Research reveals possible cause of diabetic cardiomyopathy

Researchers from the University of Texas Medical Branch at Galveston have discovered one of the pathogenic components of diabetes in the heart, as published in the Journal of Biological Chemistry.

While both heart disease and diabetes are widely studied, how diabetic cardiomyopathy develops is not well understood, other than that it seemed to be linked to protein kinase C (PKC) — a family of enzymes that controls the functions of other proteins by using phosphates to turn them on and off.

Researchers at UTMB, led by assistant professor of biochemistry Dr. Muge Kuyumcu-Martinez, studied the effects of PKC signals in the hearts of diabetic mice.

"We now know that the leading cause of diabetic cardiomyopathy can be attributed to PKC activation and its downstream effects on gene expression," said Kuyumcu-Martinez. "Knowing how cardiomyopathy manifests, further research can use these results to concentrate on the prevention and treatment of heart failure in diabetics."

Cardiomyopathy, a known symptom of diabetes, occurs when the muscles of the heart weaken, and the heart is no longer strong enough to pump blood and properly circulate it throughout the body. Adults with diabetes are two to four times more likely to die of heart failure than the rest of the population.

The researchers discovered that when PKC is over-activated, the cells of the adult heart revert to splicing methods used during the embryonic stages. Genes contain codes for certain processes and products, such as proteins, and they send signals to the body to complete these processes and products through messenger RNA. Alternative splicing occurs when one gene contains the codes for multiple proteins. The human genome contains 20,000 protein-coding genes, so using one gene to create more than one protein is an efficient process - when it's running correctly. But problems occur when the genetic information is abnormally spliced or mis-spliced to messenger RNA, giving it mutated instructions. As much as one-third of genetic disease and many cancers are attributed to splicing changes.

In the case of diabetic cardiomyopathy, the research team used RNA sequencing technology to identify 22 specific alternative splicing events that occur, causing a developmental shift in the gene expression. This shift causes mechanisms of the heart to behave as though it were still an embryo, which prevents the heart from functioning correctly in a full-grown adult fighting diabetes.

Diabetic Cardiomyopathy

It has been over 30 years since Rubler et al. described four diabetic patients with congestive heart failure (CHF), normal coronary arteries, and no other etiologies for CHF and proposed that it was due to diabetic cardiomyopathy. Eight years ago, I reviewed the evidence for diabetic cardiomyopathy as a unique entity unassociated with coronary artery disease and concluded that diabetic cardiomyopathy was a distinct entity characterized by diastolic dysfunction, which was rarely clinically apparent unless associated with hypertension (when it was likely to become clinically apparent) and/or with myocardial ischemia (when it was likely to present with severe clinical manifestations). At that time the evidence also suggested that diastolic dysfunction was due to myocellular hypertrophy and myocardial fibrosis, and at the cellular level there were defects in calcium transportation, myocardial contractile protein collagen formation, and fatty acid metabolism . Since then we have learned that diabetic cardiomyopathy is not a rare condition but instead a very common one, and that its etiology is largely due to hyperglycemia with contributions from the insulin resistance syndrome that cause left ventricular hypertrophy.