GEN Exclusives

More »

GEN News Highlights

More »
Oct 1, 2013

Biological Pathway Identified Linking Diabetes and Heart Disease

  • Scientists at the UC Davis Health System say they have identified for the first time a biological pathway that is activated when blood sugar levels are abnormally high causing cardiac arrhythmias that are linked with heart failure and sudden cardiac death.

    The investigators reported their work online today (“Diabetic hyperglycaemia activates CaMKII and arrhythmias by O-linked glycosylation”) in Nature. They point out that the discovery helps explain why diabetes is a significant independent risk factor for heart disease.

    “In human, rat and mouse, we identify a novel mechanism linking CaMKII [Ca2+/calmodulin-dependent protein kinase II] and hyperglycemic signaling in diabetes mellitus, which is a key risk factor for heart and neurodegenerative diseases,” wrote the researchers in the Nature article. “CaMKII is an enzyme with important regulatory functions in the heart and brain, and its chronic activation can be pathological. CaMKII activation is seen in heart failure, and can directly induce pathological changes in ion channels, Ca2+ handling, and gene transcription.”

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

    Through a series of experiments, Dr. Bers, his UC Davis team and their 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-linked N-acetylglucosamine, or O-GlcNAc) in heart muscle cells to fuse to a specific site on CaMKII.

    CaMKII’s fusion with O-GlcNAc led to chronic overactivation of CaMKII and pathological changes in the finely tuned calcium signaling 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 hyperglycemia,” continued Dr. Bers.

    “This represents the most clear-cut mechanistic study to date of how high glucose can directly affect the function of a critical regulatory protein,” according to Gerald Hart, Ph.D., DeLamar Professor and director of biological chemistry at Johns Hopkins University School of Medicine, and one of Dr. Bers’ collaborators. “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 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,” said Dr. Bers. “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.”



Related content

Jobs

GEN Jobs powered by HireLifeScience.com connects you directly to employers in pharma, biotech, and the life sciences. View 40 to 50 fresh job postings daily or search for employment opportunities including those in R&D, clinical research, QA/QC, biomanufacturing, and regulatory affairs.
 Searching...
More »

GEN Poll

More » Poll Results »

Should “Special K” Get Special Treatment?

In the near term, what is the best way to use ketamine in treating depression?