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How diabetes harms the heart

Date: Tuesday, December 13, 2016

Study in mice reveals heart-damaging pathway triggered by insulin, identifies possible drug targets to prevent or treat heart failure

Diabetes is hard on the heart.

Cardiovascular disease is the leading cause of death in people with diabetes, and risk for heart failure—where the heart can’t pump enough blood—is two to three times higher in men and up to five times higher in women with diabetes compared to people without diabetes.

In the case of heart failure, diabetes presents another problem: Some of the therapies that treat diabetes may actually make heart failure worse.

But new research from the University of Iowa and the University of California at Davis finds that two different drugs—a beta blocker and an antidepressant—might both have potential for preventing or treating heart failure by blocking an insulin signaling pathway in the heart muscle.

“We often have a conundrum when we are treating a person with diabetes who also has heart failure. If we treat the diabetes, then we get better blood sugar numbers, but, depending on the drugs we choose, we could increase the risk of hospitalization for heart failure. It puts us between a rock and a hard place,” says E. Dale Abel, UI professor and DEO of internal medicine at the University of Iowa Carver College of Medicine. “To improve our ability to care for these patients, it is really important for us to understand what is happening in the failing heart in the context of diabetes.”

Previous research points to high levels of insulin, a hallmark of Type 2 diabetes, as a key factor in heart failure associated with diabetes. The new study, led by Abel and Kevin Xiang at UC Davis, shows that too much insulin in the blood (hyperinsulinemia) contributes to heart failure by triggering a molecular chain reaction that damages heart muscle cells. Using mice with diabetes, the study traced the links in this chain reaction—a newly discovered insulin signaling pathway in heart muscle cells. Blocking the pathway with the beta blocker carvedilol or the antidepressant paroxetine reverses heart muscle damage and restores heart function in the mice. The findings, published Nov. 4 in the journal Circulation, suggest that these drugs might have potential for preventing or treating heart failure associated with Type 2 diabetes.

“The notion that activating insulin signaling can be damaging in the failing heart has been reinforced by this study,” says Abel, who also is director of the Fraternal Order of Eagles Diabetes Research Center at the UI. “I think the main clinical implication is that physicians who are treating these complex patients who have these two dangerous co-morbidities, diabetes and heart failure, need to think about the effect of high levels of insulin on the heart and aim to improve metabolism (blood sugar levels) without getting the insulin levels too high such that that harms the heart.”

The signaling pathway that Abel and Xiang discovered involves direct interaction and crosstalk between insulin receptors and another family of receptors called beta-adrenergic receptors.

There are two classes of beta-adrenergic receptors: beta1, which is more abundant and is responsible for regulating the strength of the heartbeat, and beta2, which is believed to be a minor, less important receptor. Targeting beta receptors with beta-blocker drugs is a mainstay treatment for heart failure.

The new study shows that when the insulin receptor is activated by high levels of insulin, it sends a message to the beta2 receptor, which disrupts signaling through the beta1-adrenergic pathway and reduces the heart’s ability to pump, leading to heart failure.

The new understanding of this signaling pathway identifies the beta2 receptor and a protein called G-protein receptor kinase 2 (GRK2) as potential targets for preventing heart failure associated with diabetes. Inhibiting beta2 with the beta-blocker drug carvedilol and GRK2 with a drug called paroxetine reverses some of the heart damage and improves heart function in diabetic mice, even without altering metabolic problems such as high blood sugar and high insulin.

Paroxetine, which is better known as Paxil, is a selective serotonin reuptake inhibitor (SSRI) that is currently used to treat depression.

“The dose (of paroxetine) we used in the mice to block GRK2 and produce the beneficial heart effects was much higher than the corresponding human dose used to treat depression,” Abel notes. “We are definitely not advocating that people with diabetes and heart failure could use Paxil to help their heart. However, now that we know that GRK2 could be involved in heart failure, it might be possible to develop drugs that can be used to target this protein in heart muscle.”

The research was supported in part by grants from the National Institutes of Health.