Scientists find biological link between heart disease and diabetes

by Barbara Hewitt on October 4, 2013

A biological link between diabetes and heart disease has been found which may explain why diabetics have an increased risk of heart disease and lead to new cardiovascular treatments.

Researchers from the UC Davis Health System in Sacramento, California, found that when blood sugar levels are abnormally high this activates a biological pathway that causes irregular heartbeats, a condition known as cardiac arrhythmia that is linked with heart failure and sudden cardiac death.

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The risk of heart disease is up to four times greater for diabetics, according to the National Institutes of Health

The discovery paves the way for new therapeutic strategies that protect the heart health of patients with diabetes, according to Donald Bers, chairman of the UC Davis Department of Pharmacology.

While heart disease is common in the general population, the risk is up to four times greater for diabetics, according to the National Institutes of Health in the United States and the American Heart Association estimates that at least 65% of people with diabetes die from heart disease or stroke.

The UC Davis team and collaborators at the Johns Hopkins University School of Medicine showed that the moderate to high blood glucose levels characteristic of diabetes caused a sugar molecule (O-GlcNAc) in heart muscle cells to fuse to a specific site on a protein known as calcium/calmodulin-dependent protein kinase II, or CaMKII.

CaMKII has important roles in regulating normal calcium levels, electrical activity and pumping action of the heart, according to Bers. Its fusion with O-GlcNAc, however, led to chronic over activation of CaMKII and pathological changes in the finely tuned calcium signalling system it controls, triggering full blown arrhythmias in just a few minutes. The arrhythmias were prevented 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 hyperglycaemia,’ said Bers.

The research involved detailed molecular experiments in rat and human proteins and tissues, calcium imaging in isolated rat cardiac myocytes exposed to high glucose, and assessments of whole heart arrhythmias with optical mapping in isolated hearts and in live diabetic rats.

This comprehensive approach allowed Bers and his team to identify the specific site of sugar attachment to CaMKII, along with how that attachment activated CaMKII and 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,’ explained Gerald Hart, DeLamar Professor and director of biological chemistry at Johns Hopkins University School of Medicine, and one of Bers’ collaborators.

‘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. 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,’ he added.

In an additional experiment, the team found elevated levels of O-GlcNAc-modified CaMKII in both hearts and brains of deceased humans who were diagnosed with diabetes, with the highest levels in the hearts of patients who had both heart failure and diabetes.

‘Our discovery is likely to have ripple effects in many other fields. 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,’ said Bers.


The opinions expressed in this article do not necessarily reflect the views of the DiabetesForum.com Community and should not be interpreted as medical advice. Please see your doctor before making any changes to your diabetes management plan.

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