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Researchers from the UC Davis Health System have discovered a biological link between diabetes and heart disease, which may explain why diabetes sufferers have an increased risk for heart disease. This is according to a study published in the journal Nature.
The researchers found that when blood sugars are abnormally high (hyperglycemia), this activates a biological pathway that causes irregular heartbeats - a condition called cardiac arrhythmia - that is linked to heart failure and sudden cardiac death.
For this study, UC Davis researchers, alongside collaborators at the Johns Hopkins University School of Medicine, conducted a series of experiments to determine any biological reasons as to why diabetes sufferers are at higher risk of cardiovascular disease.
The experiments involved detailed molecular analysis in rat and human proteins and tissues, calcium imaging in isolated rat cardiac myocytes (cells found in muscle tissues) that were exposed to high glucose, as well looking at whole heart arrhythmias with optical mapping within isolated hearts and live diabetic rates.
Their findings showed that moderate to high blood glucose levels, similar to those found in diabetics, triggered a sugar molecule called O-GlcNAc (O-linked N-acetylglucosamine) in heart muscle cells to bind to a specific site on a protein called CaMKII (calcium/calmodulin-dependent protein kinase II).
According to the researchers, CaMKII plays an important part in regulating normal calcium levels, electrical activity and the pumping action of the heart.
But they found its interaction with O-GlcNAc caused CaMKII to overactivate, causing pathological changes in the calcium signaling system it controls. This action triggered fully active arrhythmias within minutes.
However, the researchers say the arrhythmias were prevented by inhibiting CaMKII and its binding to O-GlcNAc.
An additional experiment, which involved analyzing the hearts and brains of deceased humans who had diabetes, revealed high levels of O-GlcNAc-modified CaMKII. The highest levels were found in patients who suffered from both heart failure and diabetes.
"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," says Gerald Hart, DeLamar professor and director of biological chemistry at Johns Hopkins University School of Medicine, and study author.
"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."
Prof. Hart notes that these findings will undoubtedly lead to development of treatments for diabetic cardiovascular disease and potential therapeutics for glucose toxicity in other tissues affected by diabetes, such as the nervous system, the kidney and the retina.
Donald Bers, chair of the Department of Pharmacology at UC Davis and senior study author, says:
"The novel molecular understanding we have uncovered paves the way for new therapeutic strategies that protect the heart health of patients with diabetes.
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."
The study authors say that further studies are needed, particularly to identify whether the fusion of O-GlcNAc to CaMKII plays a part in disorders of the peripheral nervous system, a condition that is also common in diabetics.
Medical News Today recently reported on a study detailing the discovery of a particular gene variant in type 2 diabetics that is linked to higher risk of heart disease.
Written by Honor Whiteman
Copyright: Medical News Today
Not to be reproduced without the permission of Medical News Today.
Diabetic hyperglycaemia activates CaMKII and arrhythmias by O-linked glycosylation, doi:10.1038/nature12537, published online in Nature, 29 September 2013, Abstract
UC Davis researchers discover a biological link between diabetes and heart disease, news release from UC Davis Health System, accessed 1 October 2013.
Visit our Heart Disease category page for the latest news on this subject.
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