Thesis

GLUT4 dispersal at the plasma membrane : a molecular and microscopy-based journey from single cells to intact tissues

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Awarding institution
  • University of Strathclyde
Date of award
  • 2025
Thesis identifier
  • T17149
Person Identifier (Local)
  • 202068935
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Qualification Name
Department, School or Faculty
Abstract
  • The regulation of glucose uptake in adipocytes and muscle cells fundamentally depends on the glucose transporter GLUT4, which is critical in maintaining glucose homeostasis. GLUT4 is known to undergo translocation from intracellular compartments to the plasma membrane in response to insulin, facilitating glucose entry into cells. While GLUT4 translocation to the plasma membrane has been well-studied since its discovery in 1988, the finer details of GLUT4 behaviour at the plasma membrane have only recently been uncovered. In adipocytes, advances in light microscopy have shed light on GLUT4's ability to transition from a clustered formation into dispersed monomers upon insulin stimulation. This dispersal process is thought to enhance glucose uptake efficiency, and recent evidence has suggested a correlation between impaired GLUT4 dispersal and insulin resistance, a key characteristic of type 2 diabetes. To deepen the understanding of GLUT4’s dynamics at the cell surface, this thesis first focuses on two newly identified regulatory proteins at the plasma membrane, EFR3a and PI4K-IIIα, hypothesised to drive GLUT4 dispersal in adipocytes. This thesis aims to investigate how these proteins regulate GLUT4 behaviour at the single-cell level using molecular and microscopy-based techniques. Facing the limitations inherent to superresolution microscopy, it seeks to develop a DNA-PAINT imaging system for enhanced single-GLUT4 localisation accuracy at the plasma membrane. Additionally, this thesis extends beyond adipose tissues to explore the often-overlooked GLUT4 machinery in cardiac muscle tissues, addressing the challenges associated with cardiovascular research, both at the cellular level and within intact hearts. Significantly, we present here a novel optical mesoscopy approach that, using the imaging capability of the Mesolens, allows for precise measurement of the spatial location of GFP-tagged GLUT4 within specific anatomical structures across the myocardium in ultrathick sections (5 mm × 5 mm × 3 mm) of intact mouse hearts. Overall, this research offers new tools for high-resolution imaging, advances our understanding of GLUT4 dispersal machinery in adipocytes and contributes to improved methodologies for studying cardiovascular metabolism.
Advisor / supervisor
  • Gould, Gwyn W.
  • Currie, Susan
Resource Type
DOI

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