Liver Inflammation Linked to Vascular Disease in Diabetics

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Researchers say they now understand the mechanism by which inflammatory processes in the liver cause an increase in cholesterol and thus heart disease.

Researchers have identified a previously unknown mechanism that could explain why vascular disease affects diabetics at such a high rate.

Inflammatory processes in the livers of patients with diabetes set off a chain reaction that results in the production of excess cholesterol, which then contributes to vascular disease, according to researchers from the Technical University of Munich and the Heidelberg University Hospital.

Vascular disease is a known source of complications for patients with diabetes. Research has shown that atherosclerosis, as well as related heart conditions, are among the most common reasons for hospitalizations among patients with diabetes. According to the National Institutes of Health, patients with diabetes are twice as likely as patients without diabetes to die from heart disease or stroke.

Stephan Herzig, PhD (pictured), professor and director of the Institute for Diabetes and Cancer at the Technical University Munich, said the findings offer key insights for researchers trying to find ways to better treat patients with diabetes.

To understand why vascular disease has proven to be such a problem, the researchers focused in on inflammatory processes in the liver. Previous studies indicated that metabolic diseases like type 2 diabetes (T2D) are associated with higher levels of the inflammatory cytokine tumor necrosis factor alpha (TNF-alpha), as well as elevated levels of interleukins 1-beta and 6.

In this new study, researchers used in vitro and animal models to see what affect the increase in TNF-alpha might have on patients. TNF-alpha induces the production of reactive oxygen species (ROS) in the liver. However, the researchers showed that the increase in ROS in the liver inactivates the transcription factor complex GA-binding protein (GAbp).

In the study’s models, the lack of GAbp hampered the protein AMPK, which acts as an energy sensor in the cell. The inhibition of AMPK thus led to the production of additional cholesterol. Despite GAbp’s regulatory processes that protect the body from excess cholesterol (and ultimately, atherosclerosis), the inflammatory processes associated with diabetes appeared to inhibit that protective effect.

“As GAbp inhibition is caused by the diabetes-driven accumulation of reactive oxygen species (ROS), a potential avenue towards new therapies is represented by the identification of specific ROS-generating pathways upstream of GAbp and their inhibition,” Herzig told MD Magazine.

In addition to their efforts to inhibit ROS, Herzig said the team is also looking at ways to generate GAbp with targeted liver-specific delivery systems.

“We are currently trying to define sub-cohorts in diabetic patients that are characterized by GAbp inactivation and who preferentially benefit from a GAbp-directed therapeutic approach,” Herzig said. “That research is ongoing.”

Researchers said the link between the liver and high cholesterol appeared to hold regardless of how well blood glucose levels were controlled in the patient.

The study, titled “A Hepatic GAbp-AMPK Axis Links Inflammatory Signaling to Systemic Vascular Damage,” was published in Cell Reports and online.

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