Abstract

Insulin-like Growth Factor-1 (IGF-1) is involved in the normal development and survival of retinal cells. Low-density lipoprotein Receptor-related Protein-1 (LRP1) plays a key role on the regulation of several membrane proteins, such as the IGF-1 receptor (IGF-1R). In brain astrocytes, LRP1 interact with IGF-1R and the glucose transporter type 1 (GLUT1), regulating the glucose uptake in these cells. Although GLUT1 is expressed in retinal Müller Glial Cells (MGCs), its regulation is not clear yet. Here, we investigated whether IGF-1 modulates GLUT1 traffic to plasma membrane (PM) and glucose uptake, as well as the involvement of LRP1 in this process in the human Müller glial-derived cell line (MIO-M1). We found that IGF-1 produced GLUT1 translocation to the PM, in a time-dependent manner involving the intracellular signaling activation of MAPK/ERK and PI3K/Akt pathways, and generated a significant glucose uptake. Moreover, we found a molecular association between LRP1 and GLUT1, which was significantly reduced by IGF-1. Finally, cells treated with specific siRNA for LRP1 showed an impaired GLUT1 expression on PM and decreased glucose uptake induced by IGF-1. We conclude that IGF-1 regulates glucose homeostasis in MGCs involving the expression of LRP1.

Highlights

  • Abbreviations Akt or PKB Protein kinase B p-Akt Phospho-Akt ERK Extracellular signal-regulated kinase p-ERK Phospho-ERK glucose transporter type 1 (GLUT1) Glucose transporter type 1 IGF-1 Insulin-like growth factor-1 MGCs Müller glial cells lipoprotein Receptor-related Protein-1 (LRP1) Low-density lipoprotein receptor-related protein-1 PI3K Phosphatidylinositol-4,5-bisphosphate 3-kinase siRNA Small interference RNA 2-NBDG (2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl) Amino)-2-Deoxyglucose

  • The expressions of GLUT2 and GLUT4 were weakly detected in MIO-M1 cells, these proteins shown a different pattern of distribution compared to GLUT1 in mouse retina (Fig. 1c)

  • Several reports indicated that GLUT1 is the main glucose transporter in different cells of the retina, included retinal pigment epithelium (RPE), photoreceptors and blood-retinal b­ arrier[8,32,33,34,35], the regulation in MGCs is not clearly established yet

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Summary

Introduction

Abbreviations Akt or PKB Protein kinase B p-Akt Phospho-Akt ERK Extracellular signal-regulated kinase p-ERK Phospho-ERK GLUT1 Glucose transporter type 1 IGF-1 Insulin-like growth factor-1 MGCs Müller glial cells LRP1 Low-density lipoprotein receptor-related protein-1 PI3K Phosphatidylinositol-4,5-bisphosphate 3-kinase siRNA Small interference RNA 2-NBDG (2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl) Amino)-2-Deoxyglucose. The Low-density lipoprotein Receptor-related Protein-1 (LRP1) is an endocytic receptor involved in multiple signaling pathways by its ability to interact and regulate the function of others cell surface receptors in several ­tissues[20,21,22]. In this way, it has been demonstrated that LRP1 interacts with insulin receptor (IR) and regulates insulin-induced intracellular signaling and glucose uptake in the brain and ­cardiomyocytes[23,24]. GLUT1 is the main glucose transporter in the retina, the regulation of its intracellular traffic and activity in this tissue remains slightly explored

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