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.
According to the World Heart Federation, people who suffer from diabetes are two to four times more likely to develop cardiovascular disease, compared with people who do not have diabetes.
The American Heart Association says that around 65% of diabetes sufferers die from heart disease or stroke, emphasizing the need for new research looking at links between the conditions.
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.
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."
Donald Bers, chair of the Department of Pharmacology at UC Davis and senior study author, says:
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.
According to the World Heart Federation, people who suffer from diabetes are two to four times more likely to develop cardiovascular disease, compared with people who do not have diabetes.
The American Heart Association says that around 65% of diabetes sufferers die from heart disease or stroke, emphasizing the need for new research looking at links between the conditions.
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.
O-GlcNAc-modified CaMKII a trigger of arrhythmias
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.
US Davis researchers have discovered that a sugar molecule, O-GlcNAc,
binds to a protein called CaMKII to trigger arrhythmias in subjects
with high blood glucose levels.
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."
Findings will 'undoubtedly' lead to new treatments
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.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.
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."
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