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

• 成果类型: Article
• 署名作者: Pallavi, Anuma; Sinha, Neha; ArunKumar, Nagapriya K.; Kothegala, Lakshmi; Gandasi, Nikhil R.
• 署名单位: Indian Institute of Science (IISC) - Bangalore; University of Gothenburg; Uppsala University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13774
• DOI: 10.1073/pnas.2425955122
• 发表日期: 2025-08-19
• 关键词: beta-cells; docked granules; plasma-membrane; transporters; munc13-1; release; mice; mitochondrial; endocytosis; expression

摘要

Glucose transporters (GLUT1/2) facilitate glucose uptake in pancreatic beta 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 beta 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 beta 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.