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Opinion Article
Revised

Insulin Receptors and Intracellular Ca2+ Form a Double-Negative Regulatory Feedback Loop Controlling Insulin Sensitivity

[version 2; peer review: 3 approved]
PUBLISHED 13 Jan 2021
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Abstract

Since the discovery of insulin and insulin receptors (IR) in the brain in 1978, numerous studies have revealed a fundamental role of IR in the central nervous system and its implication in regulating synaptic plasticity, long-term potentiation and depression, neuroprotection, learning and memory, and energy balance. Central insulin resistance has been found in diverse brain disorders including Alzheimer’s disease (AD). Impaired insulin signaling in AD is evident in the activation states of IR and downstream signaling molecules. This is mediated by Aβ oligomer-evoked Ca2+ influx by activating N-methyl-D-aspartate receptors (NMDARs) with Aβ oligomers directly, or indirectly through Aβ-induced release of glutamate, an endogenous NMDAR ligand. In the present opinion article, we highlight evidence that IR activity and free intracellular Ca2+ concentration [Ca2+]i form a double-negative regulatory feedback loop controlling insulin sensitivity, in which mitochondria play a key role, being involved in adenosine triphosphate (ATP) synthesis and IR activation. We found recently that the glutamate-evoked rise in [Ca2+]i inhibits activation of IR and, vice versa, insulin-induced activation of IR inhibits the glutamate-evoked rise in [Ca2+]i. In theory, such a double-negative regulatory feedback loop predicts that any condition leading to an increase of [Ca2+]i may trigger central insulin resistance and explains why central insulin resistance is implicated in the pathogenesis of AD, with which glutamate excitotoxicity is a comorbid condition. This model also predicts that any intervention aiming to maintain low [Ca2+]i may be useful for treating central insulin resistance.

Keywords

Insulin, insulin receptor, glutamate, NMDA receptor, Ca2+, double-negative feedback loop, mitochondria, ATP

Revised Amendments from Version 1

The manuscript has been revised in accordance with reviewer's notes that (a) bistability is not a necessary consecuence of a double negative regulatory feedback loop and (b) figure 1 will be more useful when signal transduction pathways will be shown. Sentences related to "bistability" have been removed from the abstract, main text, and reference list. Figure 1 has been revised and includes now pathways described in the text of the first version.

See the authors' detailed response to the review by Kevin N Hascup
See the authors' detailed response to the review by Venkatesh V. Kareenhalli

Introduction

Since the discovery of insulin1 and insulin receptors (IR)2 in the brain in 1978, numerous studies have revealed a fundamental role of IR in the central nervous system (CNS). IR-mediated signaling is implicated in the regulation of diverse functions in the CNS, including synaptic plasticity, long-term potentiation and depression, neuroprotection, learning and memory, and energy balance3. Central insulin resistance has been found in neurodegenerative diseases such as Alzheimer’s disease (AD)4,5 and Parkinson’s disease (PD)6, stroke, and traumatic brain injury (TBI)7. Impaired insulin signaling in AD is evident in the activation states of IR and downstream signaling molecules5. Compared with control cases, insulin in AD brains induced 24–58% less activation at the level of IR and 90% less activation of insulin receptor substrate 1 (IRS-1)5. It has been presumed5 that the inhibition of IR activation is mediated by Aβ oligomer-triggered Ca2+ influx, in part by activating N-methyl-D-aspartate receptors (NMDARs)8, followed by a rise in Akt1 pS4739, which can inhibit insulin-induced IR activation through Thr phosphorylation of the IR β subunit10. Aβ oligomers may activate the NMDAR-gated Ca2+ influx directly11 or indirectly through the intermediate release of glutamate, a ligand of NMDAR1115. This suggests that the rise in intracellular free Ca2+ concentration ([Ca2+]i), evoked by either Aβ oligomers or glutamate, leads to dysfunctional activation of IR in AD. In the present opinion article, we highlight evidence that IR and [Ca2+]i form a double-negative regulatory feedback loop controlling insulin sensitivity, and mitochondria have a key role in this feedback loop, being involved in adenosine triphosphate (ATP) synthesis and IR activation.

Glutamate-evoked rise in [Ca2+]i causes inhibition of IR activation

Glutamate serves as the major excitatory neurotransmitter in the CNS. Its excessive accumulation in a synaptic cleft can trigger excitotoxicity, a pathologic process leading to neuronal cell death. Glutamate-induced activation of the NMDAR-gated Ca2+ influx is generally considered central to the development of excitotoxicity16. Prolonged glutamate exposure causes a rapid initial increase in the [Ca2+]i, followed by a larger secondary [Ca2+]i increase concomitant with a decrease in the mitochondrial inner membrane potential (ΔΨm)1719. We recently found that on Ca2+-induced mitochondrial depolarization, insulin induced 48% less activation of IR (assessed by pY1150/1151) compared with control20. Earlier, we showed that a decrease in ΔΨm can abrogate IR activation18, since the ΔΨm-dependent hydrogen peroxide (H2O2) mitochondrial signal at complex II is critically involved in the activation of IR in neurons2123. Thus, the glutamate-evoked increase in [Ca2+]i, followed by the drop in ΔΨm, leads to the inhibition of insulin-induced activation of IR (Figure 1a).

Insulin prevents glutamate-evoked rise in [Ca2+]i

Normally, the NMDAR-gated Ca2+ influx is counterbalanced with Ca2+ efflux, which is governed by plasma membrane Ca2+ ATPase (PMCA) and the Na+/Ca2+ exchanger (NCX)24,25. NCX-mediated Ca2+ efflux is also ATP-dependent, since NCX exchanges one Ca2+ for three Na+, and the three Na+ are then pumped out by the Na+/K+ ATPase at the expense of one ATP. In excitotoxicity, prolonged stimulation with glutamate leads to ATP depletion and an abnormal rise in [Ca2+]i, since the massive Ca2+ influx is no longer counterbalanced by Ca2+ efflux26. Therefore, maintenance of ATP production is crucial for preventing the rise in [Ca2+]i in excitotoxicity. We found recently that pre-treatment with insulin prevents neurons from glutamate-evoked ATP depletion due to its protective effect on spare respiratory capacity (SRC), a measure that relates to the amount of extra ATP that can be produced via oxidative phosphorylation in case of increased energy demand19. The effect of insulin on SRC relates to its action on mitochondrial metabolism. It has long been known that the tricarboxylic acid cycle is the intracellular site of insulin action and that insulin acutely stimulates succinate oxidation at mitochondrial complex II26,27. Succinate oxidation at mitochondrial complex II has been identified recently as the main source of SRC28. In line with this, insulin prevented the glutamate-evoked rise in [Ca2+]i in our experiments with glutamate excitotoxicity19 (Figure 1b).

IR and [Ca2+]i form a double-negative feedback loop controlling insulin sensitivity

Collectively, this evidence suggests that a double-negative regulatory feedback loop exists between IR activity and [Ca2+]i. The glutamate-evoked rise in [Ca2+]i inhibits activation of IR and, vice versa, insulin-induced activation of IR inhibits the glutamate-evoked rise in [Ca2+]i (Figure 1c).

023069ff-eee1-4d84-9254-433a9a7d041b_figure1.gif

Figure 1. A double-negative feedback loop between insulin receptors (IR) activity and intracellular free Ca2+ concentration [Ca2+]i.

(a) glutamate-evoked increase in [Ca2+]i, followed by drop in ΔΨm, leads to inhibition of insulin-induced H2O2 signal at mitochondrial complex II, thereby inhibiting IR activation (IR-pYpY↓)20,21; (b) insulin-triggered increase in ATP levels enhances ATP-dependent Ca2+ efflux via PMCA and NCX, thereby lowering [Ca2+]i19; (c) glutamate triggers NMDA receptor-gated Ca2+ influx, inhibiting IR activation, and insulin triggers activation of IR, inhibiting [Ca2+]i rise. Abbreviations: ΔΨm , mitochondrial inner membrane potential; H2O2, hydrogen peroxide; pY, phosphotyrosine; ATP, adenosine triphosphate; PMCA, plasma membrane Ca2+ ATPase; NCX, Na +/Ca2+ exchanger; NMDA, N-methyl-D-aspartate.

This double-negative feedback loop model predicts that any condition leading to an increase in [Ca2+]i may trigger insulin resistance. It appears to explain why central insulin resistance is implicated in the pathogenesis of disorders such as AD4,5, PD6, stroke, and TBI7, with which glutamate excitotoxicity is a comorbid condition29. The model also predicts that any intervention aiming to prevent Ca2+ influx of or enhance efflux of Ca2+ from neurons, thereby maintaining low [Ca2+]i, may be useful for treating central insulin resistance. Given that Ca2+ efflux is ATP-dependent, any intervention directed to enhance ATP production in neurons may be especially useful to improve insulin sensitivity in the brain.

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No data are associated with this article.

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Version 2
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Pomytkin I and Pinelis V. Insulin Receptors and Intracellular Ca2+ Form a Double-Negative Regulatory Feedback Loop Controlling Insulin Sensitivity [version 2; peer review: 3 approved]. F1000Research 2021, 9:598 (https://doi.org/10.12688/f1000research.24558.2)
NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.
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Open Peer Review

Current Reviewer Status: ?
Key to Reviewer Statuses VIEW
ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions
Version 2
VERSION 2
PUBLISHED 13 Jan 2021
Revised
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2
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Reviewer Report 29 Jan 2021
Kevin N Hascup, Department of Neurology, Center for Alzheimer's Research and trEatment (CARE), Springfield, IL, USA 
Approved
VIEWS 2
Although the authors have adequately presented point-by-point responses to my initial concerns, they have taken a minimalistic approach to incorporating some of these concepts into the actual manuscript.  It would have been interesting to read the authors ideas on how ... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Hascup KN. Reviewer Report For: Insulin Receptors and Intracellular Ca2+ Form a Double-Negative Regulatory Feedback Loop Controlling Insulin Sensitivity [version 2; peer review: 3 approved]. F1000Research 2021, 9:598 (https://doi.org/10.5256/f1000research.52891.r77179)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
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3
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Reviewer Report 27 Jan 2021
Venkatesh V. Kareenhalli, Indian Institute of Technology Bombay, Mumbai, Maharashtra, India 
Approved
VIEWS 3
The manuscript can now be accepted ... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Kareenhalli VV. Reviewer Report For: Insulin Receptors and Intracellular Ca2+ Form a Double-Negative Regulatory Feedback Loop Controlling Insulin Sensitivity [version 2; peer review: 3 approved]. F1000Research 2021, 9:598 (https://doi.org/10.5256/f1000research.52891.r77181)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
Version 1
VERSION 1
PUBLISHED 12 Jun 2020
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16
Cite
Reviewer Report 02 Nov 2020
Venkatesh V. Kareenhalli, Indian Institute of Technology Bombay, Mumbai, Maharashtra, India 
Approved with Reservations
VIEWS 16
The authors propose an existence of double negative feedback loop which may result in bistable response. It is clear that Ca signaling and insulin signaling play a role in the CNS and the related pathogenesis of neurogenerative diseases. The mitochondrial ... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Kareenhalli VV. Reviewer Report For: Insulin Receptors and Intracellular Ca2+ Form a Double-Negative Regulatory Feedback Loop Controlling Insulin Sensitivity [version 2; peer review: 3 approved]. F1000Research 2021, 9:598 (https://doi.org/10.5256/f1000research.27092.r72629)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
  • Author Response 13 Jan 2021
    Igor Pomytkin, Department of Advanced Cell Technologies, Sechenov First Moscow State Medical University (Sechenov University), Moscow, 119991, Russian Federation
    13 Jan 2021
    Author Response
    The manuscript has been revised in accordance with notes that (a) bistability is not a necessary consecuence of a double negative regulatory feedback loop and (b) figure 1 will be ... Continue reading
COMMENTS ON THIS REPORT
  • Author Response 13 Jan 2021
    Igor Pomytkin, Department of Advanced Cell Technologies, Sechenov First Moscow State Medical University (Sechenov University), Moscow, 119991, Russian Federation
    13 Jan 2021
    Author Response
    The manuscript has been revised in accordance with notes that (a) bistability is not a necessary consecuence of a double negative regulatory feedback loop and (b) figure 1 will be ... Continue reading
Views
10
Cite
Reviewer Report 03 Aug 2020
Zhen Deng, Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China 
Approved
VIEWS 10
This model predicts that any disease that causes elevated [Ca2+]i may trigger central insulin resistance, and explains why central insulin resistance is related to the pathogenesis of AD, and glutamate excitotoxicity is a comorbidity. The model also predicts that any ... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Deng Z. Reviewer Report For: Insulin Receptors and Intracellular Ca2+ Form a Double-Negative Regulatory Feedback Loop Controlling Insulin Sensitivity [version 2; peer review: 3 approved]. F1000Research 2021, 9:598 (https://doi.org/10.5256/f1000research.27092.r67002)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
Views
20
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Reviewer Report 01 Jul 2020
Kevin N Hascup, Department of Neurology, Center for Alzheimer's Research and trEatment (CARE), Springfield, IL, USA 
Not Approved
VIEWS 20
The authors put forth an opinion article in regard to a double negative feedback loop that controls cerebral insulin receptor signaling during times of either high glutamate or insulin levels. They briefly go onto hypothesize that any disease state resulting ... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Hascup KN. Reviewer Report For: Insulin Receptors and Intracellular Ca2+ Form a Double-Negative Regulatory Feedback Loop Controlling Insulin Sensitivity [version 2; peer review: 3 approved]. F1000Research 2021, 9:598 (https://doi.org/10.5256/f1000research.27092.r64837)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
  • Author Response 10 Jul 2020
    Igor Pomytkin, Department of Advanced Cell Technologies, Sechenov First Moscow State Medical University (Sechenov University), Moscow, 119991, Russian Federation
    10 Jul 2020
    Author Response
    Our opinion article relates only to relationship between intracellular Ca2+ concentrations [Ca2+]i and insulin receptor activation state, and not between [Ca2+]i and insulin signaling system as a whole. Insulin resistance ... Continue reading
COMMENTS ON THIS REPORT
  • Author Response 10 Jul 2020
    Igor Pomytkin, Department of Advanced Cell Technologies, Sechenov First Moscow State Medical University (Sechenov University), Moscow, 119991, Russian Federation
    10 Jul 2020
    Author Response
    Our opinion article relates only to relationship between intracellular Ca2+ concentrations [Ca2+]i and insulin receptor activation state, and not between [Ca2+]i and insulin signaling system as a whole. Insulin resistance ... Continue reading

Comments on this article Comments (0)

Version 2
VERSION 2 PUBLISHED 12 Jun 2020
Comment
Alongside their report, reviewers assign a status to the article:
Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions
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