Why the Blood Sugar Level Gets Out of Balance in Diabetes
Molecular controller CARM1 regulates the pacers of glucose synthesis
Scientists of the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) have found out why specific genes are read as a response to hunger signals such as glucagon or glucocorticoids and, thus, mediate glucose release from the liver. A team of researchers headed by Dr. Anja Krones-Herzig identified the CARM1 molecule as a transcription factor that activates key enzymes of glucose synthesis under certain conditions, thus causing the blood sugar level to rise. The research results were presented recently in the Journal of Biological Chemistry*.
A typical feature of metabolic disorders such as type 2 (adult onset) diabetes is that important organs such as liver, muscles, and fatty tissue cease to respond to the pancreatic hormone insulin (insulin resistance), while other, opposing hormones such as glucagon or glucocorticoids continue to unfold their effects. The result is that sugar from the blood is no longer transported to and stored in muscle tissue or the liver. On the contrary: the hunger signal glucagon or its intracellular “mediator” cAMP, respectively, triggers a signaling cascade in liver cells. One of the consequences is that the genes for special enzymes of the sugar household are read. The enzymes PEPCK and G6Pase are biocatalysts which are in charge of synthesis of new glucose in the liver and its release into the blood (gluconeogenesis).
The secret of how PEPCK and G6Pase, the pacers of glucose synthesis, are regulated, has now been disclosed by Dr. Anja Krones-Herzig from the working group “Molecular Metabolic Control”. Jointly with team colleagues and researchers from the Institute of Genetics and Center for Molecular Medicine at Cologne University, Krones-Herzig found out that the CARM1 transcription factor plays an important role in the activation of key enzymes of gluconeogenesis. Depending on the messenger substance cAMP, CARM1 attaches itself to the starting sequence of the blueprints for PEPCK and G6Pase, thus giving the signal for the genes to be read.
Another case of disrupted insulin-dependent metabolism is cachexia, a frequent and severe condition associated with advanced cancer. The consequences are weight loss, weakness and increasing failure of organ functions. Group leader Dr. Stephan Herzig plans to investigate with his team whether the same or related genes or gene products – transcription factors, to be more precise – that influence the insulin-dependent metabolism in diabetes, might also play a role in tumor-asociated cachexia. While in diabetes the liver is in the center of attention, in the wasting syndrome (cachexia) researchers are focusing on the metabolism of the muscle tissue.
The medium-term goal of the cancer researchers is to find out whether dysregulated components of the insulin signaling cascade might be used as targets for drugs. “Once we have sufficient evidence suggesting that a transcription factor is causally involved in one of the metabolic disorders, we will start looking for suitable substances to counteract or reinforce the effect.”
* Anja Krones-Herzig et al.: “Signal-dependent control of gluconeogenic key enzyme genes through coactivator- associated arginine methyltransferase 1“, Journal of Biological Che¬mistry, Dec 2005; doi:10.1074/jbc.M509770200
The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 3,000 employees is the largest biomedical research institute in Germany. At DKFZ, more than 1,000 scientists investigate how cancer develops, identify cancer risk factors and endeavor to find new strategies to prevent people from getting cancer. They develop novel approaches to make tumor diagnosis more precise and treatment of cancer patients more successful. The staff of the Cancer Information Service (KID) offers information about the widespread disease of cancer for patients, their families, and the general public. Jointly with Heidelberg University Hospital, DKFZ has established the National Center for Tumor Diseases (NCT) Heidelberg, where promising approaches from cancer research are translated into the clinic. In the German Consortium for Translational Cancer Research (DKTK), one of six German Centers for Health Research, DKFZ maintains translational centers at seven university partnering sites. Combining excellent university hospitals with high-profile research at a Helmholtz Center is an important contribution to improving the chances of cancer patients. DKFZ is a member of the Helmholtz Association of National Research Centers, with ninety percent of its funding coming from the German Federal Ministry of Education and Research and the remaining ten percent from the State of Baden-Württemberg.