September 30, 2013

Diabetes And Heart Disease Linked By Biochemical Pathway, Say Researchers

Brett Smith for redOrbit.com - Your Universe Online

While heart disease is a significant health problem among members of the general population, it is particularly prevalent among individuals with diabetes, who have four times the risk of others.

New research published in the journal Nature may provide a window into the unique connection between blood sugar levels and heart problems. The study revealed a biochemical pathway that causes irregular heartbeats when blood sugar levels become abnormally high.

“The novel molecular understanding we have uncovered paves the way for new therapeutic strategies that protect the heart health of patients with diabetes,” said study author Donald Bers, chair of the pharmacology department at the University of California, Davis.

Through molecular experiments involving rat and human proteins and tissues, the team of American and New Zealand researchers was able to show that the high blood glucose levels characteristic of diabetes caused a sugar molecule called O-GlcNAc in heart cells to fuse to a specific site on a protein known as CaMKII.

The discovery is important because CaMKII has major roles in modulating calcium levels, electrical activity and the heart beat, Bers said. The protein’s bonding to O-GlcNAc was seen to cause chronic overactivation of CaMKII , resulting full-blown arrhythmias in the span of a few minutes. The team was able to prevent the arrhythmias by inhibiting CaMKII or its union with O-GlcNAc.

“While scientists have known for a while that CaMKII plays a critical role in normal cardiac function, ours is the first study to identify O-GlcNAc as a direct activator of CaMKII with hyperglycemia,” Bers said.

Using state-of-the-art imaging techniques, the scientists identified the particular site where sugar attached to CaMKII and how that attachment caused calcium-dependent arrhythmias.

“Since O-GlcNAc is directly made from glucose and serves as a major nutrient sensor in regulating most cellular processes, it is perhaps not surprising that attachment of this sugar to proteins is emerging as a major molecular mechanism of glucose toxicity in diabetes,” said study author Gerald Hart, a director of biological chemistry at Johns Hopkins University School of Medicine.

“However, this represents the most clear-cut mechanistic study to date of how high glucose can directly affect the function of a critical regulatory protein,” Hart said. “The Bers group’s findings undoubtedly will lead to development of treatments for diabetic cardiovascular disease and, potentially, therapeutics for glucose toxicity in other tissues that are affected by diabetes such as the retina, the nervous system and the kidney.”

In another part of the study, the team discovered elevated levels of O-GlcNAc-bound CaMKII in both heart and brain samples of deceased humans who had been diagnosed with diabetes, with the highest amounts seen in patients who had heart failure and diabetes.

“Our discovery is likely to have ripple effects in many other fields,” Bers said. “One key next step will be to determine if the fusion of O-GlcNAc to CaMKII contributes to neuropathies that are also common among diabetics.”

The study’s findings are undoubtedly good news for diabetics, more than 65 percent of whom will die from heart disease or stroke, according to the American Heart Association.