A recent study from the Indian Institute of Science (IISc) offers new insights into the cellular mechanisms underlying Type 2 diabetes (T2D), highlighting a critical breakdown in the “molecular traffic system” that manages glucose uptake/signalling in pancreatic β-cells. The research, published in the Proceedings of the National Academy of Sciences, pinpoints dysregulated trafficking of glucose transporters (GLUTs) as a key factor in the impaired insulin secretion seen in T2D.
The investigation, led by the lab of Nikhil Gandasi at the Department of Developmental Biology and Genetics, focused on the step preceding insulin release: the entry of glucose into pancreatic β-cells. This process is mediated by GLUTs—proteins that move to the β-cell surface in response to rising blood glucose levels. The study examined both GLUT1, the primary transporter in human β-cells, and GLUT2, its counterpart in mice.
Using advanced live-cell imaging, the researchers observed that in healthy β-cells, an increase in glucose prompts a rapid deployment of GLUTs to the cell membrane. These transporters are then continuously cycled in and out via clathrin-mediated endocytosis, ensuring an efficient and sustained uptake of glucose from the bloodstream.
However, this process is significantly impaired in β-cells from individuals with T2D. Key findings include:
- Reduced GLUT Deployment: Fewer glucose transporters reach the cell membrane in response to high glucose levels.
- Impaired Transporter Cycling: The dynamic process of moving GLUTs to and from the surface is slowed, leading to a “traffic jam” that hinders glucose entry.
- Compromised Insulin Release: The slowdown in glucose uptake directly reduces the docking of insulin granules to the β-cell membrane, particularly those primed for rapid release after a meal. This weakens the body’s first-line response to postprandial hyperglycemia.
These findings suggest that the dysfunction in T2D begins earlier than previously emphasized, disrupting the very entry of glucose that triggers insulin secretion.
Therapeutic Implications
This research shifts focus from fixing insulin resistance in peripheral tissues to improving the fundamental function of the pancreatic β-cell itself. By identifying the breakdown in GLUT trafficking as a critical failure point, the study opens a new avenue for therapeutic intervention. Restoring proper transporter dynamics could potentially improve β-cell function, slow disease progression, and lead to more personalized therapies tailored to a patient’s specific metabolic state.
The research team has previously identified a plant-derived molecule, Pheophorbide A, that can enhance insulin release by interacting with glucose transporters, demonstrating the potential of this new therapeutic target. The study underscores the importance of understanding the intricate dynamics of glucose transport as a foundation for developing novel treatments for Type 2 diabetes.
Journal article Pallavi A, Sinha N, ArunKumar NK, Kothegala L, Gandasi NR, Dynamic GLUT trafficking at high glucose levels enhances insulin secretion: Dysregulation leads to decreased insulin secretion during type 2 diabetes, Proceedings of the National Academy of Sciences (2025). https://www.pnas.org/doi/10.1073/pnas.2425955122
