An insulin signaling molecule may protect against stress-induced arrhythmias

University of Iowa research has uncovered a critical role for the insulin signaling molecule insulin receptor substrate 2 (IRS2) in protecting the heart from stress-induced arrhythmias. The discovery may suggest new targets for preventing arrhythmias (abnormal heart rhythms) in high-risk individuals. 

The new research, a collaborative effort between UI researchers led by Long-Sheng Song, MD, at the University of Iowa, and E. Dale Abel, MD, PhD, at UCLA, provides new insights into how IRS2 helps maintain heart health during stressful conditions. The findings, which were published Dec. 10 in Circulation, have significant implications for individuals at higher risk for heart arrhythmias, including those with cancer, diabetes, and obesity. 

“IRS2 is well-known for its role in regulating metabolism, and IRS2 dysfunction has been linked to a range of metabolic diseases. However, until now, its specific role in cardiac health, particularly in the context of stress-related arrhythmias, has remained unclear,” says Song, a UI professor of internal medicine-cardiovascular medicine. “This new study demonstrates how IRS2 stabilizes calcium handling in heart cells, an essential function that prevents potentially life-threatening arrhythmias during cardiac stress.” 

IRS2 signaling safeguards cardiac function during stress 

The study began with a retrospective analysis of clinical data from a global health research network containing millions of de-identified patient records. The researchers found that cancer patients with IRS2 mutations were at higher risk for severe arrhythmias, such as ventricular tachycardia. This underscores the importance of understanding IRS2’s role in heart function. 

Next, using a mouse model with specific deletion of IRS2 in heart cells (cIRS2-KO), the research team observed abnormal behaviors in calcium handling. These alterations included a marked increase in spontaneous calcium release events and elevated phosphorylation levels of proteins that are critical in regulating calcium ion homeostasis in heart cells. These disturbances contribute to the development of arrhythmias. 

The study also identified the AKT1 signaling pathway as a critical factor in IRS2-related arrhythmias. Without IRS2, AKT1 becomes overactive, impairing calcium balance and increasing the risk of arrhythmias. Notably, inhibiting AKT1 activity in cIRS2-KO mice led to a marked reduction in ventricular tachycardia associated with cardiac stress, suggesting that targeting this pathway may offer a promising therapeutic approach. 

Further investigations showed that stabilizing calcium handling, either by genetically modifying the RyR2 protein or inhibiting the AKT1 pathway, could reduce arrhythmia risk in the mice. 

Potential for new anti-arrhythmic therapies 

These findings may open the door to new therapeutic strategies aimed at preventing arrhythmias, particularly in individuals at elevated risk, such as cancer patients or those with metabolic disorders. 

“The discovery of this unexpected function of IRS2 in maintaining calcium homeostasis in the heart, especially during times of stress, is really fascinating” says Qian Shi, PhD, UI research assistant professor of internal medicine, and first author of the study. “By understanding how IRS2 interacts with key pathways like AKT1, we are opening exciting possibilities for developing therapies that could prevent life-threatening arrhythmias in patients at high risk.” 

“These findings also have implications for screening patients known to harbor IRS2 variants,” adds co-senior author E. Dale Abel, MD, PhD, now professor and chair of the Department of Medicine at the David Geffen School of Medicine at UCLA. “Moreover, AKT inhibitors have already been developed and used in oncology, thus translation of these findings is feasible.” 

The research was primarily conducted by Shi in the laboratory of Song. Other contributors include Jinxi Wang, PhD; Hamza Malik, MD; Xuguang Li, MD, PhD; Jennifer Streeter, MD, PhD; Jacob Sharafuddin; Eric Weatherford, PhD; Biyi Chen, MD, PhD; and Duane Hall, PhD from the University of Iowa Carver College of Medicine, Abel from UCLA, and David Stein and Yuval Itan, PhD, from Icahn School of Medicine at Mount Sinai.