With more than 400 million clinically diagnosed patients, the worldwide prevalence of type 2 diabetes has reached epidemic proportions, according to the World Health Organization. At Helmholtz Zentrum München, scientists are investigating the underlying mechanisms of this metabolic disease in order to develop new preventive and therapeutic solutions. In her research, Dr. Anja Zeigerer is focusing on endocytosis. This term is defined as processes for absorbing molecules from the surroundings of a cell by invaginating regions of the cell membrane.
Two key mechanisms
In type 2 diabetes or rather insulin resistance, the liver plays a central role. This not only occurs via the glucose metabolism. Via endocytosis, nutrients as well as signal molecules reach the cell interior. At the same time, the glucose metabolism is controlled via the storage or release of glucose. "Both processes must be synchronized to regulate glucose storage and release," Zeigerer said. "Malfunctioning of these interdependent processes can promote the development of type 2 diabetes."
The scientist reports several indications that glucose metabolism and endocytosis are reciprocally regulated:
- A genome-wide RNAi screen showed that the inactivation of specific metabolic genes has dramatic effects on endosomal transport.
- Sucrose induces high regulation of the endocytosis genes in Drosophila, which indicates a requirement of the endosomal system in the case of high intake of sugar.
- The small GTPase Rab5 is essential for the new formation and maintenance of endosome organelles in the liver. In mice lacking this functional gene, there was a change in glucose metabolism and improved hyperglycemia in diabetic db/db mice.
"All in all, these data underscore the relationship between endocytosis and metabolism," the researcher said. She has already found that different nutritional conditions in diabetes also lead to differences in the expression and regulation of signaling molecules, which in turn influence the transport system through membranes. She is continuing to pursue research on this topic. "Our goal is to gain new insights into the intracellular regulation of the glucose metabolism by the involvement of membrane transport processes in the liver and to pave the way for their application in the regulation of liver glucose production and thus the treatment of type 2 diabetes," the scientist said. Fascinated by the topic since the beginning of her career The question of the significance of endocytosis processes is a central theme of Anja Zeigerer's career: "Since the beginning of my scientific career, I have been fascinated by the mechanisms of intracellular transport, especially how these can regulate metabolism and cellular homeostasis."As Master’s student at the Memorial Sloan Kettering Cancer Center, New York, she investigated the selective transport of secretory proteins and their regulated sorting by coat proteins at the endoplasmic reticulum. She worked in the laboratory of James Edward Rothman, a Nobel Laureate in Medicine. In her doctoral thesis, she investigated the relationships between insulin-induced signal transduction and intracellular transport of glucose transporter 4 in the laboratory of Tim McGraw at Weill Cornell Medical College, New York. Here, under his direction, she became acquainted with the concept of metabolic regulation through intracellular transport processes. "Inspired by my doctoral research, I initially focused on the secretion of leptin from adipocytes during my first postdoc position with Jeffrey Friedman at Rockefeller University New York," Zeigerer said. After eight years in the USA, she returned to Germany and worked under Marino Zerial at the Max Planck Institute of Molecular Cell Biology and Genetics, Dresden. There for the first time she showed the link between the Rab5-mediated endosomal transport and the regulation of the glucose metabolism in the liver. Environment with "high-caliber diabetes and obesity research”Now Zeigerer is looking forward to her upcoming tasks at Helmholtz Zentrum München: "My goal is to combine the modules of endocytosis and metabolic regulation, which were previously investigated in an isolated way, and to investigate their potential dysregulation in diabetes and obesity. I wanted to do this in an environment that specializes in diabetes and obesity research and is engaged in high-caliber and innovative research."At a conference, Anja Zeigerer met the diabetes researchers Professor Matthias Tschöp and Professor Stephan Herzig of Helmholtz Zentrum München. She was enthusiastic about the idea of the Helmholtz Diabetes Center (HDC). Further talks followed. Since February 2015 she has been leading a young investigator group at the Institute for Diabetes and Cancer directed by Herzig.
Zeigerer A, et al. (2012), Rab5 is necessary for the biogenesis of the endo-lysosomal system in vivo. Nature. May 23;485(7399):465-70. Abstract...
Gilleron J, et al. (2013), Image-based analysis of lipid nanoparticle-mediated siRNA delivery, intracellular trafficking and endosomal escape. Nat Biotechnol. Jul;13(7):638-46. Abstract...
Zeigerer A, et al. (2015), Regulation of liver metabolism by the endosomal GTPase Rab5. Cell Rep. May 12;11(6):884-92. Abstract...
Zeigerer A, et al. (2017), Functional properties of hepatocytes in vitro are correlated with cell polarity maintenance. Exp Cell Res. Jan 1;350(1):242-252. Abstract...
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