Excitotoxic glutamate causes neuronal insulin resistance by inhibiting insulin receptor/Akt/mTOR pathway
Abstract Aim An impaired biological response to insulin in the brain, known as central insulin resistance, was identified during stroke and traumatic brain injury, for which glutamate excitotoxicity is a common pathogenic factor. The exact molecular link between excitotoxicity and central insulin re...
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| Format: | Article |
| Language: | English |
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BMC
2019-12-01
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| Series: | Molecular Brain |
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| Online Access: | https://doi.org/10.1186/s13041-019-0533-5 |
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| author | Igor Pomytkin Irina Krasil’nikova Zanda Bakaeva Alexander Surin Vsevolod Pinelis |
| author_facet | Igor Pomytkin Irina Krasil’nikova Zanda Bakaeva Alexander Surin Vsevolod Pinelis |
| author_sort | Igor Pomytkin |
| collection | DOAJ |
| description | Abstract Aim An impaired biological response to insulin in the brain, known as central insulin resistance, was identified during stroke and traumatic brain injury, for which glutamate excitotoxicity is a common pathogenic factor. The exact molecular link between excitotoxicity and central insulin resistance remains unclear. To explore this issue, the present study aimed to investigate the effects of glutamate-evoked increases in intracellular free Ca2+ concentrations [Ca2+]i and mitochondrial depolarisations, two key factors associated with excitotoxicity, on the insulin-induced activation of the insulin receptor (IR) and components of the Akt/ mammalian target of rapamycin (mTOR) pathway in primary cultures of rat cortical neurons. Methods Changes in [Ca2+]i and mitochondrial inner membrane potentials (ΔΨm) were monitored in rat cultured cortical neurons, using the fluorescent indicators Fura-FF and Rhodamine 123, respectively. The levels of active, phosphorylated signalling molecules associated with the IR/Akt/mTOR pathway were measured with the multiplex fluorescent immunoassay. Results When significant mitochondrial depolarisations occurred due to glutamate-evoked massive influxes of Ca2+ into the cells, insulin induced 48% less activation of the IR (assessed by IR tyrosine phosphorylation, pY1150/1151), 72% less activation of Akt (assessed by Akt serine phosphorylation, pS473), 44% less activation of mTOR (assessed by mTOR pS2448), and 38% less inhibition of glycogen synthase kinase β (GSK3β) (assessed by GSK3β pS9) compared with respective controls. These results suggested that excitotoxic glutamate inhibits signalling via the IR/Akt/mTOR pathway at multiple levels, including the IR, resulting in the development of acute neuronal insulin resistance within minutes, as an early pathological event associated with excitotoxicity. |
| first_indexed | 2024-12-16T09:42:52Z |
| format | Article |
| id | doaj.art-caa7739e3eac4798948fd603d0c43234 |
| institution | Directory Open Access Journal |
| issn | 1756-6606 |
| language | English |
| last_indexed | 2024-12-16T09:42:52Z |
| publishDate | 2019-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Brain |
| spelling | doaj.art-caa7739e3eac4798948fd603d0c432342022-12-21T22:36:13ZengBMCMolecular Brain1756-66062019-12-011211410.1186/s13041-019-0533-5Excitotoxic glutamate causes neuronal insulin resistance by inhibiting insulin receptor/Akt/mTOR pathwayIgor Pomytkin0Irina Krasil’nikova1Zanda Bakaeva2Alexander Surin3Vsevolod Pinelis4Institute of Regenerative Medicine, I.M. Sechenov First Moscow State Medical UniversityNational Medical Research Center for Children’s Health, Russian Ministry of Health, Lomonosov’s prospectNational Medical Research Center for Children’s Health, Russian Ministry of Health, Lomonosov’s prospectNational Medical Research Center for Children’s Health, Russian Ministry of Health, Lomonosov’s prospectNational Medical Research Center for Children’s Health, Russian Ministry of Health, Lomonosov’s prospectAbstract Aim An impaired biological response to insulin in the brain, known as central insulin resistance, was identified during stroke and traumatic brain injury, for which glutamate excitotoxicity is a common pathogenic factor. The exact molecular link between excitotoxicity and central insulin resistance remains unclear. To explore this issue, the present study aimed to investigate the effects of glutamate-evoked increases in intracellular free Ca2+ concentrations [Ca2+]i and mitochondrial depolarisations, two key factors associated with excitotoxicity, on the insulin-induced activation of the insulin receptor (IR) and components of the Akt/ mammalian target of rapamycin (mTOR) pathway in primary cultures of rat cortical neurons. Methods Changes in [Ca2+]i and mitochondrial inner membrane potentials (ΔΨm) were monitored in rat cultured cortical neurons, using the fluorescent indicators Fura-FF and Rhodamine 123, respectively. The levels of active, phosphorylated signalling molecules associated with the IR/Akt/mTOR pathway were measured with the multiplex fluorescent immunoassay. Results When significant mitochondrial depolarisations occurred due to glutamate-evoked massive influxes of Ca2+ into the cells, insulin induced 48% less activation of the IR (assessed by IR tyrosine phosphorylation, pY1150/1151), 72% less activation of Akt (assessed by Akt serine phosphorylation, pS473), 44% less activation of mTOR (assessed by mTOR pS2448), and 38% less inhibition of glycogen synthase kinase β (GSK3β) (assessed by GSK3β pS9) compared with respective controls. These results suggested that excitotoxic glutamate inhibits signalling via the IR/Akt/mTOR pathway at multiple levels, including the IR, resulting in the development of acute neuronal insulin resistance within minutes, as an early pathological event associated with excitotoxicity.https://doi.org/10.1186/s13041-019-0533-5InsulinGlutamate excitotoxicityCentral insulin resistance |
| spellingShingle | Igor Pomytkin Irina Krasil’nikova Zanda Bakaeva Alexander Surin Vsevolod Pinelis Excitotoxic glutamate causes neuronal insulin resistance by inhibiting insulin receptor/Akt/mTOR pathway Molecular Brain Insulin Glutamate excitotoxicity Central insulin resistance |
| title | Excitotoxic glutamate causes neuronal insulin resistance by inhibiting insulin receptor/Akt/mTOR pathway |
| title_full | Excitotoxic glutamate causes neuronal insulin resistance by inhibiting insulin receptor/Akt/mTOR pathway |
| title_fullStr | Excitotoxic glutamate causes neuronal insulin resistance by inhibiting insulin receptor/Akt/mTOR pathway |
| title_full_unstemmed | Excitotoxic glutamate causes neuronal insulin resistance by inhibiting insulin receptor/Akt/mTOR pathway |
| title_short | Excitotoxic glutamate causes neuronal insulin resistance by inhibiting insulin receptor/Akt/mTOR pathway |
| title_sort | excitotoxic glutamate causes neuronal insulin resistance by inhibiting insulin receptor akt mtor pathway |
| topic | Insulin Glutamate excitotoxicity Central insulin resistance |
| url | https://doi.org/10.1186/s13041-019-0533-5 |
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