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Study Highlights Mechanism Connecting Diabetes, Elevated Cholesterol

Mary Caffrey
The connection between diabetes and cardiovascular disease is well-known, but a new study gets at the mechanism of how this occurs.
The connection between diabetes and cardiovascular disease is well-established. According to the American Heart Association, diabetes tends to lower high-density lipoprotein or “good” cholesterol, while increasing low-density lipoprotein (LDL) or “bad” cholesterol, thus increasing the likelihood of heart disease or stroke.

But just how does this happen? Researchers from Helmholtz Zentrum Munchen, Technisch Universitat Munchen, known as TUM, conducted a series of experiments to uncover the mechanism that can cause hypercholesterolemia and increased lipid deposits in the arteries. Their study appeared last week in Cell Reports.

Not surprisingly, the process starts with inflammation—which is proving to be a culprit across the board in diabetes, obesity, and other metabolic disorders. The scientists turned their attention to the liver and specifically to a binding protein called GAbp, which is strongly expressed in the organ.

Metabolic dysfunction in the liver, they wrote, “represents a key feature of various inflammation-associated pathologies, including obesity, insulin resistance, and non-alcoholic fatty liver disease.” Via a series of experiments, some involving mice, the scientists sought to turn on and turn off the triggers they suspected would block the function of GAbp when inflammation was present, setting off the process that led to the elevation of LDL cholesterol.

Because inflammatory signaling often starts with the cytokine tumor necrosis factor alpha, or TNF-α, the key step was identifying the link between TNF-α and GAbp. TNF-α was known to trigger production of reactive oxygen species oxygen (ROS) in the liver. The scientists demonstrated how TNF-α signaling, via ROS, blocked GAbp. It turns out the liver protein is a regulator of another protein, AMPK, which controls levels of cholesterol.

“Our data suggest the liver plays a key role in the development of common diabetes vascular diseases,” Katharina Niopek, PhD, a researcher at Helmholtz Zentrum Munchen and the study’s lead author, said in a statement. The work in this study shows the key role of GAbp as a regulator between inflammation, cholesterol homeostasis, and atherosclerosis, she said. Without the “protective effect” of GAbp, Niopek said, “this leads to hypercholesterolemia, and increased lipid deposition in the arteries.”

Thus, inflammation in diabetes sets off a chain of events that elevates cholesterol causes atherosclerosis to develop over time, the researchers found. The results have implications for patients, according to the researchers.

Stephan Herzig, a co-leader of the study and director of the Institute for Diabetes and Cancer at TUM, said, “Since initial patient data supported our findings, the new signaling pathway—regardless of how well the blood glucose levels of the patient are controlled—may be a key component in the development of long-term diabetes complications, which could be utilized therapeutically.”

Right now, a group of patients and advocates are calling on FDA and payers to recognized that measures “Beyond A1C” must be considered when approving new therapies and devices to manage the disease. At the most recent meeting of the American Diabetes Association, a session on diabetes and cardiovascular disease discussed the need for heart failure to be a primary endpoint in studies.

Reference

Niopek K, Bilgen EU, Seitz S, et al. A Hepatic GAbp-AMPK axis links inflammatory signaling to systemic vaascular damage. Cell Reports, 2017; 20:1422-1434. DOI: 10.1016/j.celrep.2017.07.023.

 
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