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World J Diabetes. Jul 15, 2024; 15(7): 1430-1447
Published online Jul 15, 2024. doi: 10.4239/wjd.v15.i7.1430
Insulin resistance as the molecular link between diabetes and Alzheimer's disease
Mona Mohamed Ibrahim Abdalla, Department of Human Biology, School of Medicine, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
ORCID number: Mona Mohamed Ibrahim Abdalla (0000-0002-4987-9517).
Author contributions: Abdalla MMI designed the research, searched the databases, and wrote the paper.
Conflict-of-interest statement: The author has nothing to disclose.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Mona Mohamed Ibrahim Abdalla, MSc, PhD, Senior Lecturer, Department of Human Biology, School of Medicine, International Medical University, No. 126 Jln Jalil Perkasa 19, Bukit Jalil 57000, Kuala Lumpur, Malaysia. monamohamed@imu.edu.my
Received: February 14, 2024
Revised: April 8, 2024
Accepted: May 6, 2024
Published online: July 15, 2024
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Abstract

Diabetes mellitus (DM) and Alzheimer's disease (AD) are two major health concerns that have seen a rising prevalence worldwide. Recent studies have indicated a possible link between DM and an increased risk of developing AD. Insulin, while primarily known for its role in regulating blood sugar, also plays a vital role in protecting brain functions. Insulin resistance (IR), especially prevalent in type 2 diabetes, is believed to play a significant role in AD's development. When insulin signalling becomes dysfunctional, it can negatively affect various brain functions, making individuals more susceptible to AD's defining features, such as the buildup of beta-amyloid plaques and tau protein tangles. Emerging research suggests that addressing insulin-related issues might help reduce or even reverse the brain changes linked to AD. This review aims to explore the rela-tionship between DM and AD, with a focus on the role of IR. It also explores the molecular mechanisms by which IR might lead to brain changes and assesses current treatments that target IR. Understanding IR's role in the connection between DM and AD offers new possibilities for treatments and highlights the importance of continued research in this interdisciplinary field.

Key Words: Alzheimer's disease, Insulin resistance, Obesity, Dementia, Diabetes, Metabolic syndrome

Core Tip: Insulin resistance (IR), commonly associated with type 2 diabetes, is a crucial factor linking diabetes mellitus to Alzheimer's disease (AD). While insulin is primarily known for regulating blood sugar, it also plays a significant role in brain health. Dysfunctional insulin signaling, characteristic of IR, adversely impacts brain functions and is implicated in the development of AD's defining features, such as beta-amyloid plaques and tau protein tangles. Understanding and addressing IR early could offer new treatment strategies for AD, highlighting the importance of continued research in this interdisciplinary field.



INTRODUCTION

The interplay between metabolic and neurodegenerative disorders has emerged as a focal point of scientific inquiry, highlighting the complex relationship between insulin resistance (IR) and Alzheimer's disease (AD)[1-3]. While Type 2 diabetes mellitus (T2DM) stands as a global concern predominantly characterized by IR, the scope of research extends beyond T2DM to elucidate IR's broader impact on neurological health[4]. Notably, AD, the foremost cause of dementia, exhibits a profound connection with IR, suggesting a complex metabolic-neurodegenerative link[5,6].

Globally, the prevalence of both T2DM and AD is on an upward trajectory, presenting significant public health challenges. In 2022, France reported nearly 1.65 million individuals with mild cognitive impairment due to AD, with over 925000 cases evolving into clinical AD dementia[7]. Similarly, the United States has demonstrated significant racial and ethnic disparities in AD prevalence, with notably higher rates observed among non-Hispanic Blacks and Hispanics[8]. Regions such as Maryland, New York, and Mississippi noted particularly high AD prevalence[9]. Simultaneously, the global diabetic population, driven by factors such as obesity, reached approximately 529 million in 2021, with projections indicating a rise to over 1.31 billion by 2050[10]. Importantly, the prevalence of dementia, including AD, among individuals with T2DM in Spain increased significantly over a decade, highlighting a notable intersection between these diseases[11]. This convergence accentuates the imperative for early detection and management of IR to possibly attenuate AD progression and highlights the necessity for multidisciplinary research aimed at unveiling novel therapeutic strategies and deciphering the intricate metabolic-neurodegenerative interplay.

AD is classified into two types: Early-onset, which has a genetic basis and typically manifests in the forties or fifties, and late-onset, appearing after the age of 65[12]. The traditional understanding of AD, focused on the accumulation of beta-amyloid (Aβ) plaques and hyperphosphorylated tau protein tangles, is evolving[13-16]. Current insights reveal insulin's broader neuroprotective role, suggesting that its dysregulation contributes significantly to neuronal damage and cognitive decline, key features of AD[17-23]. This revelation has led to the conceptualization of AD as "type 3 diabetes", a term that highlights impaired insulin signaling within the brain as a pivotal aspect of AD's pathology, drawing parallels with the systemic IR observed in T2DM[24-26].

Epidemiological, clinical, neuroimaging, and post-mortem studies collectively affirm the correlation between IR and an elevated risk of AD, highlighting shared pathophysiological pathways that contribute to neuronal dysfunction and cognitive impairment[6,27-29]. This body of evidence, demonstrating reduced insulin receptor density, altered phos-phorylation of insulin receptor substrates, and decreased insulin activity in brain regions critical for memory and cognition, supports the notion that brain IR might actively contribute to AD's development rather than merely result from it[30-33].

Despite progress in understanding the mechanisms linking IR and AD, including the role of IR in disrupting glucose metabolism and exacerbating oxidative stress and neuroinflammation within the central nervous system (CNS), significant gaps remain[27-29]. The exacerbation of neuroinflammation and oxidative stress by peripheral IR—affecting both metabolic dysfunction and neural health[34-39], highlights the need for targeted therapies that can modify AD's progression by addressing IR specifically.

This bi-directional influence mandates a comprehensive treatment approach, addressing both systemic IR and its neurological manifestations. Such dual-pathway exploration not only enriches our understanding of the disease mechanism but also unveils new therapeutic targets for AD, fostering optimism in a field that has faced considerable challenges in achieving treatment breakthroughs.

INSULIN'S ROLE IN BRAIN HEALTH AND FUNCTION

Insulin, a peptide hormone synthesized by pancreatic β-cells, plays a crucial role in regulating blood glucose levels by facilitating glucose uptake in muscle and adipose tissues and inhibiting hepatic glucose production, thereby maintaining euglycemia[40]. This hormonal regulation is critical for energy balance and metabolic stability, with dysregulation leading to diabetes mellitus, characterised by hyperglycemia and associated metabolic complications[41]. The rising global incidence of T2DM, exacerbated by increasing obesity rates and sedentary lifestyles, underscores the pressing challenge of IR[41,42].

Beyond its well-known role in peripheral glucose metabolism, insulin also exerts significant effects within the CNS, influencing neuronal growth, synaptic plasticity, and neurotransmitter regulation, key processes for cognitive functions[6,43-46]. These actions are mediated via insulin receptors distributed across the brain, particularly in regions integral to memory and cognition such as the hippocampus and cerebral cortex[47,48]. Disruption in insulin signaling is linked to neurodegenerative diseases like AD, contributing to pathological outcomes including impaired glucose metabolism, oxidative stress, and altered lipid metabolism[38,49,50].

At the molecular level, insulin activates pathways such as phosphoinositide 3-kinase (PI3K)/Akt and glycogen synthase kinase-3β (GSK-3β) within the brain, influencing cell survival, tau phosphorylation, and amyloid-beta production, central elements in AD pathology[6,51-53]. Furthermore, insulin regulates neurotransmitters’ release, including acetylcholine, dopamine, and serotonin[54,55], with IR in the brain leading to cognitive decline and mood disorders[56]. Additionally, insulin supports neurogenesis and brain plasticity, which are compromised under IR conditions, raising the risk of neurodegenerative diseases[23,38,45].

Insulin's source in the brain involves transport from peripheral circulation across the blood-brain barrier (BBB) and potentially local production within the brain itself[57,58], This transport occurs via the choroid plexus into the cerebrospinal fluid (CSF)[59] and directly from plasma into the brain's endothelial cells[60], with insulin concentrations in the CSF being notably lower than in plasma[61,62], a difference exacerbated in obesity[63]. This mechanism may involve insulin receptors or megalin, a transporter associated with insulin and leptin transport[64]. Intranasal insulin delivery has emerged as a promising method for bypassing slower transport mechanisms, directly enhancing CSF insulin levels without affecting plasma concentrations and showing potential for cognitive enhancement in AD[65].

Local insulin synthesis within the brain has been a contentious topic. Early studies proposed high brain insulin levels compared to plasma[48], but later research challenged these findings[66], leading to debates about the brain's insulin production capabilities. Despite challenges in differentiating between pancreatic and brain-sourced insulin due to identical epitopes recognized by anti-insulin antibodies[67], evidence supports brain insulin synthesis, as indicated by the localization of C-peptide and proinsulin-like immunoreactivity in the CNS and gene expression analyses[68] which further validate local brain insulin production, especially in areas like the hippocampus, suggesting a link between neuronal insulin production and local metabolic demands[69,70].

Furthermore, insulin's role within the CNS extends to modulating peripheral metabolic functions, including indirect regulation of hepatic glucose production via neuronal pathways, a phenomenon documented in rodent models but debated in human studies[71-75]. Intranasal insulin administration in humans provides evidence of the brain's capability to sense insulin and influence hepatic glucose production, although the physiological relevance of this interaction requires further clarification[76,77].

Furthermore, insulin exerts effects on lipolysis and lipogenesis, influencing the body's lipid storage and utilization processes[78]. Additionally, insulin within the CNS is instrumental in managing reproductive health, overseeing the hormonal regulation critical for fertility in both sexes[79]. A significant aspect of insulin's central function includes mediating the counterregulatory response to hypoglycemia, whereby insulin enhances the brain's capacity to detect low glucose levels and trigger necessary physiological responses to restore euglycemia[80].

Insulin's central effects on lipid metabolism, reproductive health, and the counterregulatory response to hypoglycemia further illuminate its comprehensive roles beyond glucose regulation, emphasizing its critical contribution to metabolic homeostasis and underscoring the necessity for continued research into insulin's multifaceted roles in health and disease.

Recent research challenges the traditional belief that the brain's glucose uptake is independent of insulin, suggesting instead that insulin may influence glucose transporters and metabolism within the CNS, particularly under conditions of IR. This significant revelation implies that peripheral IR could detrimentally affect brain functionality and health, potentially accelerating the progression of neurodegenerative diseases[81,82]. However, the impact of peripheral insulin on brain insulin levels and activity remains a subject of debate, due to the selective permeability of the BBB and unique insulin sensitivity regulation mechanisms within the brain. This ongoing discussion highlights the necessity for further research into the complex role of insulin in the CNS and its links to neurodegenerative disorders[83-85].

IR AND AD

The complex relationship between IR and AD is increasingly recognized through a blend of epidemiological, molecular, and clinical research. These studies collectively suggest that IR significantly contributes to cognitive impairments and AD's hallmark pathologies. Impaired insulin signaling, evident even in the early stages of AD absent of diabetes, may serve as a potential biomarker for AD, underscoring IR's pivotal role in the disease's development[27,30,32,33,53].

Dysfunctional insulin signaling in the brain is detrimental, exacerbating oxidative stress and inflammation, fostering an environment conducive to the production of neurotoxic species. This cascade of metabolic dysfunction further precipitates neuronal damage and cognitive decline. One of the most compelling connections between IR and AD is the impact of insulin dysregulation on the accumulation of Aβ plaques and tau protein tangles, the defining pathological features of AD. Insulin has been shown to regulate enzymes which are involved in the production and clearance of Aβ[32,86]. Dysfunctional insulin signaling can lead to an imbalance in these enzyme activities, resulting in increased production or decreased clearance of Aβ, contributing to plaque formation[87,88]. Concurrently, altered insulin pathways contribute to the hyperphosphorylation of tau proteins, a process that results in the formation of neurofibrillary tangles, another hallmark of AD. This hyperphosphorylation impairs tau's ability to stabilize microtubules, essential for neuron structure and function, further contributing to neurodegeneration[89-91].

MOLECULAR MECHANISMS LINKING IR TO AD

The intricate relationship between IR and AD can be elucidated through an in-depth examination of the molecular pathways affected by IR and their contribution to AD pathogenesis. This section explores the underlying molecular mechanisms that bridge IR to AD, highlighting the critical pathways disrupted by IR and analyzing how these disruptions contribute to the development of AD.

IR, fundamentally, is characterized by the impaired signaling of insulin through its primary pathways. The canonical insulin signaling pathway involves the binding of insulin to its receptor, activating the receptor's tyrosine kinase activity. This activation leads to the phosphorylation of insulin receptor substrates, which in turn triggers downstream signaling cascades involving PI3K and Akt (protein kinase B). These cascades play critical roles in glucose uptake, glycogen synthesis, lipid metabolism, and protein synthesis. In the context of IR, there is a disruption in these signaling pathways, leading to reduced glucose uptake, altered lipid metabolism, and impaired cell survival and growth mechanisms.

In the brain, these pathways are crucial for neuronal health, synaptic plasticity, and cognitive function. IR-induced impairments in these pathways have been associated with reduced neuronal survival, altered synaptic transmission, and impaired cognitive function, all of which are characteristic of AD. Figure 1 graphically represents the intricate molecular mechanisms linking IR and AD.

Figure 1
Figure 1 Simplified mechanisms of insulin resistance-induced Alzheimer’s disease. BBB: Blood-brain barrier; GSK-3B: Glycogen synthase kinase-3β; mTOR: Mechanistic target of rapamycin pathway.
Glucose metabolism disruption

One of the key aspects of IR's contribution to AD is through the dysregulation of glucose metabolism in the brain. The brain relies heavily on glucose as its primary energy source, and IR impairs the brain's ability to utilize glucose efficiently, leading to an energy deficit in neurons[92]. This scenario is nuanced by findings from euglycemic hyperinsulinemic conditions, where enhanced brain glucose uptake is observed in insulin-resistant individuals, suggesting an acute compensatory response aimed at maintaining energy supply despite peripheral IR[93]. However, this increased brain glucose uptake does not mitigate the chronic metabolic disturbances caused by IR, including the significant energy deficit that culminates in reduced ATP production. The consequent escalation in reactive oxygen species (ROS) production induces oxidative stress, a condition that damages DNA, proteins, and lipids, and may trigger apoptotic pathways. Such oxidative stress and neuronal damage are critical factors in the pathogenesis of AD[94-97].

accumulation and tau hyperphosphorylation

IR influences the metabolism of the amyloid precursor protein (APP), promoting the amyloidogenic pathway[98]. This pathway involves the sequential cleavage of APP by beta-secretase (BACE1) and gamma-secretase, resulting in the production of Aβ peptides. In IR, the activity of BACE1 is increased, leading to an accumulation of Aβ peptides which aggregate to form amyloid plaques[98,99]. Furthermore, insulin regulates enzymes like GSK-3β, a key kinase involved in tau phosphorylation. In the setting of IR, the activity of GSK-3β is dysregulated, leading to the hyperphosphorylation of tau proteins and subsequent formation of neurofibrillary tangles[23,30,53].

Neuroinflammation and microglial activation

The chronic inflammation characteristic of IR significantly influences AD development[100]. Elevated pro-inflammatory cytokine levels, such as Tumour necrosis factor alpha and Interleukin 6, exacerbate neuronal damage[101,102]. Activation of microglia, the brain's innate immune cells, is observed in IR. These activated microglia can release pro-inflammatory cytokines, which may promote neurodegeneration[103-105]. Chronic inflammation driven by IR may facilitate the progression of AD by sustaining a harmful cycle of neuronal damage and inflammatory response. This process can induce the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase, leading to further neuronal damage and contributing to the pathogenesis of AD[106-110].

Research into AD and IR has unveiled a myriad of interconnected pathways that extend beyond the core mechanisms of glucose metabolism disruption, mitochondrial dysfunction, and inflammation. These additional mechanisms not only deepen our understanding of the intricate relationship between metabolic dysfunctions and neurodegeneration but also open new avenues for therapeutic interventions.

Autophagy impairment and protein aggregation

Insulin signaling is involved in the regulation of autophagy, a cellular process essential for clearing misfolded proteins and damaged organelles. IR can impair autophagy in neurons, leading to the accumulation of toxic proteins, including Aβ and phosphorylated tau. This impairment contributes to the aggregation of these proteins and the formation of the characteristic plaques and tangles in AD[111-113].

Mitochondrial dysfunction and endoplasmic reticulum stress

IR precipitates a cascade of cellular stress responses in the brain, critically undermining neuronal health and exacerbating AD pathology through mitochondrial dysfunction and endoplasmic reticulum (ER) stress. Mitochondrial dysfunction manifests as diminished energy production and escalated oxidative stress, leading to a depletion of neuronal ATP and an increase in ROS. This mitochondrial impairment results in energy shortages, cellular damage, and ultimately, neuronal death, contributing to the neurodegenerative processes observed in AD[114]. Concurrently, IR triggers ER stress within neurons, activating the unfolded protein response (UPR) pathways, including IRE1, ATF6, and PERK[115,116]. Persistent ER stress and UPR activation exacerbate the accumulation of misfolded proteins, a hallmark of AD, driving neuronal degeneration[117]. The interplay between mitochondrial dysfunction and ER stress, fueled by IR, underscores a multifaceted mechanism contributing to the neuronal vulnerability and cognitive decline characteristic of AD, high-lighting the intricate relationship between metabolic dysfunction and neurodegeneration.

Lipid metabolism alterations

IR is associated with dysregulated lipid metabolism, leading to altered lipid profiles in the brain. These changes can affect the composition and fluidity of neuronal membranes, impacting neurotransmitter receptor function and synaptic plasticity. Altered lipid profiles can also influence the processing of APP, potentially increasing the production of Aβ[118-120].

Neurovascular dysfunction and impaired BBB integrity

IR contributes to neurovascular dysfunction, compromising the BBB integrity and cerebral blood flow regulation. This dysfunction can facilitate the entry of neurotoxic substances into the brain parenchyma and impair the clearance of Aβ, further contributing to AD pathology. The vascular impairment can contribute to the cerebral hypoperfusion and hypoxia observed in AD, exacerbating neuronal damage and cognitive decline[121-125]. Additionally, IR is associated with the degradation of tight junction proteins, such as claudins and occludins, essential for maintaining the BBB's selective permeability. Consequently, the BBB becomes more permeable, facilitating the entry of peripheral immune cells into the brain and the buildup of neurotoxic elements, including Aβ. These changes contribute significantly to AD's pathology by promoting inflammation, neuronal damage, and further accumulation of pathological proteins[126-128]. Addressing the vascular components and enhancing BBB integrity could play a pivotal role in slowing or preventing the progression of AD, highlighting the importance of targeting metabolic and vascular dysfunctions in comprehensive AD management strategies.

Neurotransmitter imbalance and alterations in neurotrophic factor signaling

IR significantly impacts neurotransmitter balance in the brain, contributing to the cognitive deficits observed in AD. IR affects key neurotransmitters like acetylcholine, dopamine, and serotonin, essential for memory, mood, and cognitive function[129-131]. This imbalance leads to a disruption in the equilibrium between excitatory and inhibitory neurotransmissions, particularly impacting the cholinergic system and exacerbating memory loss[132,133]. Furthermore, IR-induced chronic inflammation and alterations in pathways of neurotrophic factors, notably brain-derived neurotrophic factor (BDNF), further destabilize neurotransmitter systems. BDNF plays a pivotal role in neuronal survival, growth, and synaptic plasticity. IR disrupts BDNF signaling, notably through the TrkB receptor pathway, precipitating synaptic dysfunction, and neuronal loss[134-135]. The reduction in BDNF activity correlates with the cognitive decline observed in AD, emphasizing the intertwined roles of metabolic dysfunction, neurotransmitter imbalance, and neurotrophic factor signaling disruption in the disease's neuropathology. Addressing both metabolic dysfunction and neurotransmitter imbalance through therapeutic strategies could therefore be crucial in mitigating AD's progression, highlighting the role of IR in the disease's neuropathology[136].

Epigenetic and genetic modulations

Emerging evidence suggests a strong link between IR and epigenetic alterations that may contribute to AD's progression. Epigenetic modifications, including DNA methylation and histone modification, are key regulators of gene expression without altering the DNA sequence itself. These changes can profoundly affect neuronal function and are implicated in the regulation of genes associated with AD pathology[137].

DNA methylation, an epigenetic mechanism involving the addition of a methyl group to the DNA molecule, can influence the expression of genes critical for neural function and the pathological processes underlying AD[137,138]. Studies have shown that abnormal DNA methylation patterns are associated with the dysregulation of APP and tau protein genes, leading to increased Aβ production and tau hyperphosphorylation, hallmark features of AD[138-140]. For instance, hypermethylation of the promoter region of the APP gene has been linked to its increased expression and subsequent amyloid-beta accumulation[141,142].

Histone modifications, another form of epigenetic regulation, involve the chemical alteration of histone proteins around which DNA is wrapped, influencing chromatin structure and gene accessibility. Alterations in histone acetylation and methylation have been observed in AD, affecting genes involved in synaptic plasticity, neuronal survival, and inflammatory responses[143,144]. These modifications can exacerbate or mitigate AD pathology by regulating the transcriptional activity of genes implicated in Aβ deposition and tau pathology. Furthermore, genetic factors, such as polymorphisms in the apolipoprotein E (APOE) gene, have been well-documented to affect the risk of developing AD[145]. The APOE E4 allele is the strongest genetic risk factor for sporadic AD, influencing Aβ aggregation and clearance. Research suggests that individuals with IR carrying the APOE E4 allele have an increased risk of cognitive decline and AD, potentially due to synergistic effects on lipid metabolism, Aβ accumulation, and brain insulin signaling[146-148].

Insulin-derived amyloidosis

Recent studies have highlighted a novel aspect of insulin's behavior, showing that it can aggregate into amyloid-like fibrils under specific conditions, such as changes in pH, temperature, and ionic strength, which are reminiscent of the environment found in IR[149,150]. This phenomenon, primarily observed in vitro, suggests a potential link between elevated insulin levels associated with IR and the formation of amyloid fibrils in the brain, akin to those seen in AD[151]. The structural similarities between insulin-derived amyloids and Aβ plaques highlight a possible mechanistic connection between metabolic dysfunctions, such as IR, and neurodegenerative processes. This emerging insight not only enriches the understanding of the relationship between IR and AD but also proposes new therapeutic targets for AD, focusing on preventing or disrupting the amyloidogenic potential of insulin as a means to address neurodegeneration in patients with metabolic disorders[152-154].

Hormonal dysregulation

IR significantly affects the neuroprotective hormonal axis, particularly leptin and ghrelin, potentially accelerating AD's pathogenesis[155]. Leptin, beyond its critical role in energy regulation and appetite suppression, exerts significant neuroprotective effects. It fosters neuronal growth, synaptic plasticity, and protects neurons from apoptotic triggers. Leptin resistance, induced by IR, impairs neuroprotection, affecting memory and learning, further contributing to the pathophysiology of AD[156-160]. Similarly, ghrelin, often known as the "hunger hormone," has been recognized for its roles beyond appetite stimulation, including the promotion of neuronal survival, enhancement of neurogenesis, and facilitation of synaptic plasticity. Ghrelin's neuroprotective effects are particularly pronounced in the hippocampus, a brain region pivotal for memory formation and one of the first regions to suffer damage in the course of AD[161-163]. IR-associated alterations in ghrelin levels and signaling can disrupt these beneficial processes, leading to impaired cognitive functions and increased risk of neurodegeneration. This hormonal imbalance due to IR contributes to cognitive decline and AD pathology, highlighting the need for therapeutic strategies targeting these hormonal pathways to mitigate AD progression in individuals with metabolic disorders[162,164,165].

Impaired cellular communication

IR disrupts critical brain signaling pathways, particularly the Wnt/β-catenin pathway, which is essential for neurodevelopment and synaptic plasticity. This disruption affects the communication between neurons and glial cells, including astrocytes and oligodendrocytes, pivotal for supporting neuronal function and integrity. The consequences of disrupted Wnt/β-catenin signaling extend beyond synaptic plasticity, affecting various aspects of brain function and health by altering gene expression, neuronal connectivity, and the brain's ability to respond to neural damage, potentially contributing to cognitive dysfunction and the pathogenesis of neurodegenerative diseases such as AD[166-168]. The debate continues on how directly IR-induced signaling disruptions contribute to neurodegeneration and whether these effects are reversible through interventions that improve insulin sensitivity[169-170]. Ongoing research aims to unravel the complexities of cellular signaling affected by IR and explore therapeutic strategies to restore brain function and mitigate neurodegenerative processes[169,170,171]. Understanding the role of IR in impaired cellular communication within the brain is crucial for developing targeted treatments for AD and related conditions[172].

Altered ion homeostasis and neuronal excitability

Ion channels and transporters play critical roles in maintaining the electrochemical gradients essential for neuron firing, signal transduction, and synaptic activity. IR, possibly disrupts the regulatory mechanisms governing these ion channels and transporters, leading to altered neuronal excitability and impaired signaling[173,174].

One of the most significant impacts of IR on ion homeostasis is observed in the regulation of calcium ions (Ca2+). Calcium plays a pivotal role in numerous neuronal processes, including neurotransmitter release, synaptic plasticity, and activation of intracellular signaling pathways. Disruption in calcium homeostasis due to IR can lead to an imbalance in intracellular Ca2+ levels, potentially triggering synaptic dysfunction and promoting neuronal death. These disturbances in calcium signaling are critical contributors to the pathophysiology of AD, as they can exacerbate the neurodegenerative processes characteristic of the disease[175].

Furthermore, altered ion homeostasis in the context of IR can influence the activity of other essential ions, such as sodium (Na+) and potassium (K+), further complicating neuronal excitability and signaling. The dysregulation of these ion channels and transporters contributes to a cascade of neural dysfunctions, laying the groundwork for synaptic loss, neuronal death, and cognitive decline observed in AD[176,177].

Advanced glycation end products and receptor for advanced glycation end products activation

The interplay between IR and the accumulation of advanced glycation end products (AGEs) presents a significant potential pathway contributing to the pathogenesis of AD. AGEs are complex molecules formed through the non-enzymatic glycation of proteins, lipids, and nucleic acids. IR exacerbates the formation of AGEs due to persistent hyperglycemia and altered metabolic states, leading to an accumulation of these harmful compounds in various tissues, including the brain[178-180].

AGEs exert their detrimental effects primarily through interaction with the receptor for AGEs (RAGE) expressed on neuronal cells and other brain cells, such as microglia and astrocytes[181,182]. The binding of AGEs to RAGE triggers a cascade of downstream signaling pathways that promote oxidative stress and inflammation, two critical processes implicated in the neurodegenerative mechanisms of AD. The oxidative stress induced by this interaction contributes to neuronal damage and death, while the inflammatory response exacerbates the pathological environment within the AD brain[183,184].

Alteration of sirtuin pathways

Sirtuins, a family of NAD+-dependent deacetylases, play a pivotal role in cellular metabolism, stress resistance, and longevity. Among them, sirtuin 1 (SIRT1) is of particular interest due to its extensive involvement in metabolic regulation, DNA repair, and neuroprotection. Research has demonstrated that SIRT1 exerts a protective effect against neurodegeneration, promoting neuronal survival, enhancing DNA repair mechanisms, and modulating inflammatory responses in the brain[185,186].

In the context of IR, the activity of SIRT1 and other sirtuins can be significantly impacted. IR, characterized by a diminished response to insulin signaling, leads to metabolic disturbances not only in peripheral tissues but also within the CNS. These disturbances can alter the NAD+/NADH ratio, a critical cofactor for sirtuin activity, thereby affecting the functional capacity of SIRT1 and its neuroprotective effects[187,188].

The potential role of sirtuins, especially SIRT1, in AD stems from their ability to modulate several pathways implicated in the disease's pathogenesis. SIRT1 can influence amyloid-beta metabolism, tau protein phosphorylation, and cellular stress responses, all of which are key factors in AD development. By deacetylating transcription factors and other proteins, SIRT1 can suppress the expression of genes involved in amyloid-beta production and promote pathways that enhance neuronal survival and plasticity[187].

However, the exact mechanisms through which IR affects SIRT1 activity in the brain and its implications for AD remain areas of active research. Some studies suggest that enhancing SIRT1 activity could offer a therapeutic strategy to mitigate the effects of IR on neuronal health and slow AD progression[186,187]. Conversely, the multifaceted roles of SIRT1 in different cellular contexts highlight the complexity of targeting this pathway for disease intervention. The challenge lies in elucidating the specific conditions under which SIRT1 activation or inhibition could be beneficial in the context of AD and IR.

Alterations of mechanistic target of rapamycin signaling

The mechanistic target of rapamycin (mTOR) pathway, critical for cellular metabolism and growth, intersects significantly with IR and AD. IR disrupts insulin signaling, leading to mTOR dysregulation, which is implicated in AD pathogenesis through the accumulation of amyloid-beta and hyperphosphorylated tau proteins[189,190]. This dysregulation hampers autophagy, essential for clearing these neurotoxic proteins[191,192]. Conversely, targeted mTOR inhibition has shown potential in reducing AD markers in experimental models, suggesting modulation of this pathway as a therapeutic strategy[193,194]. However, the complexity of mTOR's role in integrating various cellular signals necessitates nuanced approaches to leverage its therapeutic potential without disrupting essential cellular functions. Understanding the intricate relationship between mTOR signaling, metabolic dysfunction, and neurodegeneration highlights a promising avenue for AD research and treatment development.

Gut-brain axis

The gut-brain axis plays a crucial role in linking IR with AD through complex interactions involving the gut microbiome and neuroinflammatory processes[195,196]. Alterations in the gut microbiota due to IR can increase intestinal per-meability, leading to systemic inflammation and exacerbating neuroinflammation, which contributes to AD pathology[197,198]. The gut microbiota also influences the production of neuroactive substances like short-chain fatty acids, which have anti-inflammatory properties and support the BBB's integrity[199,200]. Moreover, gut-derived metabolites can affect neurotransmitter production in the brain, impacting mood and cognitive functions. This evidence suggests the gut-brain axis as a potential target for AD therapeutic strategies, focusing on dietary interventions and probiotics to restore gut health, reduce inflammation, and slow AD progression[201,202]. Further research is needed to fully understand these interactions and their implications for AD treatment.

Lipid rafts and cell signaling

IR may disrupt the composition of lipid rafts in neuronal membranes, impacting the organization and function of essential signaling molecules. This disruption affects various cellular pathways crucial for neuronal health, synaptic function, and the processing of APP, potentially leading to increased Aβ accumulation, a key feature of AD. Furthermore, altered lipid raft integrity may impair receptor-mediated signaling, including insulin and neurotransmitter receptors, contributing to synaptic dysfunction and cognitive decline observed in AD. Addressing the changes in lipid raft composition due to IR could offer new therapeutic avenues for mitigating AD progression[203-207].

It's essential to note that while these mechanisms provide a deeper understanding of the potential links between IR and AD, the exact contribution and interplay of each mechanism in the pathophysiology of AD remain areas of active research. Further studies are needed to elucidate these relationships fully and to develop effective therapeutic strategies targeting these mechanisms.

CURRENT THERAPEUTIC APPROACHES TARGETING IR

Effective management of IR is crucial in addressing not only metabolic disorders but also neurodegenerative diseases like AD. This section synthesizes current treatment modalities for IR, examines their potential impact on AD progression, and assesses their effectiveness in mitigating AD symptoms, integrating recent data and research findings.

Current therapeutic landscape for IR

The management of IR employs a multidimensional strategy focused on enhancing insulin sensitivity and addressing metabolic imbalances. Fundamental to this approach are lifestyle modifications, where dietary optimization aimed at reducing refined sugars and increasing fiber intake, combined with regular physical activity, has been proven to significantly improve insulin sensitivity. Such modifications are pivotal in IR management, highlighting their importance in promoting metabolic health[208-210]. Pharmacologically, metformin stands as a cornerstone in treating type 2 diabetes by improving insulin sensitivity and reducing hepatic glucose production, underlining its key role in diabetes care[211,212]. Additionally, thiazolidinediones (TZDs), such as pioglitazone, act as PPAR-γ agonists to substantially increase tissue responsiveness to insulin, demonstrating their effectiveness in enhancing metabolic functions[213,214]. Glucagon-like peptide-1 (GLP-1) receptor agonists, like liraglutide, not only augment insulin secretion but also offer neuroprotective benefits, indicating their dual benefit in IR treatment[215,216]. Furthermore, SGLT2 inhibitors, represented by empag-liflozin, contribute to lowering glucose reabsorption in the kidneys, thus indirectly boosting insulin sensitivity and presenting an innovative tactic in IR management[217,218].

Impact of IR treatments on AD’s progression

Emerging research highlights the potential impact of IR therapies on the progression of AD. Metformin, known for its glycemic control properties, has been observed to reduce the risk of cognitive decline and dementia in diabetic patients, potentially through the activation of AMP-activated protein kinase and reduction in neuroinflammation[219,220]. TZDs, with pioglitazone in particular, have demonstrated the potential to decrease AD risk, likely attributed to their anti-inflammatory effects and improvements in cerebral glucose metabolism[221,222]. GLP-1 receptor agonists, such as liraglutide, are being explored for their ability to reduce amyloid plaque formation and enhance cognitive function, showing promising results in early trials[223]. SGLT2 inhibitors, originally utilized for diabetes management, are under research for their possible neuroprotective effects and impact on glucose metabolism in AD[224,225].

The effectiveness of these IR treatments in the context of AD is an area of active research. Observational studies of metformin suggest neuroprotective benefits, yet randomized controlled trials are needed to confirm these effects[211,220]. Clinical trials involving TZDs have yielded mixed results, with some indicating cognitive benefits in the early stages of AD, while others report minimal impact[222]. Initial trials with GLP-1 receptor agonists hint at cognitive improvements in patients with mild AD, but further, more extensive research is required to solidify these findings[223]. The potential neuroprotective role of SGLT2 inhibitors in AD remains an exciting field of study, indicating the necessity for continued investigation into the efficacy of IR treatments in mitigating AD progression[225].

Emerging and adjunctive therapies

Emerging and adjunctive therapies are broadening the horizon of IR management, encompassing a range of innovative and supplementary strategies. Novel insulin sensitizers are being developed to enhance insulin sensitivity through new mechanisms, aiming to minimize the side effects associated with current drugs like TZDs[226]. Nutraceuticals, including omega-3 fatty acids, curcumin, and resveratrol, are gaining attention for their potential to improve insulin sensitivity, attributed to their anti-inflammatory and antioxidant properties[227,228]. Dietary approaches such as intermittent fasting and caloric restriction are linked to both improved insulin sensitivity and neuroprotection, suggesting a beneficial effect on metabolic and neuronal pathways[229-231]. Cognitive training, though not directly addressing IR, is proposed to boost brain plasticity and possibly curb cognitive decline related to IR and AD[232,233]. The modulation of the gut microbiome through probiotics, prebiotics, and dietary changes is another area of interest, reflecting the growing recognition of the gut-brain axis in influencing insulin sensitivity and cognitive function[234,235]. Gene and cell therapies represent cutting-edge interventions in the early research stages, with the potential to directly target metabolic pathways and restore insulin sensitivity[236,237]. Anti-inflammatory therapies are being explored for their capacity to specifically target inflammatory pathways common to both IR and AD, highlighting the intertwined role of inflammation in these conditions[238,239]. Lastly, a holistic approach that integrates medication, lifestyle modifications, and cognitive training offers a comprehensive strategy for managing IR and its potential repercussions on AD, underlining the necessity of a multifaceted treatment paradigm to address the complex interplay between metabolic dysfunction and neurodegeneration.

In summary, the spectrum of therapeutic approaches targeting IR, from lifestyle modifications to emerging pharmacological interventions, offers promising avenues not only in managing metabolic symptoms but also in potentially influencing AD progression. While preliminary studies and trials indicate beneficial roles for these treatments in AD, extensive and long-term research is essential to fully ascertain their efficacy and mechanisms of action. This evolving field underscores the importance of a multifaceted approach in treating conditions with overlapping metabolic and neurological implications, like IR and AD.

FUTURE PERSPECTIVES AND RESEARCH DIRECTIONS

The exploration of the complex relationship between IR and AD presents promising avenues for advancements in early detection, therapeutic interventions, and a deeper understanding of both conditions. The emphasis on early identification and management of IR as a strategy to potentially alter AD's progression is gaining momentum. Research suggests that metabolic disturbances, including IR, often precede the onset of neurodegenerative changes, offering a critical window for early intervention[227]. Developing biomarkers for IR associated with cognitive decline and exploring non-invasive detection methods for IR-related metabolic dysfunctions in at-risk individuals are key research directions[240].

Moreover, emerging therapeutic strategies are increasingly addressing both the metabolic and neurological facets of IR and AD. Novel pharmacological agents targeting molecular pathways common to both conditions, drugs enhancing insulin sensitivity or mimicking insulin's neuroprotective effects without worsening peripheral IR, and the modulation of neurotrophic factors to mitigate IR's adverse effects in the brain are under investigation. The exploration of anti-inflammatory agents also reflects the recognized role of chronic inflammation in the pathogenesis of both IR and AD[100,220,221]. This ongoing research highlights the need for continued interdisciplinary efforts to uncover effective treatments and preventive measures, highlighting the critical intersection of metabolic dysfunction and neurodegeneration in advancing the approach to managing IR and AD.

CONCLUSION

The intricate link between IR and AD underscores a critical intersection in metabolic and neurodegenerative disorders. Research reveals that IR, a hallmark of DM, significantly contributes to the pathogenesis of AD through shared pathways such as impaired insulin signaling, inflammation, and disrupted glucose metabolism. This connection not only highlights the increased AD risk among diabetic patients but also opens new avenues for treatment, including metabolic health interventions and repurposing diabetic medications for AD. Ongoing interdisciplinary research in this domain is vital, promising transformative advances in understanding and managing these prevalent conditions.

Footnotes

Provenance and peer review: Invited article; Externally peer reviewed.

Peer-review model: Single blind

Specialty type: Endocrinology and metabolism

Country of origin: Malaysia

Peer-review report’s classification

Scientific Quality: Grade A, Grade A, Grade C, Grade C

Novelty: Grade A, Grade A, Grade B

Creativity or Innovation: Grade A, Grade A, Grade B

Scientific Significance: Grade A, Grade A, Grade B

P-Reviewer: Moriyama K, Japan; Qureshi W, India; Soreq L, United Kingdom S-Editor: Liu H L-Editor: A P-Editor: Chen YX

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