Dr. Anja Zeigerer

Diabetes – a hitchhiker’s guide to the cell membrane

Dr. Anja Zeigerer heads the Endocytosis and Metabolism Junior Group at the Institute of Diabetes and Cancer (IDC) at the Helmholtz Zentrum München. In an interview, she explains why the transport through the cell membrane is of key importance in type 2 diabetes, and why she has been fascinated by this topic for years.

Dr. Anja Zeigerer, Source: Helmholtz Zentrum München

According to WHO information, the global prevalence of type 2 diabetes has reached epidemic proportions, with more than 400 million clinically diagnosed patients. Scientists at the Helmholtz Zentrum München are investigating the mechanisms underlying this metabolic condition in order to develop new approaches for solutions. Dr. Anja Zeigerer is taking a closer look at endocytosis, which is the process responsible for the uptake of molecules from a cell’s surroundings by invagination (the formation of surface pockets) of areas of the plasma membrane.

Two key mechanisms

The liver plays a key role in type 2 diabetes (insulin resistance) due to its central function in controlling glucose homeostasis. This is achieved by two cellular processes: endocytosis and glucose metabolism. Endocytosis results in the systematic penetration of nutrients, but also signaling molecules, into the cell interior. At the same time, glucose metabolism is regulated by the storage and release of glucose. “The two processes must be synchronized in order to control glucose metabolism,” Zeigerer explains. “Dysfunctions of these mutually dependent processes can encourage the development of type 2 diabetes.”

The scientist reports a number of indications that glucose metabolism and endocytosis regulate each other:

  • During a genome-wide RNAi screen, it was seen that the inactivation of specific metabolic genes has dramatic effects on endosomal transport.
  • In the fruit fly (Drosophila), sucrose induces an upregulation of endocytosis genes, which indicates a demand on the endosomal system when a large amount of sugar is present.
  • The small GTPase Rab5 is essential for the development and maintenance of the endosomal organelles in the liver. Interestingly, mice lacking this functional gene exhibit changes in the glucose metabolism and show improved hyperglycemia in diabetic db/db mice.

“Altogether, these data emphasize the connection between endocytosis and metabolism,” the researcher reports. She has already discovered that various dietary conditions in diabetes also lead to differences in the expression and regulation of trafficking molecules, which influence the transport rates through cellular membranes.

Zeigerer now wants to know, whether changes in the expression of regulators of endosomal transport can affect metabolic processes. Do these alterations influence hepatic glucose metabolism? “Our objective is to acquire new insights into the intracellular regulation of glucose metabolism by the participation of membrane transport processes in the liver and to pave the way for their application in the control of liver glucose production and consequently the treatment of type 2 diabetes,” the scientist says.

Fascinated by the topic since the beginning of her career

The question of the importance of endocytic processes for metabolism is a red thread that runs through Anja Zeigerer’s career: “Since beginning my scientific career, I have been fascinated by the mechanisms in intracellular transport, especially in how it can regulate metabolism and cellular homeostasis.”

As a Master’s student at Memorial Sloan Kettering Cancer Center in New York, she examined the selective transport of secretory proteins and their regulated sorting by coat proteins on the endoplasmic reticulum. She worked in the laboratory of James Edward Rothman, recipient of the Nobel Prize in Physiology or Medicine.

As a doctoral student, she investigated the connections between insulin-induced signal transduction and intracellular transport of the glucose transporter type 4 in the laboratory of Tim McGraw at Weill Cornell Medical College, New York. While there, she first became familiar with the concept of metabolic regulation by intracellular transport processes.

“Inspired by my doctoral work, I first investigated the secretion of leptin from adipocytes during my first postdoc with Jeffrey Friedman at Rockefeller University in New York,” Zeigerer says. After eight years in the USA, she returned to Germany and worked with Marino Zerial at the Max Planck Institute of Molecular Cell Biology and Genetics, Dresden. She was the first to show the connection between the Rab5-mediated endosomal transport and the regulation of glucose metabolism in the liver.

Environment with “top-level diabetes and obesity research”

Zeigerer says, “My goal is to connect endocytosis and metabolic regulation, two cellular processes that have been mostly studied in isolation until now, and to examine their potential defective regulation in diabetes and obesity. I wanted to do this in an environment that was specializing in diabetes and obesity research and that was conducting top-level and innovative research.”

Anja Zeigerer met the diabetes researchers Prof. Dr. Matthias Tschöp and Prof. Dr. Stephan Herzig from Helmholtz Zentrum München at a conference. She was impressed by the idea of the Helmholtz Diabetes Center (HDC). Further talks followed. Since February 2015, she has been the head of a junior group at the Institute for Diabetes and Cancer, where Herzig is director.

Further information

Important publications:

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: https://www.ncbi.nlm.nih.gov/pubmed/22622570

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: https://www.ncbi.nlm.nih.gov/pubmed/2379263