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Pinelis, V.G. Brain Insulin Resistance. Encyclopedia. Available online: https://encyclopedia.pub/entry/8896 (accessed on 18 May 2024).
Pinelis VG. Brain Insulin Resistance. Encyclopedia. Available at: https://encyclopedia.pub/entry/8896. Accessed May 18, 2024.
Pinelis, V. G.. "Brain Insulin Resistance" Encyclopedia, https://encyclopedia.pub/entry/8896 (accessed May 18, 2024).
Pinelis, V.G. (2021, April 22). Brain Insulin Resistance. In Encyclopedia. https://encyclopedia.pub/entry/8896
Pinelis, V. G.. "Brain Insulin Resistance." Encyclopedia. Web. 22 April, 2021.
Brain Insulin Resistance
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This entry is adapted from the peer-reviewed paper 10.3390/life11030262

Current hypotheses implicate insulin resistance of the brain as a pathogenic factor in the development of Alzheimer’s disease and other dementias, Parkinson’s disease, type 2 diabetes, obesity, major depression, and traumatic brain injury. A variety of genetic, developmental, and metabolic abnormalities that lead to disturbances in the insulin receptor signal transduction may underlie insulin resistance. Insulin receptor substrate proteins are generally considered to be the node in the insulin signaling system that is critically involved in the development of insulin insensitivity during metabolic stress, hyperinsulinemia, and inflammation. Emerging evidence suggests that lower activation of the insulin receptor (IR) is another common, while less discussed, mechanism of insulin resistance in the brain.

insulin insulin receptor brain insulin resistance mitochondria brain neuron H2O2 glutamate excitotoxicity

1. Introduction

Insulin Resistances (IRs) are widely distributed throughout the brain and are at their highest density in the olfactory bulb, hypothalamus, hippocampus, cerebral cortex, and cerebellum [1][2]. The vast majority of IRs are localized on neurons [3], where they are concentrated at synapses as a component of post-synaptic density (PSD), indicating that the synapse is an important site of specialized insulin signaling in the brain [4].

In contrast to adult peripheral tissues, where long receptor isoform B (IR-B) prevails, neurons almost exclusively express the short isoform A (IR-A), lacking 12 amino acids within the C-terminus of the α-subunit [5][6][7]. The most significant difference between the isoforms is that IR-A binds insulin-like growth factor 2 (IGF2) at physiologically relevant affinity, while IR-B does not [8][9]. In addition, IR-A displays a two-fold higher affinity for insulin than IR-B and shows no negative cooperativity in the insulin binding [10][11][12]. A specific function of IGF2 signaling via IR-A in the brain is the promotion of self-renewal and expansion of neural stem cells [12][13]. Insulin signaling in neurons occurs through two canonic signaling pathways known as the PI3K/Akt and mitogen-activated protein kinase (MAPK) pathways [14][15].

IRs in the brain are involved in the regulation of synaptic plasticity [16]. Insulin facilitates excitatory neurotransmission, mediated by the N-methyl-D-aspartate (NMDA) receptor, by stimulating translocation of functional NMDA receptors to the cell membrane [17] and potentiating NMDA receptor currents in a dose-, time-, and NMDA subunit-specific manner [18][19][20][21][22]. Insulin also facilitates inhibitory neurotransmission through stimulation of the trafficking of the type A γ-aminobutyric acid (GABAA) receptor subunits from an intracellular compartment to the membrane surface, thereby increasing the number of functional inhibitory GABAA receptors in the cell membrane [23][24]. The IR is implicated in the modulation of long-term potentiation (LTD) and long-term depression (LTD) [25], learning and memory [26], and regulation of feeding behavior [27]. Although understanding the net functional outcome of insulin on neurotransmission is challenging, the above data suggest a direct link between insulin signaling and synaptic function. In line with this, both synaptic failure and dysfunctional insulin signaling were observed in AD prior to frank neuronal degeneration [28][29][30].

Emerging evidence suggests that insulin signaling also plays a role in glucose metabolism in the brain. The insulin-regulated glucose transporter GLUT4 has been found to be co-expressed with the major neuronal transporter GLUT3 in brain regions related to cognitive behavior, such as the basal forebrain, hippocampus, amygdala, cerebral cortex, and cerebellum [31], and in the hypothalamus that controls food intake and body weight [32]. Insulin stimulates translocation of GLUT4 to the plasma membrane in rat hippocampus [33], increases local glycolytic metabolism, and enhances spatial memory [34]. An inhibition of GLUT4 alone did not impair the spatial memory performance but prevented the insulin’s cognition enhancing effect [35]. Insulin-induced GLUT4 translocation to the neuronal membrane in the hippocampus occurs during periods of high energy demand, such as during learning, suggesting that deregulation of insulin-dependent glucose transport in several brain regions may be a cause of cognitive impairment [36]. For subjects with prediabetes and type 2 diabetes, an association between reduced cerebral glucose metabolic rate and peripheral insulin resistance has been shown even before the onset of mild cognitive impairment [37]. Given such a variety of functions of insulin in the brain, the development of brain insulin resistance can lead to numerous pathological manifestations, especially to those associated with synapse failure and energy metabolism.

2. Glutamate Excitotoxicity Impairs Activation of the Neuronal Insulin Receptor

Glutamate excitotoxicity is a common pathological condition that affects mitochondrial metabolism and complex II activity in the brain, thereby being a prominent candidate for the role of inducer of brain insulin resistance. Glutamate is the major excitatory neurotransmitter that is involved in most normal brain function, such as cognition, memory, and learning, through binding to several types of glutamate receptors [38]. However, an excessive glutamate release to the synaptic cleft may induce a specific pathophysiological process called excitotoxicity. The glutamate-induced activation of the ionotropic NMDA receptors, followed by a Ca2+ influx into the cell, is generally considered to be central to the development of excitotoxicity [39][40][41]. The Ca2+ influx is biphasic and an initial rapid increase in the intracellular free Ca2+ concentration ([Ca2+]i) is followed by a larger secondary [Ca2+]i increase, along with a marked decrease in ΔΨm, SDH activity, and ATP production [42][43][44][45][46]. The irreversible secondary [Ca2+]i increase, known as delayed calcium deregulation, is postulated to be a point-of-no-return in excitotoxicity, i.e., events occurring downstream of this point are considered to influence the timing of cell death without altering its inevitability [47].

Emerging evidence suggests that there is a functional relationship between IR and NMDA receptors in health and disease. Both types of receptors are co-localized in the PSD of the synapses [4]. The IR is involved in the regulation of NMDA receptor trafficking [17] and the potentiation of NMDA receptor currents in a dose-, time-, and NMDA subunit-specific manner [18][19][20][21][22]. The NMDA receptor is involved in the inhibition of tyrosine phosphorylation of the IR in cortical and hippocampal cultures of neurons with soluble β-amyloid oligomers [48]. The amyloid-like effect was achieved with glutamate added one hour after the insulin stimulation, i.e., at times when the active IR undergoes dephosphorylation and deactivation [48]. Glutamate also affects the activation of the IR and downstream effectors, when being added prior to insulin exposure, thereby developing acute neuronal insulin resistance within minutes (Figure 1) [49].

Figure 1. Glutamate excitotoxicity induces acute neuronal insulin resistance. Glutamate (Glu) binding to NMDA receptor evokes rapid increase in the intracellular free Ca2+ concentration ([Ca2+]i), followed by decrease in mitochondrial ΔΨm [44][49]. Within minutes, when the glutamate-induced mitochondrial depolarization occurred, insulin evoked less tyrosine phosphorylation of IR Y1150/1151, and less serine phosphorylation of Akt S473, mTOR S2448, and GSK3β S9 [48], indicating the development of acute neuronal insulin resistance as an early pathological event associated with excitotoxicity. Abbreviations: Glu, glutamate; NMDA, N-methyl-D-aspartate; [Ca2+]i, intracellular calcium concentration; ΔΨm, mitochondrial inner membrane potential; H2O2, hydrogen peroxide; SDH, succinate dehydrogenase; IRS, insulin receptor substrate; PI3K, phosphatidylinositol 3-kinase; Akt, protein kinase B; mTOR, mammalian target of rapamycin; GSK3β, glycogen synthase kinase 3 β; pY, phosphotyrosine; pS, phosphoserine.

At times where significant mitochondrial depolarization has been achieved due to glutamate-evoked massive influxes of Ca2+ into the cells, insulin induced 48% less activation of the IR kinase domain (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 [49]. Thus, the glutamate-induced development of acute neuronal insulin resistance represents one of the earliest pathological events in excitotoxicity, which occurs at the level of activation of the IR in the neurons.

It has already been shown that glutamate excitotoxicity is implicated in the pathogenesis of TBI [39] and AD [50]. However, the existence of the causal relationship between excitotoxicity and brain insulin resistance indicates that list of disorders associated with brain insulin resistance is much broader and may include stroke [51], PD [52], HD, amyotrophic lateral sclerosis [53], depression, autism spectrum disorder, schizophrenia [54], and multiple sclerosis [55], for which glutamate excitotoxicity has already been demonstrated as a pathogenic factor.

The relationship between IR activation and glutamate excitotoxicity appears to be bidirectional, since insulin itself activates mitochondrial metabolism. Although hyperinsulinemia and a long-term insulin exposure have been shown to exacerbate glutamate excitotoxicity through inducing insulin resistance [56], in contrast, a short-term insulin treatment protects neurons against glutamate excitotoxicity [45]. The short-term stimulation of cortical neurons with insulin prior to glutamate exposure protects them from the NMDA receptor-mediated increase in [Ca2+], thereby preventing the mitochondrial depolarization, decrease in ATP levels, and decrease in oxygen consumption rates due to the preservation of spare respiratory capacity (SRC) [57]. SRC, also known as the reserve respiratory capacity, refers to the measure of the amount of extra ATP that can be produced by oxidative phosphorylation in case of an increase in energy demand. It has been shown that mitochondrial complex II is a source of SRC [58]. Given that insulin enhances succinate oxidation at complex II [59][60], the insulin protective action against glutamate excitotoxicity seems to relate to the insulin-induced improvement of complex II-dependent ATP production and mitochondrial metabolism.

It should be noted that the discussed above functional relationship between IR activation and glutamate excitotoxicity is part of more complex relationships between deficient insulin signaling and Ca2+ dyshomeostasis in neurons that are associated with brain aging [61][62]. Insulin and insulin sensitizers have been shown to target several hippocampal Ca2+-related processes affected by aging, including larger Ca2+ transients and Ca2+-dependent afterhyperpolarizations [61], with the reduction of voltage-gated calcium currents being implicated in the mechanisms of these insulin effects [63].

3. Conclusions and Perspectives

Brain insulin resistance leads to a variety of abnormalities, both related and unrelated to brain glucose utilization, with deterioration of cognitive function and energy metabolism being the most recognized. The disbalance between tyrosine and serine/threonine phosphorylation of IRS protein is the most common cause of insulin resistance associated with metabolic stress, hyperinsulinemia, and inflammation. The diminished autophosphorylation (i.e., activation) of the IR during insulin stimulation is another reported cause of brain insulin resistance.

The insulin-induced mitochondrial H2O2 signal occurring from complex II is an integral part of the IR autophosphorylation process in neurons, with the IR activation occurring either completely or not at all, depending on whether the H2O2 signal can or cannot exceed a certain threshold. It remains unexplored whether the mitochondrial control of IR activation is a neuron-specific mechanism or a more general phenomenon. Neuronal IRs are localized predominantly in the PSD of dendritic spines, which are poor in mitochondria at rest, but become enriched with mitochondria in periods of synaptic activity. In this context, the mitochondrial H2O2 signaling in neurons may be a control mechanism for the selective activation of the IR only in the active synapses.

Given the critical role of H2O2 signaling in IR activation, factors downregulating the mitochondrial H2O2 signal may lead to less activation of the IRs and the development of brain insulin resistance. The incomplete list of such factors includes oxidative stress, glutamate excitotoxicity, the overexpression of antioxidant enzymes compensatory to oxidative stress, mitochondrial depolarization, and mitochondrial hypometabolism manifested as low ATP/ADP, NADH/NAD, and CoQH2/CoQ ratios.

In this context, the interventions aimed at improving mitochondrial metabolism represent a reasonable approach to the treatment of brain insulin resistance at the level of IR activation through the improvement of insulin-induced H2O2 signaling in neurons.

References

  1. Carvalho, C.; Cardoso, S.M.; Correia, S.C.; Moreira, P.I. Tortuous Paths of Insulin Signaling and Mitochondria in Alzheimer’s Disease. Adv. Exp. Med. Biol. 2019, 1128, 161–183.
  2. Havrankova, J.; Roth, J.; Brownstein, M. Insulin receptors are widely distributed in the central nervous system of the rat. Nature 1978, 272, 827–829.
  3. Unger, J.; McNeill, T.H.; Moxley, R.T., 3rd; White, M.; Moss, A.; Livingston, J.N. Distribution of insulin receptor-like immunoreactivity in the rat forebrain. Neuroscience 1989, 31, 143–157.
  4. Abbott, M.A.; Wells, D.G.; Fallon, J.R. The insulin receptor tyrosine kinase substrate p58/53 and the insulin receptor are components of CNS synapses. J. Neurosci. 1999, 19, 7300–7308.
  5. Heidenreich, K.A.; Zahniser, N.R.; Berhanu, P.; Brandenburg, D.; Olefsky, J.M. Structural differences between insulin receptors in the brain and peripheral target tissues. J. Biol. Chem. 1983, 258, 8527–8530.
  6. Gammeltoft, S.; Fehlmann, M.; Van Obberghen, E. Insulin receptors in the mammalian central nervous system: Binding characteristics and subunit structure. Biochimie 1985, 67, 1147–1153.
  7. Garwood, C.J.; Ratcliffe, L.E.; Morgan, S.V.; Simpson, J.E.; Owens, H.; Vazquez-Villaseñor, I.; Heath, P.R.; Romero, I.A.; Ince, P.G.; Wharton, S.B. Insulin and IGF1 signalling pathways in human astrocytes in vitro and in vivo; characterisation, subcellular localisation and modulation of the receptors. Mol. Brain 2015, 8, 51.
  8. Yamaguchi, Y.; Flier, J.S.; Benecke, H.; Ransil, B.J.; Moller, D.E. Ligand-binding properties of the two isoforms of the human insulin receptor. Endocrinology 1993, 132, 1132–1138.
  9. Denley, A.; Bonython, E.R.; Booker, G.W.; Cosgrove, L.J.; Forbes, B.E.; Ward, C.W.; Wallace, J.C. Structural determinants for high-affinity binding of insulin-like growth factor II to insulin receptor (IR)-A, the exon 11 minus isoform of the IR. Mol. Endocrinol. 2004, 18, 2502–2512.
  10. Mosthaf, L.; Grako, K.; Dull, T.J.; Coussens, L.; Ullrich, A.; McClain, D.A. Functionally distinct insulin receptors generated by tissue-specific alternative splicing. EMBO J. 1990, 9, 2409–2413.
  11. Yamaguchi, Y.; Flier, J.S.; Yokota, A.; Benecke, H.; Backer, J.M.; Moller, D.E. Functional properties of two naturally occurring isoforms of the human insulin receptor in Chinese hamster ovary cells. Endocrinology 1991, 129, 2058–2066.
  12. Ziegler, A.N.; Schneider, J.S.; Qin, M.; Tyler, W.A.; Pintar, J.E.; Fraidenraich, D.; Wood, T.L.; Levison, S.W. IGF-II promotes stemness of neural restricted precursors. Stem Cells 2012, 30, 1265–1276.
  13. Ziegler, A.N.; Chidambaram, S.; Forbes, B.E.; Wood, T.L.; Levison, S.W. Insulin-like growth factor-II (IGF-II) and IGF-II analogs with enhanced insulin receptor-a binding affinity promote neural stem cell expansion. J. Biol. Chem. 2014, 289, 4626–4633.
  14. van der Heide, L.P.; Ramakers, G.M.; Smidt, M.P. Insulin signaling in the central nervous system: Learning to survive. Prog. Neurobiol. 2006, 79, 205–221.
  15. Nelson, T.J.; Sun, M.K.; Hongpaisan, J.; Alkon, D.L. Insulin, PKC signaling pathways and synaptic remodeling during memory storage and neuronal repair. Eur. J. Pharm. 2008, 585, 76–87.
  16. Ferrario, C.R.; Reagan, L.P. Insulin-mediated synaptic plasticity in the CNS: Anatomical, functional and temporal contexts. Neuropharmacology 2018, 136, 182–191.
  17. Skeberdis, V.A.; Lan, J.; Zheng, X.; Zukin, R.S.; Bennett, M.V. Insulin promotes rapid delivery of N-methyl-D-aspartate receptors to the cell surface by exocytosis. Proc. Natl. Acad. Sci. USA 2001, 98, 3561–3566.
  18. Liu, L.; Brown, J.C., 3rd; Webster, W.W.; Morrisett, R.A.; Monaghan, D.T. Insulin potentiates N-methyl-D-aspartate receptor activity in Xenopus oocytes and rat hippocampus. Neurosci. Lett. 1995, 192, 5–8.
  19. Chen, C.; Leonard, J.P. Protein tyrosine kinase-mediated potentiation of currents from cloned NMDA receptors. J. Neurochem. 1996, 67, 194–200.
  20. Christie, J.M.; Wenthold, R.J.; Monaghan, D.T. Insulin causes a transient tyrosine phosphorylation of NR2A and NR2B NMDA receptor subunits in rat hippocampus. J. Neurochem. 1999, 72, 1523–1528.
  21. Liao, G.Y.; Leonard, J.P. Insulin modulation of cloned mouse NMDA receptor currents in Xenopus oocytes. J. Neurochem. 1999, 73, 1510–1519.
  22. Jones, M.L.; Leonard, J.P. PKC site mutations reveal differential modulation by insulin of NMDA receptors containing NR2A or NR2B subunits. J. Neurochem. 2005, 92, 1431–1438.
  23. Wan, Q.; Xiong, Z.G.; Man, H.Y.; Ackerley, C.A.; Braunton, J.; Lu, W.Y.; Becker, L.E.; MacDonald, J.F.; Wang, Y.T. Recruitment of functional GABA(A) receptors to postsynaptic domains by insulin. Nature 1997, 388, 686–690.
  24. Jin, Z.; Jin, Y.; Kumar-Mendu, S.; Degerman, E.; Groop, L.; Birnir, B. Insulin reduces neuronal excitability by turning on GABA(A) channels that generate tonic current. PLoS ONE 2011, 6, e16188.
  25. McNay, E.C.; Recknagel, A.K. Brain insulin signaling: A key component of cognitive processes and a potential basis for cognitive impairment in type 2 diabetes. Neurobiol. Learn. Mem. 2011, 96, 432–442.
  26. Kullmann, S.; Heni, M.; Hallschmid, M.; Fritsche, A.; Preissl, H.; Häring, H.U. Brain Insulin Resistance at the Crossroads of Metabolic and Cognitive Disorders in Humans. Physiol. Rev. 2016, 96, 1169–1209.
  27. Ono, H. Molecular Mechanisms of Hypothalamic Insulin Resistance. Int. J. Mol. Sci. 2019, 20, 1317.
  28. Talbot, K.; Wang, H.Y.; Kazi, H.; Han, L.Y.; Bakshi, K.P.; Stucky, A.; Fuino, R.L.; Kawaguchi, K.R.; Samoyedny, A.J.; Wilson, R.S.; et al. Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J. Clin. Investig. 2012, 122, 1316–1338.
  29. Selkoe, D.J. Alzheimer’s disease is a synaptic failure. Science 2002, 298, 789–791.
  30. Stanley, M.; Macauley, S.L.; Holtzman, D.M. Changes in insulin and insulin signaling in Alzheimer’s disease: Cause or consequence? J. Exp. Med. 2016, 213, 1375–1385.
  31. Apelt, J.; Mehlhorn, G.; Schliebs, R. Insulin-sensitive GLUT4 glucose transporters are colocalized with GLUT3-expressing cells and demonstrate a chemically distinct neuron-specific localization in rat brain. J. Neurosci. Res. 1999, 57, 693–705.
  32. Komori, T.; Morikawa, Y.; Tamura, S.; Doi, A.; Nanjo, K.; Senba, E. Subcellular localization of glucose transporter 4 in the hypothalamic arcuate nucleus of ob/ob mice under basal conditions. Brain Res. 2005, 1049, 34–42.
  33. Grillo, C.A.; Piroli, G.G.; Hendry, R.M.; Reagan, L.P. Insulin-stimulated translocation of GLUT4 to the plasma membrane in rat hippocampus is PI3-kinase dependent. Brain Res. 2009, 1296, 35–45.
  34. McNay, E.C.; Ong, C.T.; McCrimmon, R.J.; Cresswell, J.; Bogan, J.S.; Sherwin, R.S. Hippocampal memory processes are modulated by insulin and high-fat-induced insulin resistance. Neurobiol. Learn. Mem. 2010, 93, 546–553.
  35. Pearson-Leary, J.; Jahagirdar, V.; Sage, J.; McNay, E.C. Insulin modulates hippocampally-mediated spatial working memory via glucose transporter-4. Behav. Brain Res. 2018, 338, 32–39.
  36. Pearson-Leary, J.; McNay, E.C. Novel Roles for the Insulin-Regulated Glucose Transporter-4 in Hippocampally Dependent Memory. J. Neurosci. 2016, 36, 11851–11864.
  37. Baker, L.D.; Cross, D.J.; Minoshima, S.; Belongia, D.; Watson, G.S.; Craft, S. Insulin resistance and Alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes. Arch. Neurol. 2011, 68, 51–57.
  38. Willard, S.S.; Koochekpour, S. Glutamate, glutamate receptors, and downstream signaling pathways. Int. J. Biol. Sci. 2013, 9, 948–959.
  39. Zhou, Q.; Sheng, M. NMDA receptors in nervous system diseases. Neuropharmacology 2013, 74, 69–75.
  40. Khodorov, B. Glutamate-induced deregulation of calcium homeostasis and mitochondrial dysfunction in mammalian central neurones. Prog. Biophys. Mol. Biol. 2004, 86, 279–351.
  41. Nicholls, D.G.; Budd, S.L. Mitochondria and neuronal survival. Physiol. Rev. 2000, 80, 315–360.
  42. Tymianski, M.; Charlton, M.P.; Carlen, P.L.; Tator, C.H. Secondary Ca2+ overload indicates early neuronal injury which precedes staining with viability indicators. Brain Res. 1993, 607, 319–323.
  43. Brittain, M.K.; Brustovetsky, T.; Sheets, P.L.; Brittain, J.M.; Khanna, R.; Cummins, T.R.; Brustovetsky, N. Delayed calcium dysregulation in neurons requires both the NMDA receptor and the reverse Na+/Ca2+ exchanger. Neurobiol. Dis. 2012, 46, 109–117.
  44. Nicholls, D.G.; Budd, S.L. Mitochondria and neuronal glutamate excitotoxicity. Biochim. Biophys. Acta 1998, 1366, 97–112.
  45. Krasil’nikova, I.; Surin, A.; Sorokina, E.; Fisenko, A.; Boyarkin, D.; Balyasin, M.; Demchenko, A.; Pomytkin, I.; Pinelis, V. Insulin Protects Cortical Neurons Against Glutamate Excitotoxicity. Front. Neurosci. 2019, 13, 1027.
  46. Cui, A.L.; Zhang, Y.H.; Li, J.Z.; Song, T.; Liu, X.M.; Wang, H.; Zhang, C.; Ma, G.L.; Zhang, H.; Li, K. Humanin rescues cultured rat cortical neurons from NMDA-induced toxicity through the alleviation of mitochondrial dysfunction. Drug Des. Devel. 2017, 11, 1243–1253.
  47. Nicholls, D.G. Mitochondrial dysfunction and glutamate excitotoxicity studied in primary neuronal cultures. Curr. Mol. Med. 2004, 4, 149–177.
  48. Zhao, W.Q.; De Felice, F.G.; Fernandez, S.; Chen, H.; Lambert, M.P.; Quon, M.J.; Krafft, G.A.; Klein, W.L. Amyloid beta oligomers induce impairment of neuronal insulin receptors. FASEB J. 2008, 22, 246–260.
  49. Pomytkin, I.; Krasil’nikova, I.; Bakaeva, Z.; Surin, A.; Pinelis, V. Excitotoxic glutamate causes neuronal insulin resistance by inhibiting insulin receptor/Akt/mTOR pathway. Mol. Brain 2019, 12, 112.
  50. Mota, S.I.; Ferreira, I.L.; Rego, A.C. Dysfunctional synapse in Alzheimer’s disease—A focus on NMDA receptors. Neuropharmacology 2014, 76, 16–26.
  51. Choi, D.W. Excitotoxicity: Still Hammering the Ischemic Brain in 2020. Front. Neurosci. 2020, 14, 579953.
  52. Iovino, L.; Tremblay, M.E.; Civiero, L. Glutamate-induced excitotoxicity in Parkinson’s disease: The role of glial cells. J. Pharm. Sci. 2020, 144, 151–164.
  53. Binvignat, O.; Olloquequi, J. Excitotoxicity as a Target Against Neurodegenerative Processes. Curr. Pharm. Des. 2020, 26, 1251–1262.
  54. Olloquequi, J.; Cornejo-Córdova, E.; Verdaguer, E.; Soriano, F.X.; Binvignat, O.; Auladell, C.; Camins, A. Excitotoxicity in the pathogenesis of neurological and psychiatric disorders: Therapeutic implications. J. Psychopharmacol. 2018, 32, 265–275.
  55. Macrez, R.; Stys, P.K.; Vivien, D.; Lipton, S.A.; Docagne, F. Mechanisms of glutamate toxicity in multiple sclerosis: Biomarker and therapeutic opportunities. Lancet Neurol. 2016, 15, 1089–1102.
  56. Datusalia, A.K.; Agarwal, P.; Singh, J.N.; Sharma, S.S. Hyper-insulinemia increases the glutamate-excitotoxicity in cortical neurons: A mechanistic study. Eur. J. Pharm. 2018, 833, 524–530.
  57. Li, Z.; Okamoto, K.; Hayashi, Y.; Sheng, M. The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses. Cell 2004, 119, 873–887.
  58. Pfleger, J.; He, M.; Abdellatif, M. Mitochondrial complex II is a source of the reserve respiratory capacity that is regulated by metabolic sensors and promotes cell survival. Cell Death Dis. 2015, 6, e1835.
  59. Bessman, S.P.; Mohan, C. Insulin as a probe of mitochondrial metabolism in situ. Mol. Cell Biochem. 1997, 174, 91–96.
  60. Bessman, S.P.; Mohan, C.; Zaidise, I. Intracellular site of insulin action: Mitochondrial Krebs cycle. Proc. Natl. Acad. Sci. USA 1986, 83, 5067–5070.
  61. Thibault, O.; Anderson, K.L.; DeMoll, C.; Brewer, L.D.; Landfield, P.W.; Porter, N.M. Hippocampal calcium dysregulation at the nexus of diabetes and brain aging. Eur. J. Pharm. 2013, 719, 34–43.
  62. Biessels, G.J.; van der Heide, L.P.; Kamal, A.; Bleys, R.L.; Gispen, W.H. Ageing and diabetes: Implications for brain function. Eur. J. Pharm. 2002, 441, 1–14.
  63. Maimaiti, S.; Frazier, H.N.; Anderson, K.L.; Ghoweri, A.O.; Brewer, L.D.; Porter, N.M.; Thibault, O. Novel calcium-related targets of insulin in hippocampal neurons. Neuroscience 2017, 364, 130–142.
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