Brain Insulin Resistance: History
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Subjects: Clinical Neurology
Contributor:
V. G. Pinelis

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.

This entry is adapted from the peer-reviewed paper 10.3390/life11030262

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