The insulin-like growth factor I receptor regulates glucose transport by astrocytes

Glia. 2016 Nov;64(11):1962-71. doi: 10.1002/glia.23035. Epub 2016 Jul 27.

Abstract

Previous findings indicate that reducing brain insulin-like growth factor I receptor (IGF-IR) activity promotes ample neuroprotection. We now examined a possible action of IGF-IR on brain glucose transport to explain its wide protective activity, as energy availability is crucial for healthy tissue function. Using (18) FGlucose PET we found that shRNA interference of IGF-IR in mouse somatosensory cortex significantly increased glucose uptake upon sensory stimulation. In vivo microscopy using astrocyte specific staining showed that after IGF-IR shRNA injection in somatosensory cortex, astrocytes displayed greater increases in glucose uptake as compared to astrocytes in the scramble-injected side. Further, mice with the IGF-IR knock down in astrocytes showed increased glucose uptake in somatosensory cortex upon sensory stimulation. Analysis of underlying mechanisms indicated that IGF-IR interacts with glucose transporter 1 (GLUT1), the main facilitative glucose transporter in astrocytes, through a mechanism involving interactions with the scaffolding protein GIPC and the multicargo transporter LRP1 to retain GLUT1 inside the cell. These findings identify IGF-IR as a key modulator of brain glucose metabolism through its inhibitory action on astrocytic GLUT1 activity. GLIA 2016;64:1962-1971.

Keywords: astrocytes; glucose metabolism; glucose transporter 1; insulin like growth factor I receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-Chloro-7-nitrobenzofurazan / analogs & derivatives
  • 4-Chloro-7-nitrobenzofurazan / pharmacology
  • Animals
  • Animals, Newborn
  • Astrocytes / metabolism*
  • Biotinylation
  • Brain / cytology
  • Brain / diagnostic imaging
  • Cells, Cultured
  • Glial Fibrillary Acidic Protein / genetics
  • Glial Fibrillary Acidic Protein / metabolism
  • Glucosamine / analogs & derivatives
  • Glucosamine / pharmacology
  • Glucose / metabolism*
  • Glucose Transporter Type 1 / metabolism
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Insulin-Like Growth Factor I / deficiency
  • Insulin-Like Growth Factor I / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Physical Stimulation
  • Protein Transport / genetics
  • RNA, Messenger / metabolism
  • Transfection
  • Vibrissae / physiology

Substances

  • Glial Fibrillary Acidic Protein
  • Glucose Transporter Type 1
  • RNA, Messenger
  • insulin-like growth factor-1, mouse
  • 6-deoxy-N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)aminoglucose
  • Green Fluorescent Proteins
  • Insulin-Like Growth Factor I
  • 4-Chloro-7-nitrobenzofurazan
  • Glucose
  • Glucosamine