The greatest risks to long-term health in people with diabetes arise from diabetic complications, particularly cardiovascular disease. However the mechanisms by which the metabolic changes associated with type 2 diabetes like insulin resistance increases the risk of heart failure are less understood. In a recent publication in JCI Insight, E. Dale Abel, MD, PhD, and other members of the Fraternal Order of Eagles Diabetes Research Center in collaboration with other institutions, have uncovered an important molecular link between diabetes and heart failure.
In previous studies, Abel and his fellow researchers revealed that exposure of the heart to higher levels of insulin, which often occurs in people with Type 2 diabetes who are insulin resistant, may accelerate heart failure when heart damage occurs. This current study clarifies what signals within the cell trigger this event. Specifically, insulin receptor substrate-1 (IRS1) is a protein required for insulin to transduce its signals to the rest of the cell. Another protein, IRS2, is equally expressed in heart muscle, but it was unclear whether IRS1 or IRS2 equally contributed to accelerating heart failure in insulin resistant states.
The laboratory created genetically engineered mice lacking either IRS1 or IRS2 in cardiac muscle cells and subjected these mice to a stress that induces heart failure, namely pressure overload. The IRS1-deficient mice were completely protected from heart failure in the face of this injury, while IRS2-deficient mice were not. Calling the IRS1 protein the “bad cop,” Abel explained their next task was then to uncover why, which led to two discoveries. “Number one,” he said, “IRS1 seems to drive inflammation in the heart. Number two, IRS1 suppresses a protective pathway in the heart called ‘signaling via cyclic GMP,’ which provides additional protection.”
Another pair of signaling molecules were also identified in this recently published project, AKT1 and AKT2. Similarly to their work with IRS1 and IRS2, the researchers identified another “bad cop” in the pair. Deletions of the AKT1 gene in mice also lacking IRS2, which led to worse heart failure, were protected from heart failure, when AKT1 levels were genetically reduced.
Finally, human heart samples obtained at the time of left ventricle assist device-implantation surgeries in patients with heart failure—performed at the University of Utah—were compared with normal donor hearts. The Abel team found their results confirmed. Just as in the mice, the heart failure samples revealed hyperactivation of AKT1 and IRS1. Implications of the study point toward treatments for people with diabetes that also take the cardiac risk into account. “Therapies to treat people with diabetes at risk of heart failure should ideally seek to do so in ways that lower insulin levels,” Abel said. SGLT2 inhibitors, he explained, are the only class of diabetes treatment proven to consistently reduce the risk of heart failure. These also cause the kidney to excrete glucose, which in turn would lower circulating concentrations of insulin. “More attention to agents that might lower insulin levels might actually help to reduce the risk of heart failure in diabetes.”
Contributors to this work, which was funded by the National Institutes of Health and the American Heart Association, include researchers from the University of Iowa, the University of Utah, the University of Alabama Birmingham, Harvard Medical School, and the University of California Davis.