Elevating Insulin Signaling Using a Constitutively Active Insulin Receptor Increases Glucose Metabolism and Expression of GLUT3 in Hippocampal Neurons

Hilaree N. Frazier, Adam O. Ghoweri, Katie L. Anderson, Ruei Lung Lin, Gabriel J. Popa, Michael D. Mendenhall, Lawrence P. Reagan, Rolf J. Craven, Olivier Thibault

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


Insulin signaling is an integral component of healthy brain function, with evidence of positive insulin-mediated alterations in synaptic integrity, cerebral blood flow, inflammation, and memory. However, the specific pathways targeted by this peptide remain unclear. Previously, our lab used a molecular approach to characterize the impact of insulin signaling on voltage-gated calcium channels and has also shown that acute insulin administration reduces calcium-induced calcium release in hippocampal neurons. Here, we explore the relationship between insulin receptor signaling and glucose metabolism using similar methods. Mixed, primary hippocampal cultures were infected with either a control lentivirus or one containing a constitutively active human insulin receptor (IRβ). 2-NBDG imaging was used to obtain indirect measures of glucose uptake and utilization. Other outcome measures include Western immunoblots of GLUT3 and GLUT4 on total membrane and cytosolic subcellular fractions. Glucose imaging data indicate that neurons expressing IRβ show significant elevations in uptake and rates of utilization compared to controls. As expected, astrocytes did not respond to the IRβ treatment. Quantification of Western immunoblots show that IRβ is associated with significant elevations in GLUT3 expression, particularly in the total membrane subcellular fraction, but did not alter GLUT4 expression in either fraction. Our work suggests that insulin plays a significant role in mediating neuronal glucose metabolism, potentially through an upregulation in the expression of GLUT3. This provides further evidence for a potential therapeutic mechanism underlying the beneficial impact of intranasal insulin in the clinic.

Original languageEnglish
Article number668
JournalFrontiers in Neuroscience
StatePublished - Jul 7 2020

Bibliographical note

Funding Information:
The authors acknowledge the use of facilities in the University of Kentucky Center for Molecular Medicine Genetic Technologies Core. Funding. This research was supported by the National Institutes of Health (R01AG033649 to OT, T32DK007778 to HF, and T32AG057461 to AG), the University of Kentucky College of Medicine (fellowship to HF), and the University of Kentucky Department of Pharmacology and Nutritional Sciences (Reinvestment Fund Award). The Molecular Medicine Genetic Technology Core at the University of Kentucky is supported in part by the National Institutes of Health (P30GM110787).

Publisher Copyright:
© Copyright © 2020 Frazier, Ghoweri, Anderson, Lin, Popa, Mendenhall, Reagan, Craven and Thibault.


  • GLUT3
  • astrocyte
  • glucose metabolism
  • hippocampus
  • neuron
  • signaling

ASJC Scopus subject areas

  • Neuroscience (all)


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