Just as smart traffic management ensures smooth vehicular movement during peak hours, our body relies on a molecular traffic system to manage the surge in glucose levels after a meal. Pancreatic β-cells play a major role in this system by taking up glucose from the blood and triggering insulin release into the bloodstream. Inside these cells, glucose uptake is managed by glucose transporters (GLUTs) – proteins that move to the β-cell surface when blood glucose levels rise and facilitate the entry of glucose into the cell to kickstart insulin release.
A new study from the Department of Developmental Biology and Genetics (DBG), Indian Institute of Science (IISc), shows how this process falters in Type 2 diabetes (T2D) and how restoring it could open new therapeutic avenues. The work, carried out by the lab of Nikhil Gandasi, Assistant Professor in DBG, is published in the Proceedings of the National Academy of Sciences (PNAS) .
In humans, GLUT1 is the main glucose "gateway" in β-cells, while in mice, GLUT2 plays that role. The team studied both to understand the process of glucose uptake across systems. Using advanced live-cell imaging, the team tracked GLUT1 and GLUT2 transporters as they were recruited to the β-cell membrane under different blood glucose levels. In healthy cells, rising glucose levels prompt a rapid deployment of GLUTs to the membrane. These transporters are then cycled in and out through clathrin-mediated endocytosis – a process in which cells internalise extracellular material by forming pockets made of the protein clathrin. This ensures a constant supply of transporters at the surface for efficient glucose uptake.
In β-cells from people with T2D, however, this traffic is poorly managed. Fewer GLUTs reach the membrane, and their cycling is impaired, slowing down glucose entry. This, in turn, reduces the docking of insulin granules to the surface of the β-cell membrane – particularly those "primed" for rapid release after eating – weakening the body's ability to regulate blood sugar.
"Most studies have looked at what happens after glucose enters the β-cell," explains Anuma Pallavi, PhD student in DBG and first author of the study. "We focused on the step before that, the actual entry of glucose, and how this is disrupted in diabetes. By understanding the dynamics of these transporters, we can identify new points to intervene and improve β-cell function."
The findings have important therapeutic implications. Current diabetes treatments largely target insulin action in peripheral tissues like muscle and fat, but this new work points to β-cell glucose uptake as a promising target. Gandasi's lab has previously identified Pheophorbide A, a plant-derived molecule that can boost insulin release by interacting with glucose transporters.
"If we can restore proper GLUT trafficking, we may be able to slow down disease progression and personalise therapies based on a patient's metabolic state," says Gandasi.
