Inflammatory processes in the liver lead to elevated cholesterol levels in people with diabetes, thus promoting subsequent vascular diseases. This is the result of a study by scientists of Helmholtz Zentrum München, Technische Universität München (TUM) and the Collaborative Research Center SFB 1118 at Heidelberg University Hospital. The paper, which has now been published in the journal Cell Reports, presents a previously unknown mechanism.
Vascular diseases play a key role among the long-term complications in people with diabetes. Cardiovascular diseases are the most common reason for all hospitalizations, accounting for 75 percent, and these diseases are responsible for fifty percent of all deaths. An important risk factor for atherosclerosis, circulatory disorders and vascular complications is elevated cholesterol.*
"Even if blood glucose levels are well controlled, some people with diabetes have a higher risk of long-term complications. We wanted to understand the underlying cause for this," said metabolism researcher Dr. Mauricio Berriel Diaz, deputy director of the Institute for Diabetes and Cancer (IDC) at Helmholtz Zentrum München. He conducted the study together with Professor Stephan Herzig, director of the IDC and chair of Molecular Metabolic Control at TUM. Herzig is also the co-spokesman of the DFG Collaborative Research Center (SFB) 1118, which is studying the influence of disturbed metabolic processes on long-term diabetes complications at Heidelberg University Hospital.
In their study, the researchers focused on inflammatory processes that are known to occur in many metabolic disorders such as type 2 diabetes and obesity and contribute significantly to long-term complications. Specifically, they concentrated on the inflammatory cytokine TNF-α (tumor necrosis factor α), which is known to induce the production of reactive oxygen species (ROS)** in the liver. The scientists demonstrated that these ROS inactivate the transcription factor complex GAbp (GA-binding protein). In experimental models, this loss in turn inhibited the protein AMPK, an energy sensor of the cell. As a result, excess cholesterol was produced, and typical atherosclerosis symptoms developed.
Key Role in the Maintenance of Hepatic and Systemic Lipid Homeostasis
"Our data suggest that the liver plays a key role in the development of common diabetic vascular diseases," said first author Dr. Katharina Niopek, researcher at the IDC. "GAbp appears to be a molecular regulator at the interface between inflammation, cholesterol homeostasis and atherosclerosis. Without its protective effect, this leads to hypercholesterolemia *** and increased lipid deposition in the arteries."
"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," said Herzig, who led the study.
* Source: Diabetes Information Service "Diabetes und Gefässe" (Diabetes and the Vascular System).
** Reactive oxygen species are oxygen compounds that can cause oxidative stress in cells. These include, for example, oxygen radicals. In the organism, they are produced both in the mitochondria within the framework of cellular respiration, but also through inflammatory processes.
*** Hypercholesterolemia is a lipid metabolism disorder (dyslipidemia) characterized by an elevated cholesterol level in the blood.
Stephan Herzig is co-director of the Joint Heidelberg IDC Translational Diabetes Program, in which he collaborates with colleagues at Heidelberg University Hospital, from where he moved to Munich in 2015. The collaboration took place in the framework of the DFG Collaborative Research Center (SFB) 1118: http://www.
Niopek, K. et al. (2017): A Hepatic GAbp-AMPK Axis Links Inflammatory Signaling to Systemic Vascular Damage. Cell Reports, DOI: 10.1016/j.celrep.2017.07.023
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The Helmholtz Zentrum München, the German Research Center for Environmental Health, pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München is headquartered in Neuherberg in the north of Munich and has about 2,300 staff members. It is a member of the Helmholtz Association, a community of 18 scientific-technical and medical-biological research centers with a total of about 37,000 staff members. http://www.
The Institute for Diabetes and Cancer (IDC) is a member of the Helmholtz Diabetes Center (HDC) at the Helmholtz Zentrum München and a partner in the joint Heidelberg-IDC Translational Diabetes Program. The Institute for Diabetes and Cancer is tightly integrated into the German Center for Diabetes Research (DZD) and into the special research area "Reactive Metabolites and Diabetic Complications" at the Heidelberg University Medical School. The IDC conducts research on the molecular basis of severe metabolic disorders, including metabolic syndrome and type 2 diabetes, as well as their roles in tumor initiation and progression. http://www.
Technical University of Munich (TUM) is one of Europe's leading research universities, with more than 500 professors, around 10,000 academic and non-academic staff, and 40,000 students. Its focus areas are the engineering sciences, natural sciences, life sciences and medicine, reinforced by schools of management and education. TUM acts as an entrepreneurial university that promotes talents and creates value for society. In that it profits from having strong partners in science and industry. It is represented worldwide with a campus in Singapore as well as offices in Beijing, Brussels, Cairo, Mumbai, San Francisco, and São Paulo. Nobel Prize winners and inventors such as Rudolf Diesel, Carl von Linde, and Rudolf Mößbauer have done research at TUM. In 2006 and 2012 it won recognition as a German "Excellence University." In international rankings, TUM regularly places among the best universities in Germany. http://www.
Heidelberg University Hospital is one of the largest and most prestigious medical centers in Germany. The Medical Faculty of Heidelberg University belongs to the internationally most renowned biomedical research institutions in Europe. Both institutions have the common goal of developing new therapies and implementing them rapidly for patients. With about 12,600 employees, training and qualification is an important issue. Every year, around 66,000 patients are treated on an inpatient basis and around 1.000.000 cases on an outpatient basis in more than 50 clinics and departments with 1,900 beds. Currently, about 3,500 future physicians are studying in Heidelberg; the reform Heidelberg Curriculum Medicinale (HeiCuMed) is one of the top medical training programs in Germany. http://www.
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Scientific Contact at Helmholtz Zentrum München:
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