yu Xia, Atsushi Ishikado, Kyoungmin Park, Hisashi Yokomizo, Qian Huang, Weikang Cai, Christian Rask-Madsen and C. Ronald Kahn. Weier Qi of AstraZeneca in Mölndal, Sweden also contributed. The work was supported by the National Institutes of Health.

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