Researchers at Joslin Diabetes Center (Boston) think they have made a discovery that could one day lead to new treatments to improve the ability of patients with diabetes to survive heart attacks and live with coronary artery disease.
According to the center, for people with Type 2 diabetes, the death rate from a first myocardial infarction (MI) is two to three times the death rate of patients without the disease. Also, patients with diabetes and ischemic heart disease have a much higher mortality rate than the general population.
George King, MD, director of research and head of vascular cell biology at Joslin and a professor of medicine at Harvard Medical School (Boston), led the study, which was published Feb. 9 in the online edition of the American Heart Association (Dallas) journal, Arteriosclerosis, Thrombosis, and Vascular Biology, and it is scheduled to be published in the April print edition. Zhiheng He, MD, PhD, a Juvenile Diabetes Research Foundation International research fellow and former Iacocca Fellow, also led the study.
King told Medical Device Daily that this most recent study actually builds on findings in a published study from his group in 2002. At that time, researchers showed that the amount of VEGF, a growth factor, expressed in the heart of either insulin resistant or diabetic rats or in diabetic patients is lower than in those who don't have insulin resistance or diabetes.
“Then the question becomes: is it because of diabetes or insulin resistance,“ King said. “So, what we showed this time was that [VEGF decreases] . . . because insulin action is important to stimulate VEGF in the cells of the heart.“
Normally, when a coronary artery becomes blocked, the body responds by forming new blood vessels around the blockage to maintain blood and oxygen flow and limit heart damage. Heart cells produce the vessels by making VEGF.
“We have long recognized that in patients with diabetes, this blood vessel formation is not as robust as in people without diabetes,“ King said in a statement. “Now, we have a potential explanation.“
The researchers showed that insulin is the source of the signal the heart cells need to increase VEGF production.
“We found that when insulin in the bloodstream binds with the insulin receptors on the outer membranes of heart cells, it activates the PI3K/AKT pathway, which is the pathway that produces VEGF,“ King said. “We also found that this response is blunted in patients with insulin resistance, a major cause of Type 2 diabetes that makes it harder for cells to use insulin. The heart produces less VEGF and forms fewer new blood vessels.“
The researchers made their findings by working with two types of rodents: Zucker rats, which are genetically obese and, like humans, develop Type 2 diabetes through insulin resistance; and MIKRO (muscle-specific insulin receptor knockout) mice, a mouse model whose insulin receptor has been removed from the heart cells so they can no longer respond to the hormone, according to the center.
King said that when researchers stimulated the heart cells of Zucker rats with insulin and compared them with cells of normal rats, the insulin action in the Zucker rats was abnormal.
“That may be responsible for the reduced VEGF and blood vessel formation in the heart,“ he said. “Using a variety of interventional approaches, we then showed that the blood vessel formation was reduced because this one pathway was inhibited. The mice with the insulin receptor removed also exhibited less VEGF production and fewer new blood vessels, proving that the insulin receptor is critical to this process.“
King told MDD that the next step the researchers need to take is to “return the VEGF back to the heart and increase it in these animal models of insulin resistance or diabetes“ and then determine whether the blood vessel formation “will return to normal.“
“Additionally, what we could do is to develop a treatment that would improve insulin sensitivity in the heart, we should also [increase] VEGF, and improve [insulin-resistant and diabetic patients'] ability to withstand heart attack,“ he said.
King said he expects the continued research in animals to take one to two years, and if all goes well, to be running clinical trials in humans within two years.
He also noted that the research is important “because there are a lot of drugs out there that improve insulin sensitivity, so if we think this is due to insulin's effect on the heart, then potentially some of these drugs already on the market could be used.“
There also is a potential diagnostic use for these findings. For example, King said that in order to show that VEGF expression in the heart is increasing, the heart would be imaged as a drug or treatment is administered to increase insulin sensitivity in order to monitor the progress of the treatment.
A second diagnostic use “would be to show that the blood vessel capillary bed density in the heart is improving,“ he said, noting that both approaches would rely on diagnostic imaging methods.