Dynamic GLUT trafficking at high glucose levels enhances insulin secretion: Dysregulation leads to decreased insulin secretion during type 2 diabetes.

Glucose transporters (GLUT1/2) facilitate glucose uptake in pancreatic β cells, triggering insulin secretion. The availability of GLUTs at the plasma membrane (PM) is governed by its expression, delivery to the membrane, and endocytosis. Little is known about the dynamics of GLUT trafficking in response to glucose that triggers glucose-stimulated insulin secretion. In our study, we found that the recruitment of GLUTs to the PM of β cells correlates with increasing glucose concentrations. The recruitment of GLUTs to PM is coupled with endocytosis driven by clathrin. During endocytosis, GLUT actively translocated to clathrin pits, triggering internalization. Disruption of endocytosis with dominant negative dynamin2-K44A or pitstop2 leads to altered GLUT dynamics in response to high glucose levels, resulting in reduced glucose uptake. Augmenting this finding, GLUT distribution and endocytosis in response to glucose are impaired in human islets from type 2 diabetes (T2D) donors, further confirmed by single-cell RNA-seq from β cells of nondiabetic and T2D donors. This leads to limited availability of insulin granules at higher glucose concentrations in T2D islets. Moreover, our data suggest that the glucose-dependent spatial association between GLUT and a subset of insulin granules which are primed via Munc-13.1. In line with this, we see our results highlight the importance of GLUTs delivery to the PM and clathrin-mediated endocytosis, leading to sustained availability of GLUTs for glucose uptake and subsequent insulin secretion in response to glucose. Notably, impaired insulin secretion during T2D might be reversible by modulating GLUT trafficking.