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Updated: Jan 16, 2026

Extracellular Glucose Depletion as an Indirect Measure of Glucose Uptake in Cells and Tissues Ex Vivo
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P-Rex1 limits glucose clearance and suppresses hepatocyte glucose uptake and mitochondrial metabolism independently

Julia Y Chu1, Elpida Tsonou2, Polly A Machin1

  • 1Signalling Programme, The Babraham Institute, Cambridge, UK.

Cell Reports
|October 5, 2025
PubMed

Insights

The Rac guanine-nucleotide exchange factor (Rac-GEF) P-Rex1 regulates glucose homeostasis. P-Rex1 deficiency protects against diet-induced diabetes by enhancing hepatic glucose uptake and mitochondrial function.

Area of Science:

  • Biochemistry
  • Metabolic Diseases
  • Cell Biology

Background:

  • P-Rex1 (guanine-nucleotide exchange factor) is implicated in cellular signaling pathways.
  • Its precise role in systemic glucose homeostasis and metabolic disease remains incompletely understood.

Purpose of the Study:

  • To elucidate the function of P-Rex1 in glucose metabolism and insulin sensitivity.
  • To investigate the mechanisms by which P-Rex1 influences hepatic glucose uptake and mitochondrial function.

Main Methods:

  • Utilized P-Rex1 knockout (Prex1-/-) and catalytically inactive (Prex1GD) mouse models.
  • Administered high-fat diets to assess metabolic phenotypes.
  • Performed cell fractionation and utilized pharmacological agents (GRA2) to study protein interactions and cellular processes.

Main Results:

  • P-Rex1 deficiency maintained fasting blood glucose and insulin sensitivity via its Rac-GEF activity.
  • P-Rex1 limited glucose clearance independently of its catalytic activity, with Prex1-/- mice protected from diet-induced diabetes.
  • P-Rex1 negatively regulated hepatic glucose uptake and mitochondrial function (morphology, membrane potential, ATP production) by controlling Gpr21 trafficking and surface expression.

Conclusions:

  • P-Rex1 plays a dual role in glucose homeostasis, maintaining fasting glucose through its catalytic activity while limiting glucose clearance via Gpr21 interaction.
  • Targeting the P-Rex1-Gpr21 axis offers potential therapeutic strategies for managing glucose metabolism and diabetes.
Keywords:
CP: Cell biologyCP: MetabolismG protein-coupled receptorGEFGPCRGpr21P-Rex1glucose homeostasisguanine nucleotide exchange factorlivermitochondria

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