2. Academic Validation
  3. Insulin sensitization by small molecules enhancing GLUT4 translocation

Insulin sensitization by small molecules enhancing GLUT4 translocation

  • Cell Chem Biol. 2023 Aug 17;30(8):933-942.e6. doi: 10.1016/j.chembiol.2023.06.012.
Terry C Yin 1,  Jonathan G Van Vranken 2,  Dhiraj Srivastava 3,  Ayushi Mittal 1,  Paul Buscaglia 1,  Autumn E Moore 4,  Jissele A Verdinez 1,  Aschleigh E Graham 4,  Susan A Walsh 5,  Michael A Acevedo 5,  Robert J Kerns 4,  Nikolai O Artemyev 3,  Steven P Gygi 2,  Julien A Sebag 6
Affiliations

Affiliations

  • 1 Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA 52242, USA; Fraternal Order of Eagle Diabetes Research Center, University of Iowa, Iowa City, IA 52242, USA; Pappajohn Biomedical Institute, University of Iowa, Iowa City, IA 52242, USA.
  • 2 Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
  • 3 Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA 52242, USA.
  • 4 Fraternal Order of Eagle Diabetes Research Center, University of Iowa, Iowa City, IA 52242, USA; College of Pharmacy, University of Iowa, Iowa City, IA 52242, USA.
  • 5 Small Animal Imaging Core, University of Iowa, Iowa City, IA 52242, USA.
  • 6 Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA 52242, USA; Fraternal Order of Eagle Diabetes Research Center, University of Iowa, Iowa City, IA 52242, USA; Pappajohn Biomedical Institute, University of Iowa, Iowa City, IA 52242, USA. Electronic address: Julien-sebag@uiowa.edu.
PMID: 37453421 DOI: 10.1016/j.chembiol.2023.06.012
Abstract

Insulin resistance (IR) is the root cause of type II diabetes, yet no safe treatment is available to address it. Using a high throughput compatible assay that measures real-time translocation of the glucose transporter glucose transporter 4 (GLUT4), we identified small molecules that potentiate Insulin action. In vivo, these Insulin sensitizers improve insulin-stimulated GLUT4 translocation, glucose tolerance, and glucose uptake in a model of IR. Using proteomic and CRISPR-based approaches, we identified the targets of those compounds as Unc119 proteins and solved the structure of Unc119 bound to the Insulin sensitizer. This study identifies compounds that have the potential to be developed into diabetes treatment and establishes Unc119 proteins as targets for improving Insulin sensitivity.

Keywords

GLUT4; Unc119; Unc119b; glucose uptake; high throughput screening; insulin resistance; translocation.

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