FEATURE | Posted Jan. 11, 2017

How insulin harms the heart

Mouse study finds possible drug targets for heart failure in diabetics

UC Davis biochemist and cell biologist Yang (Kevin) Xiang has often wondered what mechanisms are responsible for increasing the risk of heart failure among diabetics.

Risk for heart failure, a debilitating, chronic condition whereby the heart cannot efficiently pump blood, is two to three times higher in men and up to five times higher in women with diabetes compared to those without diabetes.

But what exactly is happening at the cellular level?

“Endocrinologists care for diabetics and cardiologists treat heart failure, yet researchers in these two fields seldom communicate with each other,” Xiang said. “I have been fascinated with the possibility that the adrenergic nervous system, which exerts a plethora of cardiovascular effects, from increasing heart rate and cardiac contractility to decreasing the capacity of veins, may be integrated with the insulin system through evolution since both are essential in regulating energy in the body.”

Fueled by research within the past five years, interest in understanding how therapies that treat diabetes make heart failure worse has picked up momentum.

“Researchers began noticing that too much insulin stimulation may not be good in stressed hearts,” Xiang said. “Previous clinical studies that aimed to aggressively lower blood glucose levels with insulin and oral drugs weren’t able to reduce cardiovascular events among type II diabetics. In fact, intensive control of blood glucose levels actually increased mortality and other cardiovascular events.”

Xiang, working in collaboration with University of Iowa professor E. Dale Abel, discovered the mechanism by which insulin damages the heart in diabetics. The researchers published their findings Nov. 4 in the journal Circulation.

Promising new therapy for diabetics with heart failure

Using a mouse model, the team found that insulin can directly act on the cardiac beta2 adrenergic receptor, which inhibits the adrenergic signaling through the beta1-adrenergic pathway that is essential to maintain cardiac contractile function to pump blood. The researchers also found that blocking the pathway with the beta blocker carvedilol or the antidepressant paroxetine reversed heart muscle damage and restored heart function in the mice.

The work is important because it suggests that two different drugs — a beta blocker and an antidepressant — might have potential for preventing or treating heart failure associated with type 2 diabetes.

“Most beta-blockers to treat heart failure inhibit the beta1 adrenergic receptor, which is more abundant and is known to regulate the strength of the heart beat,” Xiang said. “However, our study indicates that the beta2 adrenergic receptor, which had been believed to be a minor, less important receptor, may be targeted if a heart failure patient has diabetes. This is particularly interesting since we need to manage both clinical symptoms in the patients with heart failure and diabetes.”

Xiang noted that in the Carvedilol Or Metoprolol European Trial (COMET) clinical study, which directly compared the capabilities of beta-blockers metoprolol and carvedilol on the long-term survival of patients with chronic heart failure, carvedilol, a beta blocker that targets both beta1 and beta2 adrenergic receptors reduced the prevalence of new-onset diabetes by 22 percent when compared to metaprolol, a beta1 adrenergic receptor selective blocker. This study suggests that by blocking the beta2 adrenergic receptor, patients may get additional benefit in preventing diabetes or controlling diabetic conditions.

The UC Davis and University of Iowa researchers also found that a protein called G-protein receptor kinase 2 (GRK2) could be involved in heart failure in diabetes and that it might be possible to develop drugs to target this protein to reverse heart damage and improve heart function.

“Because insulin and adrenergic regulation are distributed throughout the body, our work also implies that insulin could affect adrenergic signaling in other tissues and organs, thus presenting opportunities to examine the effects of insulin across a broad spectrum of diabetic complications, such as hypertension, liver fibrosis and dementia as well as exacerbated clinical conditions such as asthma and chronic obstructive pulmonary disease,” Xiang said.