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在我們日常生活中，「餓」是一個很直觀的感受。但你有沒有想過，大腦也會「餓」？而且這種餓，不是吃太少，而是吃再多，能量也進不了腦細胞。
Type 3 diabetes and metabolic reprogramming of brain neurons: causes and therapeutic strategies
Xiangyuan Meng, Hui Zhang, Zhenhu Zhao, Siyao Li, Xin Zhang, Ruihan Guo, Huimin Liu, Yiling Yuan, Wanrui Li, Qi Song & Jinyu Liu
Molecular Medicine volume 31, Article number: 61 (2025)
Review
Published: 18 February 2025
Type 3 diabetes and metabolic reprogramming of brain neurons: causes and therapeutic strategies
Qi Song &
volume
31, Article number: 61 (2025) Cite this article
Abstract
Abnormal glucose metabolism inevitably disrupts normal neuronal function, a phenomenon widely observed in Alzheimer’s disease (AD). Investigating the mechanisms of metabolic adaptation during disease progression has become a central focus of research. Considering that impaired glucose metabolism is closely related to decreased insulin signaling and insulin resistance, a new concept "type 3 diabetes mellitus (T3DM)" has been coined. T3DM specifically refers to the brain’s neurons becoming unresponsive to insulin, underscoring the strong link between diabetes and AD. Recent studies reveal that during brain insulin resistance, neurons exhibit mitochondrial dysfunction, reduced glucose metabolism, and elevated lactate levels. These findings suggest that impaired insulin signaling caused by T3DM may lead to a compensatory metabolic shift in neurons toward glycolysis. Consequently, this review aims to explore the underlying causes of T3DM and elucidate how insulin resistance drives metabolic reprogramming in neurons during AD progression. Additionally, it highlights therapeutic strategies targeting insulin sensitivity and mitochondrial function as promising avenues for the successful development of AD treatments.
Introduction
Alzheimer's disease (AD) is one of the most pressing public health challenges in the context of global population aging. By 2030, the number of individuals with AD is expected to increase to 82 million, placing a significant burden on global healthcare systems (2024b). Currently, two FDA-approved drugs, Lecanemab and Donanemab, directly target the removal of β-amyloid (Aβ) plaques and have shown promising results in slowing the progression of cognitive decline in AD. However, they do not exempt from unwanted secondary effects (Huang et al. 2023c; Huimin et al. 2023; Sims et al. 2023; van Dyck et al. 2023). Despite receiving treatment, patients continue to experience disease progression. These findings underscore the critical importance of advancing our understanding of the pathogenesis of AD and identifying potential therapeutic targets.
Data from epidemiological and clinical studies support the notion that obesity or diabetes, which lead to insulin resistance, are significant risk factors for AD (Ahtiluoto et al. 2010; Profenno et al. 2010; Talbot et al. 2012). Given the brain’s high sensitivity to insulin, peripheral insulin resistance results in reduced insulin signaling in the central nervous system (CNS), subsequently leading to alterations in brain metabolism (Kapogiannis and Avgerinos 2020). Increasing evidence suggests that Aβ toxicity, tau hyperphosphorylation, oxidative stress, and neuroinflammation are attributed to CNS insulin resistance, thereby contributing to neurodegeneration (Takeda et al. 2012; Wei et al. 2021; Leclerc et al. 2022). Considering the shared molecular and cellular features between type 1 diabetes, type 2 diabetes mellitus (T2DM), and insulin resistance in older adults, which are associated with memory impairment and cognitive decline, researchers have coined the term “Type 3 Diabetes mellitus (T3DM)” to emphasize the critical role of insulin in brain energy supply (Steen et al. 2005).
The brain is a highly energy-demanding organ, with mitochondria providing sufficient energy and meeting its energy needs through oxidative phosphorylation (OXPHOS). Glucose is the primary energy source for neurons, facilitating the production of more than 95% of adenosine triphosphate (ATP) through glycolysis and OXPHOS (Kapogiannis and Avgerinos 2020). While ATP can be generated through glycolysis alone, glycolysis produces only two ATP molecules, which are insufficient to meet the energy demands of neurons. This process also leads to the accumulation of reactive oxygen species (ROS). Consequently, any factor that impairs the normal OXPHOS process in neurons results in energy depletion, which can trigger neuronal death and ultimately lead to the onset of neurodegenerative diseases. Studies have shown that, before the onset of cognitive impairment, alterations in glucose metabolism pathways occur in the neurons of the brains of AD patients (Wei et al. 2023). This suggests that during the progression of AD, neurons undergo a metabolic reprogramming process, shifting from OXPHOS to glycolysis. Additionally, ATP production is reduced in the brains of at least 7% of early-onset AD, 20% of late-onset AD, and 35%-50% of advanced AD patients. Notably, the reduction in energy synthesis in neurons occurs before the onset of cognitive decline and pathological features of AD. As the disease progresses, this suggests that energy synthesis dysfunction may be one of the early characteristic pathological changes in AD (Hoyer 1992). However, the complexity of brain metabolism indicates that these findings should be interpreted with caution, as metabolic shifts may become maladaptive over time, activating a series of complex compensatory responses that contribute to the progression of AD.
Given the association between reduced brain insulin levels or insulin receptor signaling and cognitive dysfunction, as well as neurodegenerative diseases, the mechanisms involving central insulin signaling, glucose utilization, and neuronal energy homeostasis—particularly the metabolic reprogramming of neuronal energy metabolism—are emerging as promising areas of research and intervention (Chang et al. 2020; Milstein and Ferris 2021; Huang et al. 2023a;Miranda 2024). In this review, we explore the potential mechanisms underlying the induction of T3DM and how insulin resistance drives neuronal metabolic reprogramming. We also summarize therapeutic strategies for addressing T3DM.
Insulin resistance and AD
AD is the most common cause of dementia, accounting for 60–80% of all dementia cases. It is a distinct neurodegenerative disease characterized by the accumulation of amyloid plaques and tau tangles in the brain, leading to progressive cognitive decline. As a progressive neurodegenerative disorder with an insidious onset, AD is rapidly becoming a major global burden on healthcare, society, and the economy (2024b). According to the 2022 World Alzheimer’s Report, the number of individuals affected by AD is expected to exceed 100 million by 2050, placing a substantial strain on global healthcare systems (Serge Gauthier 2022).
Several widely accepted hypotheses have been proposed to explain the pathogenesis of AD, including the amyloid cascade hypothesis, the cholinergic hypothesis, the hypothesis of tau hyperphosphorylation, the neuroinflammation hypothesis, and the metal ion dysregulation hypothesis. However, the exact mechanisms underlying the disease remain unclear. Current treatments for AD, such as Donepezil, Rivastigmine, and Galantamine, are acetylcholinesterase inhibitors approved by the Food and Drug Administration (FDA) for symptom management (Rogers and Friedhoff 1996; Rösler et al. 1999; Raskind et al. 2000). In 2003, the non-competitive N-methyl-d-aspartate (NMDA) receptor (NMDAR) antagonist Namenda was also FDA-approved (Areosa and Sherriff 2003). Namzaric, a combination of Donepezil and Namenda, was approved in 2014 (Howard et al. 2012). However, these treatments primarily target cognitive symptoms such as memory loss and confusion. They do not alter the progression of the disease or address the underlying neurodegenerative processes. In recent years, the FDA has approved new AD treatments, including Aducanumab and Lecanemab, developed by Biogen/Esai (Budd Haeberlein et al. 2022; van Dyck et al. 2023). However, clinical trials for Aducanumab showed efficacy only in high-dose groups, while Lecanemab has notable side effects, such as amyloid-related imaging abnormalities, including brain edema and cerebral hemorrhage (Wu et al. 2023). While both Aducanumab and Lecanemab aim to clear amyloid plaques in the brain, their side effects and clinical efficacy still require extensive monitoring. Given the complexity of AD, it is critical to explore its pathogenic mechanisms and identify potential therapeutic targets.
Brain energy supply and insulin resistance
Although the human brain constitutes just over 2% of body weight, it consumes approximately 20% of the body’s total energy demand (Goyal et al. 2014). Neurons primarily rely on oxidative metabolism, using glucose as their main energy source, and employ OXPHOS to provide sufficient energy for synaptic transmission and the maintenance of neuronal functions (Lin and Beal 2006; Koopman et al. 2013). As a result, glucose provides the vast majority of calories consumed by the adult brain. Most glucose is oxidized to produce the substantial amounts of ATP needed to maintain membrane ion gradients and other cellular processes involved in synaptic transmission (Kapogiannis and Avgerinos 2020). Maintaining glucose homeostasis requires both hormonal and neural regulation, which supports the proper functioning of the brain and peripheral tissues. Glucose is not only the primary energy source for both neural and non-neural cells, but it also serves as a signaling molecule (Li et al. 2020). For example, AMP-activated protein kinase (AMPK) responds to changes in the intracellular AMP/ATP and/or ADP/ATP ratios, thereby regulating mTORC1 activity. This signaling pathway coordinates cell growth, proliferation, metabolism, and survival with the cell’s nutritional environment (Zhou and Liu 2022). Thus, glucose regulation mechanisms are essential to ensuring an adequate supply of glucose to meet the metabolic demands of both the central nervous system and peripheral tissues. Insulin is a key hormone that regulates blood glucose absorption and promotes anabolic metabolism, facilitating the synthesis of glycogen, fats, and proteins (Petersen and Shulman 2018). Under normal conditions, insulin-sensitive organs or tissues (such as the brain, skeletal muscles, liver, and adipose tissue) require endogenous or exogenous insulin at lower concentrations to elicit a physiological response. However, in the presence of insulin resistance, these tissues require higher concentrations of insulin to respond to its effects. This condition results in a decreased efficiency of insulin in glucose uptake and utilization, clinically defined as insulin resistance (Petersen and Shulman 2018). Insulin resistance is considered a driving factor in the pathogenesis of many modern diseases, including metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), atherosclerosis, T2DM, and neurodegenerative diseases (Zhao et al. 2023).
Insulin and the insulin signaling pathway
Insulin plays a pivotal role as a key regulatory factor in the transition from nutrient utilization to energy storage. Insulin is a hormone produced by the β-cells of the pancreatic islets of Langerhans that regulate blood glucose levels. It consists of two polypeptide chains connected by disulfide bonds, comprising 51 amino acids. Insulin exerts its effects by binding to the insulin receptor (InsR), a transmembrane glycoprotein receptor composed of two α and two β subunits (Rorsman and Ashcroft 2018). This interaction initiates a cascade of downstream signaling pathways (Fig. 1). When insulin binds to the α subunits of InsR, it induces conformational changes that activate and auto-phosphorylate several tyrosine residues in the cytoplasmic region of the β subunits. These phosphorylated residues are recognized by the phosphotyrosine-binding (PTB) domains of adapter proteins, such as insulin receptor substrates (IRS) (Petersen and Shulman 2018). Among the six mammalian IRS proteins (IRS-1, IRS-2, IRS-3, IRS-4, IRS-5, IRS-6), IRS-1 and IRS-2 are typically considered key nodes in the insulin signaling system, closely associated with the development of insulin resistance. Specifically, under conditions of obesity, stress, and inflammation, extensive serine phosphorylation of IRS-1 occurs through the action of various kinases (Machado-Neto et al. 2018; Woo et al. 2024).
Fig. 1
The production of insulin and the classical insulin signaling pathway. A, The production and structure of insulin. Insulin is synthesized by the β-cells of the islets of Langerhans in the pancreas. It consists of two polypeptide chains, linked by disulfide bonds, with a total of 51 amino acids. Insulin plays a crucial role in the regulation of glucose homeostasis, ensuring the proper balance of blood glucose levels in the body. B Classical insulin signaling pathway. In the classical insulin signaling pathway, insulin binds to the extracellular α-subunit of the insulin receptor (InsR), leading to the dimerization and autophosphorylation of the β-subunit, which subsequently activates its kinase activity. The phosphorylated InsR then catalyzes the phosphorylation of tyrosine residues on insulin receptor substrates (IRS), which in turn recruits and activates the PI3K complex. The catalytic subunit of PI3K, p110, phosphorylates phosphatidylinositol 4,5-bisphosphate (PIP2), converting it into phosphatidylinositol (3,4,5)-trisphosphate (PIP3). The phosphatase PTEN can counteract the actions of PI3K and Akt by dephosphorylating PIP3, thus reducing Akt phosphorylation levels in the cell. It is important to note that PI3K does not directly activate Akt. Instead, PI3K interacts with signaling proteins containing PH domains, such as Akt and phosphoinositide-dependent kinase 1 (PDK1), which facilitate Akt's translocation to the cell membrane. Once at the membrane, PDK1 catalyzes the phosphorylation of Akt at Thr 308, partially activating it. However, full activation of Akt requires phosphorylation at Ser 473. This phosphorylation is carried out by the mammalian target of rapamycin (mTOR) complex 2 (mTORC2), which fully activates Akt’s enzymatic activity. Activated Akt has numerous downstream effects, including: 1) Glycogen synthase kinase 3 beta (GSK3β) regulates the activity of glycogen synthase (GS), thereby promoting glycogen synthesis. Phosphorylation of GSK3β by Akt inhibits the constitutive activity of this key kinase, resulting in the activation of GS and the deposition of glucose as glycogen. 2) Activated Akt induces the phosphorylation of Forkhead Box O1 (FoxO1), causing its translocation from the nucleus and the loss of its transcriptional activity. Glucose-6-phosphatase G-6-pase (G6Pase) and Phosphoenolpyruvate carboxykinase (PEPCK) are two rate-limiting enzymes in the gluconeogenesis pathway. FoxO1 can bind to promoter regions of the G6Pase and PEPCK genes, increasing their transcriptional activity. This enhances hepatic glucose production, leading to elevated blood glucose levels. 3) Akt directly phosphorylates Tuberous Sclerosis Complex (TSC) 2 at multiple sites, thereby reducing the inhibitory effect of the TSC1-TSC2 complex on Ras homolog enriched in brain (Rheb) and mTORC1. This leads to the activation of mTORC1 in response to insulin signaling, regulating lipid, nucleotide, and glucose metabolism. 4) The most significant correlation with systemic blood glucose control is the phosphorylation of AS160, a 160-kDa Akt substrate. AS160 regulates the translocation of glucose transporter type 4 (GLUT4) to the cell membrane, facilitating glucose uptake into muscle, adipose tissue, and certain neurons. FoxO1 forkhead Box O1, G6Pase glucose-6-phosphatase G-6-pase, GLUT4 glucose transporter type 4, GS glycogen synthase, GSK3β glycogen synthase kinase 3 Beta, IRS insulin receptor substrates, InsR insulin receptor, PDK1 phosphoinositide-dependent kinase 1, PEPCK phosphoenolpyruvate carboxykinase, PIP2 phosphatidylinositol 4,5-bisphosphate, PIP3 phosphatidylinositol (3,4,5)-trisphosphate, Rheb Ras homolog enriched in brain
The brain as an insulin-sensitive organ
Brain development and the regulation of neurogenic niches are critically dependent on insulin. Insulin promotes neurogenesis by regulating the proliferation, differentiation, and survival of neural stem cells (Aberg et al. 2003). Normal insulin signaling not only plays a vital role in maintaining circuit regulation and synaptic plasticity but also in controlling neuronal and glial cell metabolism and mitochondrial function (Chen et al. 2022). It is now well-established that most tissues, including the brain, express InsR and are sensitive to insulin. Evidence indicates that InsR is expressed in both neurons and glial cells, with expression levels varying across different brain regions (Kandimalla et al. 2017; Arnold et al. 2018). InsR is particularly abundant in the hypothalamus, hippocampus, cerebral cortex, and olfactory bulb, areas critical for metabolic regulation and cognitive function (Stanley et al. 2016; Milstein and Ferris 2021). Notably, neurons and glial cells express different isoforms of the InsR α subunit. Neurons express the InsR-A isoform, whereas glial cells primarily express the InsR-B isoform (Kleinridders 2016; Cai et al. 2017). Compared to InsR-B, InsR-A exhibits a higher binding affinity for insulin, with the receptor internalization rate being ~ 1–2 times greater (Rajapaksha and Forbes 2015; Pomytkin et al. 2018). Animal studies have shown that selective disruption of neuronal InsR, particularly in the hypothalamus, increased fat mass, and peripheral insulin resistance (Wardelmann et al. 2019; Porniece Kumar et al. 2021). Conversely, restoring hypothalamic insulin action can prevent diabetes.
Under normal physiological conditions, insulin readily crosses the blood–brain barrier (BBB) via receptor-mediated transport, and this transport rate can be modulated by factors such as obesity, inflammation, and AD. Studies using endothelial cell-specific InsR knockout mice confirmed that endothelial InsR is critical for insulin trans the BBB and downstream insulin signaling in the hippocampus, hypothalamus, and frontal cortex (Konishi et al. 2017). There is also evidence suggesting that the brain can produce insulin independently (Molnár et al. 2014; Mazucanti et al. 2019; Lee et al. 2020). Proinsulin is synthesized in the pancreas and processed in the endoplasmic reticulum, where specific prohormone convertases cleave the C-peptide segment, ultimately leading to the formation of mature insulin. In response to elevated blood glucose, β-cells release insulin via exocytosis. While humans and rabbits have a single insulin-encoding gene, rodents possess two. Among these, Ins II appears to be the primary insulin gene expressed in neurons (Havrankova et al. 1978; Deltour et al. 1993; Devaskar et al. 1993). In cultured rabbit neurons and glial cells, only neurons secrete insulin into the culture medium (Devaskar et al. 1994). Limited evidence suggests that prohormone convertases are evenly distributed across various regions of the brain (Dauch et al. 1993). However, the expression of these enzymes in neurons of the paraventricular nucleus and supraoptic nucleus of the hypothalamus, which are capable of processing proinsulin, partially supports the notion of insulin production within the brain (Dong et al. 1997).
AD and T3DM
Over the past two decades, T2DM has evolved into a complex, multifactorial, and heterogeneous disease (Cefalu et al. 2022). Approximately 90–95% of all diabetes cases worldwide are classified as T2DM(2024a). Clinically, individuals are diagnosed with T2DM when there is a relative insulin deficiency (due to pancreatic β-cell dysfunction) coupled with peripheral insulin resistance (2024a).
Dysregulation of insulin signaling is associated with a range of neurological disorders. More importantly, in AD, the deficits in brain insulin and insulin resistance correspond to the characteristics observed in type 1 diabetes mellitus (T1DM) and T2DM, respectively. Consequently, the coexistence of both conditions in AD has led to the conceptualization of AD as a unique form of brain-dominant diabetes, referred to as “T3DM” (de la Monte and Wands 2008; de la Monte et al. 2018) (Fig. 2).
Fig. 2
Type 1 diabetes mellitus (T1DM), Type 2 diabetes mellitus (T2DM), and Type 3 diabetes mellitus (T3DM) each have distinct characteristics. T1DM is an autoimmune disease in which the body’s immune system attacks and destroys the insulin-producing β-cells in the pancreas, leading to absolute insulin deficiency. In healthy individuals, insulin is produced in response to elevated blood glucose levels after eating, facilitating glucose uptake into cells for energy and storage. In T1DM, the lack of insulin prevents glucose absorption, resulting in hyperglycemia and inadequate cellular energy supply. The primary feature of T2DM is insulin resistance, where the body's cells do not respond properly to insulin. Over time, the pancreas may become unable to produce enough insulin to overcome this resistance. In T2DM, insulin resistance means that cells do not respond efficiently to insulin, and the pancreas struggles to meet the body’s insulin demands, leading to the accumulation of glucose in the bloodstream and the development of hyperglycemia. "T3DM" is a term used in research to describe insulin resistance in the brain, which is associated with Alzheimer’s disease (AD) but has not yet been applied clinically. In a healthy brain, insulin plays a critical role in regulating brain functions, including memory, cognition, and synaptic plasticity. However, in AD, insulin receptors (InsR) are disrupted by β-amyloid oligomers (AβO), impairing normal insulin signaling. This disruption prevents brain cells from effectively utilizing glucose, similar to the insulin resistance observed in peripheral tissues of T2DM patients. AD Alzheimer’s disease, AβOs β-amyloid oligomers, T1DM Type 1 diabetes mellitus, T2DM Type 2 diabetes mellitus, T3DM Type 3 diabetes mellitus, InsR insulin receptors
Epidemiological data indicate that the incidence of comorbidities between T2DM and neurological diseases such as AD is high. Insulin dysregulation and alterations in glucose metabolism are considered risk factors for AD (Jiang et al. 2013; Li et al. 2015; Zhang et al. 2017). Studies have shown that T2DM increases the risk of AD by 50–100% (Grimm et al. 2016; Meng et al. 2022). In the 1990s, data from the Rotterdam Study revealed that individuals with diabetes were nearly twice as likely to develop dementia compared to age-matched non-diabetic controls (OR 1.9, 95% CI 1.2–3.1) (Ott et al. 1996). Elevated circulating blood glucose levels not only increase the risk of dementia but also accelerate the progression from mild cognitive impairment (MCI) to AD (Janson et al. 2004; Aljanabi et al. 2020). Positron emission tomography (PET) imaging using 18F-FDG/CT has shown significant reductions in brain glucose metabolism in MCI patients, suggesting that metabolic decline may serve as an important biomarker in the pathogenesis of AD, occurring prior to clinical manifestations of the disease (Mosconi et al. 2008).
MCI is strongly associated with systemic metabolic dysfunction and insulin resistance, including conditions such as T2DM, metabolic syndrome, polycystic ovary syndrome, and NAFLD (de la Monte et al. 2009; de la Monte 2012). Furthermore, peripheral insulin resistance in individuals without T2DM is considered a risk factor for AD within three years of diagnosis (Schrijvers et al. 2010). Notably, insulin resistance within the brain itself can occur independently of T2DM, potentially promoting or even triggering key pathological events in the disease, such as the formation of β-amyloid plaques and tau phosphorylation (Ohara et al. 2011; Kacířová et al. 2021; de la Monte 2023; Dybjer et al. 2023). This finding aligns with observed changes in the levels of insulin signaling molecules in the brains of AD patients, as well as improvements in memory following intranasal insulin administration in such cases (Claxton et al. 2015; McClure Yauch et al. 2022; Wong et al. 2024). Lastly, insulin resistance is a common feature of AD and is associated with increased amyloid plaque load, reduced hippocampal volume and cognitive function, and decreased cortical glucose metabolism, all of which correlate with diminished memory recall (Baker et al. 2011; Lee et al. 2016b; Tyagi and Pugazhenthi 2021; Kim and Arvanitakis 2023). Taken together, defects in insulin signaling and systemic insulin resistance may play significant roles in the pathogenesis of AD.
Potential mechanisms leading to T3DM
Aβ is a neurotoxic endogenous substance that is considered a hallmark of AD and a major trigger for T3DM. Structurally, Aβ has a hydrophilic N-terminus and a hydrophobic C-terminus (Han and He 2018). Consequently, the release of Aβ fragments initially leads to the spontaneous aggregation of Aβ monomers into soluble Aβ oligomers (AβOs), which subsequently polymerize into insoluble protofibrils that further aggregate to form amyloid plaques, also known as senile plaques (Hardy and Higgins 1992). Compared to Aβ monomers and protofibrils, the barrel-shaped structure of AβOs has a higher affinity for cell membranes, making them more likely to interact with various membrane receptors. With the InsR and the NMDAR being the most prominent (Talbot et al. 2012). In addition to binding to membrane receptors, AβOs can also induce insulin resistance by disrupting mitochondrial function (Calvo-Rodriguez and Bacskai 2021; Sayyed and Mahalakshmi 2022) (Fig. 3).
Fig. 3
Potential mechanisms leading to T3DM. Aβ oligomers (AβOs) compete with insulin for binding to the insulin receptor (InsR), leading to the internalization of InsR and a reduction in both the affinity and the number of InsR on the cell membrane. This can also induce structural abnormalities in the target receptor that binds insulin to InsR. Furthermore, internalized InsR leads to the phosphorylation of IRS, insulin receptor substrates-1 (IRS-1) at critical serine/threonine residues, which accelerates the degradation of the phosphorylated IRS-1 protein, thereby reducing the strength of insulin signaling and promoting insulin resistance. AβO can also lead to the abnormal activation and dysregulation of N-methyl-D-aspartate (NMDA) subtype glutamate receptors (NMDARs). This aberrant activation allows for the influx of Ca2⁺ ions into the cell, resulting in the nuclear translocation of forkhead box O 1 (FOXO1), which ultimately triggers the generation of reactive oxygen species (ROS) and pro-inflammatory cytokines. On another front, AβO contributes to T3DM by disrupting mitochondrial function. Due to the barrel-like structure of AβO, it forms ion channels on the cell membrane that allow the oligomers to enter the cell. Aβ can also aggregate within mitochondria-associated membranes (MAMs), forming AβO aggregates. Mitochondria are one of the primary cellular targets of AβO. The presence of AβO damages the integrity of mitochondrial cristae, stimulates mitochondrial fission, and induces endoplasmic reticulum (ER) stress, thereby disrupting mitochondrial dynamics and contributing to insulin resistance. AβOs Aβ oligomers, ER endoplasmic reticulum, FOXO1 forkhead box O 1, InsR insulin receptor, IRS-1 insulin receptor substrates-1, MAMs mitochondria-associated membranes, NMDA N-methyl-d-aspartate, NMDARs N-methyl-d-aspartate subtype glutamate receptors, ROS reactive oxygen species, T3DM Type 3 diabetes mellitus
Impact of AβO on membrane receptors
First, AβOs compete with insulin for binding to the InsR, causing internalization of InsR and leading to abnormal phosphorylation of downstream signaling molecules, thereby disrupting insulin signaling (Schrijvers et al. 2010; de la Monte 2023). The impairment of InsR binding with insulin primarily refers to a decrease in the receptor's affinity and number on the cell membrane, or to structural abnormalities of the target receptor that hinder insulin-receptor binding (Hall et al. 2020). Generally, insulin activates InsR tyrosine kinase, which aggregates and phosphorylates various substrate-docking proteins, such as members of the IRS protein family. Among the four mammalian IRS proteins (IRS-1, IRS-2, IRS-3, IRS-4), IRS-1 and IRS-2 are considered key nodes in the insulin signaling system, and their dysfunction is closely linked to the development of insulin resistance (Tanti and Jager 2009). Mechanistically, crosstalk between downstream nucleotide-binding oligomerization domain 1 (NOD1) effectors and the insulin receptor pathway may inhibit insulin signaling by reducing IRS function (Rivers et al. 2019). Indeed, although InsR levels in T2DM models are reduced by approximately 90%, both defects in InsR and downstream signaling are implicated in the development of insulin resistance (James et al. 2021).
Evidence shows that exposure of primary hippocampal neurons to AβOs in vitro results in the loss of insulin sensitivity, inhibitory phosphorylation of IRS-1, and decreased InsR expression on dendritic membranes (Zhao et al. 2008; De Felice et al. 2009). APP/PS1 mice also exhibit impaired insulin signaling in the hippocampus, as evidenced by increased phosphorylation of IRS-1 at the serine 616 site (Bomfim et al. 2012). Phosphorylation of IRS-1 at key serine/threonine residues accelerates the degradation of the phosphorylated IRS-1 protein, thereby attenuating the intensity of insulin signaling (Draznin 2006). Abnormal phosphorylation of IRS-1 results in decreased sensitivity of insulin binding to InsR and a partial translocation of IRS-1 from the membrane to the cytoplasm, which is a major molecular basis for insulin resistance (Draznin 2006). Mechanistically, AβOs may induce or exacerbate neuronal insulin resistance through the aberrant activation of the TNF-α/JNK (tumor necrosis factor α/c-Jun N-terminal kinase) pathway, leading to serine phosphorylation of IRS-1 and inducing mitochondrial oxidative stress (Kaminsky et al. 2015; Mullins et al. 2017). Similarly, the TNF-α/JNK pathway is also activated in T2DM, contributing to peripheral insulin resistance, β-cell apoptosis, and increased oxidative stress (Li et al. 2015; Mittal and Katare 2016).
Additionally, AβOs can cause abnormal activation of NMDAR (De Felice et al. 2007; Shankar et al. 2007a; Decker et al. 2010; Paula-Lima et al. 2011a). Dysregulated NMDAR function may play a role in the impairment of neuronal insulin signaling in AD, as the AβO-induced inhibition of insulin receptor signaling can be blocked by memantine (Zhao et al. 2008). Under physiological conditions, synaptic NMDAR activity exerts antioxidant effects by inhibiting FOXO1 in the hippocampus (Papadia et al. 2008; Mubarak et al. 2009). However, in AD, dysfunctional NMDAR activity and insulin resistance may lead to nuclear translocation of FOXO1, ultimately increasing ROS generation (Manolopoulos et al. 2010). This, in turn, may further exacerbate impaired insulin signaling and neuronal dysfunction. Another possibility is that excessive NMDAR activation and Ca2+ influx, triggered by AβOs, stimulate the activity of tyrosine phosphatases on IRS-1, thereby weakening insulin signaling (Shankar et al. 2007b; Zempel et al. 2010; Brito-Moreira et al. 2011; Paula-Lima et al. 2011b). These possibilities are consistent with the described IR regulation mechanisms and suggest a potential physiological feedback loop between dysregulated neuronal activity and insulin signaling.
Mitochondrial function
AβOs can specifically translocate via the translocator of the outer mitochondrial membrane (TOM) and translocase of the inner membrane (TIM) or enter the mitochondria through mitochondrial-associated endoplasmic reticulum membranes (MAM), thereby disrupting mitochondrial function and contributing to the development of T3DM. In fact, both Aβ precursor protein (APP) and Aβ have been shown to co-localize with mitochondria and even generate within lipid raft-enriched MAM regions (Lustbader et al. 2004; Manczak et al. 2006; Wilkins 2023). Additionally, mitochondrial dysfunction contributes to insulin resistance, partly through the excessive production of reactive oxygen species ROS (Shankar et al. 2007b). In this context, insulin resistance is thought to arise from excessive mitochondrial fuel production, such as NADH and FADH2, without a corresponding increase in energy demand, leading to the generation and release of H2O2 from the mitochondria (Fisher-Wellman and Neufer 2012).
Damage to mitochondrial cristae and ROS production
Mitochondrial cristae are structural folds of the inner mitochondrial membrane (IMM). The mitochondrial electron transport chain (ETC) complexes play a key role in linking cristae morphology to mitochondrial function, as these complexes are embedded within the IMM (Cogliati et al. 2013). Electron microscopy has revealed that AβOs cause severe disruption of mitochondrial cristae structures in N2a cells from mice (Manczak et al. 2010). Consistently, postmortem reports indicate that AD patients exhibit a significantly increased incidence of cristae disruption in neuronal mitochondria (Hirai et al. 2001). Cristae increases the surface area of the IMM, facilitating more efficient aerobic respiration. However, damage to cristae compromises the integrity of ETC complexes, impairing electron transfer and proton transport. This damage results in electron and proton leakage, reduced ATP production, and increased ROS generation (Lin and Beal 2006). On the one hand, ROS may induce insulin resistance by directly targeting proteins involved in glucose uptake (Anderson et al. 2009). A shift in the cellular redox state toward oxidation reduces the overall activity of serine/threonine phosphatases, which enhances the activity of stress-sensitive serine/threonine kinases and suppresses insulin signaling, thus promoting insulin resistance (Martin and McGee 2014). On the other hand, mitochondrial ROS activates inflammasomes, triggering a cascade of inflammatory responses (Zhi-Qiang et al. 2023). Many of the signaling pathways activated by inflammation involve serine/threonine kinases that can impair insulin signaling, such as JNK (Vallerie and Hotamisligil 2010). However, the precise role of mitochondrial control of inflammation in the pathogenesis of insulin resistance remains unclear, though it provides a potential mechanism through which mitochondrial dysfunction may affect insulin action.
Mitochondrial dynamics
Mitochondrial dynamics play a crucial role in maintaining mitochondrial health, bioenergetic function, quality control, and cellular vitality. Under physiological conditions, mitochondria undergo continuous dynamic fission and fusion, resulting in morphological changes that help maintain the overall stability of the mitochondrial network. Increased Aβ production and the interaction of AβOs with dynamin-related protein 1 (Drp1) are key factors in mitochondrial fragmentation, abnormal mitochondrial dynamics, and synaptic damage (Manczak et al. 2011; Manczak and Reddy 2012). Moreover, AβOs directly induce Drp1 phosphorylation at Ser616 through Akt activation, promoting mitochondrial fragmentation and triggering downstream events, including ROS production (Kim et al. 2016).
Rats fed a high-fat diet exhibit decreased expression of mitochondrial fusion protein 2 (Mfn2) in the liver, which is accompanied by impaired insulin signaling (Lionetti et al. 2014). In contrast, overexpression of Mfn2 compensates for high-fat diet-induced disruption of insulin signaling (Gan et al. 2013). Liver-specific Mfn2 knockout mice show decreased insulin sensitivity, along with an increased degree of mitochondrial fission (Sebastián et al. 2012). Similarly, increased mitochondrial fission in skeletal muscle is associated with fat-induced insulin resistance (Luo et al. 2021). In fact, reductions in mitochondrial size and Mfn2 expression in skeletal muscle have been observed in both obesity and T2DM, and these reductions correlate with impaired insulin sensitivity (Hernández-Alvarez et al. 2010; Putti et al. 2015; Eshima 2021). All of these findings suggest that disruption of mitochondrial dynamics plays a critical role in insulin resistance and T2DM.
Mitochondrial-endoplasmic reticulum stress coupling
MAMs are specialized subcellular compartments where the endoplasmic reticulum (ER) and mitochondria interact. These regions facilitate efficient communication between these organelles, exchanging Ca2+, lipids, and other metabolites to maintain cellular metabolism and integrity (Degechisa et al. 2022). MAMs exhibit lipid raft characteristics, which create a favorable environment for the γ-secretase activity of APP, emphasizing MAM as a potential site for Aβ production near the mitochondria (Li et al. 2023b). Tubbs and colleagues demonstrated in OB/OB mice and diet-induced insulin resistance mouse models that the integrity of MAMs is essential for insulin signaling. They showed that genetic or pharmacological inhibition of cyclophilin D (CypD) disrupted MAM integrity in both mouse and human primary hepatocytes, altering insulin signaling (Tubbs et al. 2014). Conversely, overexpression of CypD enhanced MAM integrity and improved insulin signaling in diabetic mouse liver cells. Shinijo et al. showed that palmitic acid-treated HepG2 cells exhibited a significant reduction in Ca2+ transfer from the ER to mitochondria and a decrease in ACSL4 (another MAM marker), suggesting that MAM disruption plays a crucial role in palmitic acid-induced insulin resistance (Shinjo et al. 2017). Furthermore, overexpression of Mfn2 partially restored MAM contact sites and improved palmitic acid-induced insulin resistance, enhancing Akt Ser473 phosphorylation (Shinjo et al. 2017). These findings underscore the important role of mitochondrial dynamics regulator Mfn2 in maintaining MAM integrity and function and highlight the potential interaction between mitochondrial fusion/fission processes and the ER in modulating insulin resistance.
Neuronal metabolic reprogramming
Metabolic reprogramming refers to the process by which cells alter their energy production pathways to adapt to changing physiological or pathological demands (Han et al. 2021). This concept is particularly significant in cancer biology, as exemplified by the Warburg effect (Samudio et al. 2009). The Warburg effect describes a phenomenon in cancer cells where energy production predominantly relies on aerobic glycolysis, even in the presence of sufficient oxygen, instead of the more efficient OXPHOS process typically utilized by normal cells. This metabolic shift, first described by German biochemist Otto Warburg in the 1920s, is a hallmark of many cancers (Koppenol et al. 2011). However, with advances in our understanding of tumor and stem cell metabolism, metabolic reprogramming is no longer synonymous with the Warburg effect but broadly refers to any alterations in cellular metabolic mechanisms.
The Embden-Meyerhof-Parnas (EMP) pathway, encompassing glycolysis and the Krebs cycle (also known as the tricarboxylic acid (TCA) cycle), forms the core metabolic route supplying biochemical precursors for biosynthesis and energy production (Peretó 2011). In neurons, glucose is metabolized through glycolysis or the pentose phosphate pathway (PPP), followed by the TCA cycle and OXPHOS, yielding water, carbon dioxide, and ATP (Magistretti and Allaman 2015). pyruvate dehydrogenase complex (PDC) plays a pivotal role at the crossroads of glycolysis and the TCA cycle, regulating the entry of carbohydrate-derived carbon into mitochondria (Patel et al. 2014). In human eukaryotic cells, the PDC is composed of three core catalytic components: pyruvate dehydrogenase (E1), dihydrolipoamide transacetylase (E2), and dihydrolipoamide dehydrogenase (E3). In addition, it is regulated by two key enzymes: pyruvate dehydrogenase kinase (PDK) and pyruvate dehydrogenase phosphatase (PDP) (Patel et al. 2014). These enzymes modulate PDC activity through the phosphorylation (inhibition) and dephosphorylation (activation) of serine residues at positions 293, 300, and 232 on the E1α subunit of the heterotetrameric pyruvate dehydrogenase enzyme (Tovar-Méndez et al. 2005). This regulation controls the aerobic conversion of pyruvate to acetyl-CoA or its anaerobic conversion to lactate.
Neurons primarily use glucose as their energy source, oxidizing it almost completely through continuous glycolysis and the OXPHOS-associated TCA cycle (Zheng et al. 2016). However, under certain conditions, such as hypoglycemia, neurons can metabolize glutamate and glutamine to generate energy (McKenna 2007). Relatively few studies have explored the metabolic changes in neurons during insulin resistance.
Insulin resistance and metabolic reprogramming
Clinically, metabolic syndrome is a pathological state characterized by the clustering of various metabolic abnormalities, collectively constituting a complex syndrome of metabolic disorders. The primary cause of metabolic syndrome is insulin resistance, marked by decreased efficiency in glucose utilization. Insulin resistance also leads to compensatory shifts in energy metabolism in metabolic syndrome. This leads to compensatory shifts in energy metabolism, collectively termed metabolic reprogramming, underscoring the intricate link between insulin resistance and energy metabolism. Metabolomics data indicate that patients with T2DM exhibit elevated serum levels of pyruvate, lactate, and citrate compared to controls, suggesting enhanced glycolysis and disrupted TCA cycle function (Messana et al. 1998; Lee et al. 2018b). Similarly, Sas et al. found significantly higher urinary concentrations of glycolysis products such as lactate, phosphoenolpyruvate, 2,3-diphosphoglycerate, and glyceraldehyde-3-phosphate in T2DM patients, alongside elevated TCA cycle intermediates such as pyruvate, citrate, succinate, fumarate, and malate (Sas et al. 2016). However, these levels gradually declined as the disease progressed. Furthermore, evidence from cerebrospinal fluid (CSF) analysis reveals distinct metabolic disturbances in T2DM, including elevated levels of alanine, leucine, valine, tyrosine, lactate, and pyruvate, alongside reduced histidine levels compared to controls. These findings highlight the metabolic dysregulation associated with insulin resistance (Lin et al. 2019). Several potential mechanisms by which insulin resistance induces metabolic reprogramming are summarized below (Fig. 4).
Fig. 4
Potential mechanisms of metabolic reprogramming induced by insulin resistance. Insulin resistance activates pyruvate dehydrogenase kinases (PDKs), which inhibit the activity of pyruvate dehydrogenase complex (PDC). This suppression reduces the conversion of pyruvate to acetyl-CoA through PDC-mediated decarboxylation, thereby decreasing tricarboxylic acid (TCA) cycle flux and adenosine triphosphate (ATP) production. Furthermore, insulin resistance leads to an increase in reactive oxygen species (ROS), which not only induces oxidative modifications of key proteins involved in oxidative phosphorylation (OXPHOS) but also results in the inactivation of prolyl hydroxylases (PHDs). This causes the dephosphorylation of hypoxia-inducible factor-1α (HIF1α) and promotes the expression of enzymes associated with glycolysis. Finally, insulin resistance induces sustained activation of AMP-activated protein kinase (AMPK). On one hand, this disrupts mitochondrial dynamics, leading to mitochondrial fragmentation, which is detrimental to OXPHOS. On the other hand, prolonged mitochondrial damage activates the PINK1-Parkin pathway, continuously marking damaged mitochondria for degradation. This results in excessive mitochondrial autophagy, reducing the number of healthy mitochondria and impairing OXPHOS efficiency. I Complex I, II Complex II, III Complex III, IV Complex IV, ATP adenosine triphosphate, AMPK AMP-activated protein kinase, Cyt C cytochrome C, HIF1α hypoxia-inducible factor-1 alpha, LDHA lactate dehydrogenase A, OXPHOS oxidative phosphorylation, PDKs pyruvate dehydrogenase kinases, PDH pyruvate dehydrogenase, PHDs prolyl hydroxylases, PINK1 PTEN-induced putative kinase 1, ROS reactive oxygen species, TCA tricarboxylic acid
Potential mechanisms underlying metabolic reprogramming in insulin resistance
Insulin resistance and PDK activation
PDKs inhibit PDC activity, thereby regulating metabolic pathways. Among the four PDK isoforms, PDK4 exhibits the highest kinase activity, whether or not it associates with the L2 or E2p/E3BP core (Wynn et al. 2008). Aberrant regulation of PDC in diabetes involves two isoforms: PDK2 and PDK4. Both are significantly upregulated in T2DM patients and animal models fed a high-fat diet (Holness et al. 2000; Rosa et al. 2003; Spriet et al. 2004; Sikder et al. 2018). Pharmacological inhibition of PDK4, such as through dichloroacetate, has been shown to improve hyperglycemia (Crabb et al. 1981; Park et al. 2021). Diseases associated with shifts from glucose to fatty acid utilization for energy production, such as diabetes and fasting states, also upregulate PDK4 expression (Kim et al. 2023). Transcriptomics and single-cell sequencing data suggest that Pdk4 is upregulated in AD models and the brains of AD patients, identifying it as a potential shared gene between T2DM and AD (Rasche et al. 2008; Wei 2020; Mathys et al. 2024).
Insulin plays a critical role in regulating PDK2 and PDK4 expression. It achieves this through downstream targets such as FOXO and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), which are primary modulators of PDK2 and PDK4 expression (Jeong et al. 2012; Shrivastav et al. 2013; Zhang et al. 2014). In mice fed a high-fat diet, insulin resistance activates PGC-1α and estrogen-related receptor alpha (ERRα), which bind to the PDK4 promoter, enhancing its mRNA and protein expression (Wende et al. 2005; Rinnankoski-Tuikka et al. 2012). Additionally, insulin inhibits PDK2 and PDK4 expression via the PI3K/Akt pathway, which phosphorylates FOXO.
Further research demonstrates that insulin reduces PDK4 gene expression by downregulating three promoter elements, including glucocorticoid response elements (GREs), FOXO1 binding sites, and ERR elements (Connaughton et al. 2010). Other regulators of PDK expression include growth hormone, adiponectin, adrenaline, and rosiglitazone, which exhibit tissue-specific effects (Attia et al. 2010; Jeong et al. 2012). PDK4 is a critical regulator of PDC activity, pyruvate oxidation, and glucose homeostasis. Knockout models of PDK4 show reduced blood glucose levels and hepatic gluconeogenesis (Jeoung et al. 2006). During fasting and diabetes, PDK4 is widely upregulated in major tissues, in response to insulin depletion and increased glucocorticoids and free fatty acids (Nakae et al. 2002). However, direct evidence linking PDK4 to AD remains limited.
ROS-induced metabolic reprogramming
The inefficient glucose utilization in insulin resistance is closely tied to oxidative damage. Insulin resistance contributes to oxidative stress via multiple mechanisms, including the production of advanced glycation end-products (AGEs), and ER stress and inflammation (Petersen and Shulman 2018). Excessive ROS production disrupts mitochondrial function, impairing OXPHOS activity while exacerbating insulin resistance, and creating a vicious cycle.
Insulin resistance fosters ROS generation through several pathways. Hyperglycemia induces non-enzymatic glycation of proteins and lipids, forming AGEs, which interact with AGE receptors (RAGE), stimulating oxidative stress (Li et al. 2022b). Additionally, insulin resistance often involves ER stress, characterized by impaired protein folding (Brown et al. 2020). This activates the unfolded protein response (UPR), which enhances ROS production through mechanisms such as JNK pathway activation (Bhattarai et al. 2021). Chronic low-grade inflammation further exacerbates ROS production, as inflammatory cytokines like TNF-α and Interleukin-6 (IL-6) impair insulin signaling by activating serine kinases that phosphorylate IRS and recruit immune cells such as macrophages to adipose tissue, amplifying local ROS levels (Hotamisligil et al. 1994; Cawthorn and Sethi 2008; Fazakerley et al. 2023).
ROS also act as molecular signals, promoting a shift from OXPHOS to glycolysis by stabilizing hypoxia-inducible factor-1 alpha (HIF1α) (Guzy et al. 2005; Semenza 2017). HIF1α drives anaerobic glycolysis and suppresses OXPHOS. Prolyl hydroxylase (PHD) is a key oxidative stress-sensitive inhibitor of HIF-1α. Under normoxic conditions, PHD induces the hydroxylation of proline and asparagine residues within the oxygen-dependent degradation domain of HIF-1α, leading to its degradation (Lee et al. 2016a). However, elevated levels of ROS can inactivate PHD through redox-dependent dimerization, thereby stabilizing HIF-1α even under normoxic conditions. This results in a shift from OXPHOS to anaerobic glycolysis. Consequently, the accumulation of lactate, a byproduct of anaerobic glycolysis, leads to a significant reduction in pyruvate and ATP production (Lee et al. 2016a). On one hand, insufficient supply of pyruvate—an essential substrate for the TCA cycle—disrupts its homeostasis. On the other hand, this shift results in energy depletion, compromising cell survival, particularly in high-energy-demanding cells.
Excessive ROS production also causes oxidative modifications of key enzymes involved in glycolysis and OXPHOS. Redox proteomic analyses of AD brain tissues have shown oxidative modifications of glycolytic enzymes, including aldolase, triosephosphate isomerase, glyceraldehyde-3-phosphate dehydrogenase, phosphoglycerate mutase 1, and α-enolase, in affected brain regions (Butterfield and Boyd-Kimball 2018). Additionally, oxidative modifications of aconitase (a key iron-sulfur enzyme in the TCA cycle), creatine kinase (an enzyme that helps maintain ATP levels in neurons), and ATP synthase in brain mitochondria have been observed in both MCI and AD patients (Kanski et al. 2002; Butterfield and Boyd-Kimball 2018). Furthermore, oxidative damage to mitochondrial DNA may impair energy production, and studies suggest that defects in Sirtuin 3 can exacerbate oxidative damage in AD mitochondria (Santos et al. 2012; Lee et al. 2018a). Indeed, mitochondrial dysfunction and insulin resistance are closely linked.
Insulin resistance and decline in mitochondrial quality
Mitochondrial quality control (MQC) refers to the processes that maintain the integrity, functionality, and quantity of mitochondria within cells (Pickles et al. 2018). On one hand, a decline in mitochondrial quality is associated with impaired pyruvate transport into mitochondria, weakening the TCA cycle. On the other hand, in the absence of sufficient mitochondrial ATP production, insulin-resistant cells often shift to glycolysis (glucose breakdown for energy) as an alternative energy source. Key components of MQC include mitochondrial biogenesis, fission, fusion, and mitophagy.
Insulin signaling is known to involve the activation of Akt, which leads to the assembly of mTORC1. mTORC1 plays a critical role in regulating protein, lipid, and fatty acid synthesis, as well as mitochondrial metabolism (Szwed et al. 2021). Through its regulation of PGC-1α and nuclear respiratory factors 1 and 2 (NRF1/2), mTORC1 is essential for mitochondrial oxidative metabolism and biogenesis. When activated by insulin, mTORC1 stimulates the production of nuclear-encoded mitochondrial proteins, integrating them into various mitochondrial metabolic pathways, including the TCA cycle, fatty acid β-oxidation, and the electron transport chain (Yoon 2017).
A second complex, mTORC2, also involves mTOR and mediates Akt activation, which negatively regulates FoxO1 (Jais et al. 2014; Jung et al. 2019). FoxO1 promotes transcription of heme oxygenase-1 (HO-1), triggering a metabolic shift from OXPHOS to glycolysis in neurons. When MQC declines, cells experience a pseudo-hypoxic state, characterized by low oxygen utilization despite sufficient oxygen availability, which activates HIF1α (Li et al. 2023c). FoxO1 forms a regulatory loop with HIF-1α, upregulating glycolysis-related enzymes such as hexokinase (HK), phosphofructokinase, and pyruvate kinase, thereby enhancing glucose metabolism via glycolysis (Li et al. 2023c). Furthermore, HIF-1α promotes the expression of lactate dehydrogenase (LDH), which converts pyruvate into lactate, enabling glycolysis to proceed even when mitochondrial oxidative capacity is diminished (Kshitiz et al. 2022).
The decline in MQC reduces the number of functional mitochondria available for OXPHOS, diminishing the cell's ability to oxidize glucose for ATP production. As mitochondrial ATP output decreases, the cell's adenosine monophosphate (AMP) /ATP ratio increases, activating AMPK (Herzig and Shaw 2018). AMPK promotes glycolysis, inhibits anabolic processes such as protein synthesis, and enhances catabolic pathways, including autophagy and mitophagy (Herzig and Shaw 2018). These processes can further reduce mitochondrial content while temporarily compensating for energy deficits by increasing glucose uptake and glycolytic flux. However, this also reinforces the metabolic shift toward glycolysis. Additionally, AMPK promotes mitochondrial fission, disrupting mitochondrial dynamics (Chen et al. 2019). Studies have shown increased mitochondrial fission in the hippocampus in response to insulin resistance (Ruegsegger et al. 2019). High glucose levels and impaired insulin signaling create an energy imbalance, leading to a mismatch between cellular energy production and demand (Chan 2020). This results in an energy deficit and dysregulated mitochondrial dynamics, characterized by reduced expression of fusion proteins and increased fission proteins. While this adaptation increases mitochondrial numbers, it also produces fragmented, dysfunctional mitochondria. Inhibiting excessive mitochondrial fission with Drp1 inhibitors helps restore mitochondrial dynamics and prevents insulin resistance in high-fat diet-induced mouse models (Filippi et al. 2017). For example, reducing Drp1 activity in primary hippocampal neurons isolated from OB/OB mice improved ATP production associated with obesity-induced deficits (Huang et al. 2015). Treatment with the Drp1 inhibitor mdivi-1 restored hippocampal synaptic plasticity, linking excessive mitochondrial fission to cognitive deficits associated with insulin resistance (Huang et al. 2015).
In the context of insulin resistance, the clearance of damaged mitochondria in insulin-sensitive cells relies on mitophagy. However, persistent mitochondrial damage can lead to sustained activation of the PINK1 (PTEN-induced putative kinase 1) -Parkin pathway, continuously tagging damaged mitochondria for degradation (Li et al. 2022a). This overactivation of mitophagy can decrease mitochondrial quality by failing to effectively remove dysfunctional mitochondria, impairing OXPHOS. Both excessive and impaired mitophagy negatively impact neuronal survival (Tang et al. 2024). Studies show that silencing Parkin or inhibiting PINK1 translation can restore mitochondrial OXPHOS (Liu et al. 2021; Wang et al. 2021a; Huang et al. 2023b). Although most research indicates that neuronal autophagy is inhibited in AD, some studies suggest that low-dose Aβ1-40 triggers mitochondrial quality decline and mitophagy activation, reducing ATP production (Li et al. 2022a). Notably, mitophagy alterations in metabolic diseases may follow a time-dependent pattern, with initial activation followed by later inhibition (Hombrebueno et al. 2019). Considering that Aβ accumulates in autophagosomes of dystrophic neurites and serves as a major intracellular reservoir of toxic peptides in the AD brain, future studies should cautiously interpret these findings (Jin et al. 2017).
Treatment strategies
Currently, treatments for both T2DM and AD are primarily symptomatic and target-specific, presenting significant challenges in disease prevention and control. Moreover, the severe side effects of existing pharmacological treatments have driven scientists to seek alternative therapeutic strategies. It is well established that insulin resistance is a hallmark of T3DM, with overlapping but distinct pathological features connecting diabetes, insulin resistance, and cognitive decline. Studies using AD mouse models demonstrate that improving insulin signaling in the brain can ameliorate disease symptoms. Consequently, various approaches have been explored to address insulin signaling defects in AD, including exogenous insulin supplementation, enhancing insulin sensitivity, improving mitochondrial function to boost OXPHOS, and employing supplementary or alternative interventions. A table has been compiled based on clinical data registered on ClinicalTrials.gov to facilitate an appropriate analysis of treatment strategies for T3DM. Further details can be found in the identifiers listed in the table (Table 1).
Table 1 Clinical trials under recruitment or ongoing were summarized according to different targets
Targeting insulin resistance
Insulin infusion
Although there is a steep gradient between plasma and CSF insulin levels in healthy individuals, the transport of insulin from plasma to CSF is slow (Strubbe et al. 1988; Schwartz et al. 1990; Mazucanti et al. 2019). Even after pharmacological elevation of plasma insulin levels for four hours, CSF insulin concentrations remain below the typical fasting plasma insulin levels (Wallum et al. 1987). This suggests that reversing brain insulin resistance through peripheral insulin supplementation is challenging. While systemic high-dose insulin therapy is a viable clinical option for treating T2DM patients, it is unsuitable for addressing brain insulin resistance in AD patients or individuals without diabetes due to the risk of hypoglycemia (McCall et al. 2023).
Interestingly, limited studies have reported that intravenous insulin infusion, while maintaining plasma glucose at fasting baseline levels, can significantly improve memory in AD patients (Craft et al. 1996). However, increasing peripheral insulin levels has the potential to deplete brain insulin-degrading enzyme, a key enzyme responsible for degrading Aβ in the brain (Qiu and Folstein 2006; Tian et al. 2023). This depletion could negatively impact Aβ degradation, counteracting the intended therapeutic effects. Therefore, supplementing peripheral insulin to enhance brain insulin signaling is not an optimal solution, and increasing brain insulin levels remains a significant challenge. To address this issue, researchers have explored intranasal insulin delivery, which bypasses the blood–brain barrier and directly transports insulin to the brain via the cavernous sinus capillaries into cerebral circulation. Preliminary studies indicate that intranasal insulin delivery holds promise for improving cognitive function and AD biomarkers (Reger et al. 2008; Craft et al. 2012, 2017, 2020). These findings suggest that intranasal insulin could offer a more effective and targeted approach to addressing brain insulin resistance in AD.
Insulin sensitizers
The degree of brain insulin resistance varies significantly among individuals and is challenging to quantify. Merely increasing brain insulin levels may enhance the binding of insulin to its receptor, potentially causing downregulation of available InsR and exacerbating insulin resistance (Bar et al. 1976). As an alternative to intranasal insulin administration, insulin receptor sensitizers can enhance insulin-InsR binding or its downstream effects through various mechanisms (Storozhevykh et al. 2007; Storozheva et al. 2008; Miller et al. 2011). Currently, metformin and thiazolidinediones (TZDs) are considered promising candidates for treating AD and other forms of dementia. A meta-analysis revealed that these insulin sensitizers reduce the combined relative risk of dementia in diabetic patients by 22% during combined therapy. When used as monotherapies, metformin and TZDs independently reduce dementia risk by 21% and 25%, respectively (Basutkar et al. 2023). Additionally, liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has been shown to restore hippocampal insulin responsiveness via the InsR/IRS-1/Akt pathway and improve working memory in APP/PS1 transgenic mice (Talbot and Wang 2014). Although treatment with this drug for six months improved brain glucose uptake in patients, no differences were observed in amyloid plaque deposition or cognitive function compared to the placebo. Currently, liraglutide remains in the preclinical research phase (Gejl et al. 2016).
Targeting metabolic reprogramming
Targeting PDKs
Mounting evidence suggests that energy metabolism alterations associated with neurological disorders play a central role in their molecular neuropathophysiology (An et al. 2018; Mullins et al. 2018; Weise et al. 2018; Kellar and Craft 2020). The functional link between cytosolic glycolysis and mitochondrial OXPHOS places PDC at the core of mitochondrial metabolism. Impaired PDC activity, whether due to natural aging or acquired diseases, exhibits similar pathological patterns, emphasizing PDC and its regulatory kinases as critical therapeutic targets for a range of neurological conditions.
Dichloroacetate (DCA), a pyruvate mimetic compound and specific PDK inhibitor, promotes a metabolic shift from glycolysis to OXPHOS, facilitating pyruvate oxidation within mitochondria (Wang et al. 2021b; Schoenmann et al. 2023). DCA administration has been shown to reduce elevated lactate levels in both serum and CSF (Stacpoole et al. 2003). Furthermore, DCA has been reported to alleviate symptoms such as abdominal pain, headaches, and stroke-like episodes while also improving cognitive function in patients (Saitoh et al. 1998).
In addition to DCA, several other PDK inhibitors have demonstrated the potential to enhance PDC activity and restore ATP levels across various organs. These include SDZ048-619, AZD7545 (a selective PDK2 inhibitor), diisopropylamine dichloroacetate (a PDK4 inhibitor), and phenylbutyrate (Morrell et al. 2003; Ferriero et al. 2013; Yamane et al. 2014). These compounds have been shown to significantly improve PDC activity. Similarly, FX11, a small-molecule inhibitor of LDHA, can pharmacologically inhibit PDK via reducing lactate production, thereby mitigating inflammation and chronic pain driven by diabetic neuropathy (Rahman et al. 2016; Han et al. 2023). These additional PDK inhibitors, along with approaches that reduce lactate accumulation or neutralize its effects, represent promising pharmacological tools. They provide a foundation for further exploration of glucose oxidation stimulation as a therapeutic target for various neurological diseases.
Targeting mitochondria
Mitochondrial OXPHOS enzymes play a pivotal role in metabolic reprogramming by regulating ATP production, ROS signaling, redox balance, and the availability of biosynthetic precursors. By modulating OXPHOS enzyme activity, cells can reconfigure their metabolic pathways to meet physiological demands, adapt to stress, or shift between catabolic and anabolic states. Coenzyme Q10 (CoQ10), a critical component of the ETC, functions as an electron acceptor to promote ATP generation and acts as an antioxidant within the mitochondrial matrix and inner membrane (Wang et al. 2024). Several studies have identified CoQ10 as a potential therapeutic target for AD, stabilizing mitochondria damaged by neurotoxins and oxidative stress, and improving memory and behavioral performance in Tg19959 and APP/PS1 mouse models of AD (Dumont et al. 2011; Muthukumaran et al. 2018). Targeted mitochondrial antioxidants, such as MitoQ, a modified CoQ10 molecule, offer enhanced therapeutic potential. Unlike CoQ10, MitoQ is a smaller molecule with improved cellular uptake and an affinity for negatively charged mitochondria. MitoQ treatment has been shown to prevent cognitive decline and oxidative stress in 3 × Tg AD mice, extend lifespan, improve ETC function, and protect mitochondrial cardiolipin content (McManus et al. 2011; Young and Franklin 2019).
Given that ROS are byproducts of OXPHOS, mitigating ROS accumulation while maintaining ATP production is a critical focus. Alpha-lipoic acid (LA), an essential cofactor for PDC and alpha-ketoglutarate dehydrogenase (α-KGDH), has been shown to enhance mitochondrial function, activate antioxidant responses, reduce ROS generation, and improve insulin sensitivity (Dieter et al. 2022). LA can cross the BBB, reduce Aβ-induced neuronal damage, and induce Akt expression, underscoring its neuroprotective effects mediated partially through PKB/Akt signaling (Della Giustina et al. 2017). Similarly, β-hydroxybutyrate targets mitochondrial complex I to reduce ROS levels, induce ATP production in brain mitochondria and improve memory in AD patients (Tieu et al. 2003; Maalouf et al. 2007).
Polyphenols, a diverse class of plant-derived secondary metabolites with antioxidant properties, are abundant in fruits, vegetables, tea, and red wine. Dietary supplementation with polyphenols or monomeric phenols has been extensively studied for AD prevention and treatment. For example, resveratrol, a polyphenol found in red wine and grapes, and epigallocatechin gallate (EGCG), found in green tea, activate AMPK and Sirtuin 1, which upregulate PGC-1α, the master regulator of mitochondrial biogenesis (Teixeira et al. 2019). This activation promotes new mitochondrial formation and improves cellular energy metabolism. The combination of resveratrol and EGCG has been shown to regulate mitochondrial biogenesis and restore mitochondrial OXPHOS (He et al. 2022; Meng et al. 2023). Furthermore, polyphenols like gallic acid, an LDH inhibitor, have been demonstrated to suppress lactate production by inhibiting pyruvate-to-lactate conversion, thereby enhancing OXPHOS efficiency (Han et al. 2015).
Stem cells and regenerative medicine
Stem cell and regenerative medicine strategies hold promise for metabolic reprogramming in AD through mechanisms such as improving insulin signaling, reducing inflammation, and exerting autocrine/paracrine effects. Brain-derived neurotrophic factor (BDNF), a neurotrophic factor secreted by stem cells, binds to tropomyosin receptor kinase B (TrkB), activating the IRS1/2, PI3K, and Akt pathways (Bathina and Das 2015; Żebrowska et al. 2018). BDNF has been shown to lower blood glucose levels to normal in db/db mice in a dose-dependent manner and increase pancreatic insulin levels (Nonomura et al. 2001). However, the delivery of neurotrophic factors is not the primary benefit of stem cell therapy for neurodegenerative diseases. While neurotrophic factor delivery appears less effective in reversing neurodegeneration, it can enhance the therapeutic efficacy of stem cell transplantation (Duncan and Valenzuela 2017).
A healthy neurovascular system is essential for delivering insulin to brain cells. Stem cells can promote neurovascular repair, facilitating insulin and glucose transport to support metabolic reprogramming in AD (Vargas-Rodríguez et al. 2023). Stem cell therapies have also shown promise in restoring BBB integrity, thereby improving the delivery of insulin and other nutrients to the brain. Additionally, stem cells can transfer healthy mitochondria to the brain (Liu et al. 2023). Studies indicate that mitochondrial transfer not only restores bioenergetics but also reprograms the metabolic state of recipient cells, enabling them to adapt to stress or environmental changes (Brestoff et al. 2021; Korpershoek et al. 2022; Patel et al. 2023). This approach highlights the potential for developing therapeutic strategies targeting mitochondrial dysfunction in disease contexts.
Other therapeutic approaches
Exercise is one of the most potent regulators of peripheral insulin resistance and has emerged as an active area of research for preventing AD and cognitive decline. Physical activity has been shown to reduce the risk of AD (Stephen et al. 2017; Song 2023). Specifically, exercise mitigates cognitive deficits by improving cerebral blood flow and metabolism (Stojanovic et al. 2020). In rodent studies, exercise enhanced brain insulin sensitivity, improved mitochondrial function, reduced oxidative stress, and decreased tau hyperphosphorylation and aggregation in neurons (Jeong et al. 2018; Ruegsegger et al. 2019). Furthermore, a three-month aerobic exercise program was found to promote neurogenesis and cognition in AD patients by increasing brain ketone transport, effectively improving cerebral energy metabolism (Castellano et al. 2017).
Dietary interventions are effective modulators of peripheral insulin resistance and AD. Among the most notable is the DASH diet (Dietary Approaches to Stop Hypertension) (Agarwal et al. 2023). Adhering to the DASH diet has been shown to improve fasting insulin levels, which are associated with better cognitive performance (van den Brink et al. 2019). Additionally, a randomized controlled trial (RCT) demonstrated that cognitively normal adults and individuals with MCI who followed either a high-fat, high-simple carbohydrate diet or a low-saturated fat, low-sugar isocaloric diet for four weeks experienced distinct outcomes (Bayer-Carter et al. 2011). The high-fat, high-sugar diet decreased cerebrospinal fluid insulin concentrations, shifting healthy adults toward patterns commonly observed in AD patients, whereas the low-fat, low-sugar diet increased insulin concentrations in MCI patients to levels comparable to healthy controls.
Moreover, caloric restriction has shown significant benefits for a wide range of chronic conditions, including obesity, T2DM, cardiovascular diseases, cancer, and neurodegenerative brain disorders. A meta-analysis of 12 RCTs involving 545 participants revealed that intermittent fasting significantly reduced body mass index (BMI) and fasting glucose levels (Cho et al. 2019). Animal studies further indicate that intermittent fasting improves memory by enhancing hippocampal insulin signaling and inhibiting Aβ deposition in AD models (Shin et al. 2018). The potential mechanism underlying the benefits of intermittent fasting involves periodic metabolic shifts, wherein the body transitions from hepatic glucose metabolism to fatty acid-derived ketone body production. During fasting, intermediates of the TCA cycle are redirected toward gluconeogenesis—a liver-dominant process for glucose synthesis. As a result, acetyl-CoA accumulates and is diverted into the ketogenesis pathway, producing ketone bodies that are exported from the liver. In the brain, ketone bodies are metabolized to generate acetyl-CoA, which inhibits the PDC, preserving pyruvate. This preserved pyruvate, a key glycolytic intermediate, further suppresses glycolysis, reducing the rate of glucose metabolism. Ketone bodies also modulate the expression and activity of various proteins and molecules crucial for health and aging, including PGC-1α, fibroblast growth factors, NAD+, sirtuins, poly(ADP-ribose) polymerase 1 (PARP1), and ADP-ribosyl cyclase. These factors are closely associated with the pathophysiology of neurodegenerative diseases, highlighting the therapeutic potential of metabolic reprogramming (Puchalska and Crawford 2021).
Conclusions and prospects
As research into metabolic diseases deepens, metabolic reprogramming is no longer confined to oncology. Convincing evidence suggests that abnormal glucose metabolism is a critical component of AD pathology and progression. However, the mechanisms underlying glucose metabolism defects and their detrimental downstream effects on cellular function and survival remain at an early stage of investigation. This review analyzed the molecular links between insulin resistance and AD, explored how insulin resistance drives metabolic reprogramming in neurons, and summarized therapeutic strategies targeting insulin resistance and energy metabolism.
Despite these advances, several key questions remain. First, how does AβO interact with InsR, and how does this affect downstream insulin signaling pathways? Current understanding is limited to clinical observations. Given the small spatial constraints of AβO's tubular binding interface, which offers flexibility for small-molecule interactions, future research should integrate chemical, computational, and biological approaches to address this question. Second, how can brain insulin levels be accurately quantified? Clinical methods currently rely on functional magnetic resonance imaging (fMRI) to measure whole-brain cerebral blood flow (CBF) as a proxy for brain insulin sensitivity (Kullmann et al. 2022; Li et al. 2023a). However, these methods have low temporal resolution and are costly. Identifying specific biomarkers to streamline clinical assessment and improve sensitivity is imperative. Finally, any metabolic reprogramming events in the brain, whether pathological or therapeutic, must be approached with caution. Both neurons and glial cells are metabolically sensitive and may exert beneficial or detrimental effects on AD progression.
In summary, understanding the connections between insulin resistance, metabolic reprogramming, and AD remains a complex challenge. However, these efforts hold significant promise for advancing early diagnosis, effective prevention, and therapeutic interventions for AD.
Data availability
No datasets were generated or analysed during the current study.
Abbreviations
α-KGDH:
Alpha-ketoglutarate dehydrogenase
Aβ:
β-Amyloid
AβOs:
Aβ oligomers
AD:
Alzheimer's disease
AGEs:
Advanced glycation end-products
AMP:
Adenosine monophosphate
AMPK:
AMP-activated protein kinase
APP:
Aβ precursor protein
ATP:
Adenosine triphosphate
Bad:
Bcl-2-associated death promoter
BBB:
Blood–brain barrier
BDNF:
Brain-derived neurotrophic factor
BMI:
Body mass index
CBF:
Cerebral blood flow
CNS:
Central nervous system
CoQ10 :
Coenzyme Q10
CypD:
Cyclophilin D
DASH:
Dietary approaches to stop hypertension
DCA:
Dichloroacetate
Drp1:
Dynamin-related protein 1
EGCG:
Epigallocatechin gallate
EMP:
Embden-Meyerhof-Parnas
ER:
Endoplasmic reticulum
ETC:
Electron transport chain
FDA:
Food and Drug Administration
fMRI:
Functional magnetic resonance imaging
FOXO:
Forkhead box O
GLP-1:
Glucagon-like peptide-1
GREs:
Glucocorticoid response elements
GSK3β:
Glycogen synthase kinase-3β
HIF1α:
Hypoxia-inducible factor-1 alpha
HK:
Hexokinase
HO-1:
Heme oxygenase-1
IL-6:
Interleukin-6
IMM:
Inner mitochondrial membrane
InsR:
Insulin receptor
IRS:
Insulin receptor substrates
JNK:
C-Jun N-terminal kinase
LA:
Alpha-lipoic acid
LDH:
Lactate dehydrogenase
MAM:
Mitochondrial-associated endoplasmic reticulum membranes
MCI:
Mild cognitive impairment
Mfn2:
Mitochondrial fusion protein 2
MQC:
Mitochondrial quality control
mTORC2:
Mammalian target of rapamycin complex 2
NAFLD:
Non-alcoholic fatty liver disease
NMDA:
N-Methyl-d-aspartate
NMDAR:
N-Methyl-d-aspartate receptor
NOD1:
Nucleotide-binding oligomerization domain 1
NRF1/2:
Nuclear respiratory factors 1 and 2
OXPHOS:
Oxidative phosphorylation
PARP1:
Poly(ADP-ribose) polymerase 1
PDC:
Pyruvate dehydrogenase complex
PDK:
Pyruvate dehydrogenase kinase
PDK1:
3-Phosphoinositide-dependent protein kinase 1
PDP:
Pyruvate dehydrogenase phosphatase
PET:
Positron emission tomography
PGC-1α:
Peroxisome proliferator-activated receptor gamma coactivator 1-α
PH:
Pleckstrin homology
PHD:
Prolyl hydroxylase
PI3K:
Phosphoinositide 3-kinase
PINK1:
PTEN-induced putative kinase 1
PIP2:
Phosphatidylinositol-4,5-bisphosphate
PIP3:
Phosphatidylinositol-3,4,5-trisphosphate
PPP:
Pentose phosphate pathway
PTB:
Phosphotyrosine-binding
RAGE:
AGE receptors
RCT:
Randomized controlled trial
ROS:
Reactive oxygen species
SH2:
Src homology 2
T1DM:
Type 1 diabetes mellitus
T2DM:
Type 2 diabetes mellitus
T3DM:
Type 3 diabetes mellitus
TCA:
Tricarboxylic acid
TIM:
Translocase of the inner membrane
TNF-α:
Tumor necrosis factor alpha
TOM:
Translocator of the outer mitochondrial membrane
TrkB:
Tropomyosin receptor kinase B
TSC2:
Tuberous sclerosis complex 2
TZDs:
Thiazolidinediones
UPR:
Unfolded protein response
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摘要
異常的葡萄糖代謝不可避免地破壞正常的神經元功能，這一現象在阿茲海默症（AD）中被廣泛觀察。研究病程中代謝適應的機制，已成為研究的核心焦點。考慮到受損的葡萄糖代謝與胰島素信號降低及胰島素阻抗密切相關，一個新的概念 “第 3 型糖尿病（T3DM）” 被創造出來。T3DM 專指大腦內神經元對胰島素失去反應性，強調糖尿病與 AD 之間的強烈聯繫。近期研究顯示，在腦部胰島素阻抗期間，神經元會表現出線粒體功能障礙、葡萄糖代謝下降與乳酸水準升高。這些發現表明，由 T3DM 所致的胰島素信號受損，可能誘發神經元向醣解作用的代謝補償性轉換。因此，本綜述旨在探討 T3DM 的潛在成因，以及胰島素阻抗如何在 AD 進展過程中驅動神經元代謝重編程。此外，也強調針對胰島素敏感性與線粒體功能的治療策略，是成功開發 AD 治療之有希望途徑。
引言
阿茲海默症（AD）是全球人口老化背景下最緊迫的公共衛生挑戰之一。到 2030 年，AD 患病人數預期將增至 8200 萬人，給全球醫療體系帶來重大負擔。當前有兩種美國 FDA 核准藥物，Lecanemab 和 Donanemab，直接針對去除 β‑澱粉樣蛋白（Aβ）斑塊，並在減緩 AD 認知衰退上顯示出有希望的結果。然而，它們並不能避免不良副作用。即便經過治療，患者仍持續經歷病程進展。這些發現凸顯深入理解 AD 發病機制與尋找潛在治療靶點的重要性。
流行病學與臨床研究資料支持，導致胰島素阻抗的肥胖或糖尿病，是 AD 的顯著風險因素。由於大腦對胰島素高度敏感，外周胰島素阻抗導致中樞神經系統（CNS）中的胰島素信號減弱，進而引發腦部代謝改變。越來越多證據顯示，Aβ 毒性、tau 過度磷酸化、氧化壓力與神經發炎都可歸因於 CNS 胰島素阻抗，從而促進神經退化。鑑於第 1 型糖尿病、第 2 型糖尿病（T2DM）及老年人胰島素阻抗間的分子與細胞特徵具共性，而這些亦與記憶功能受損與認知衰退相關，研究者提出 “第 3 型糖尿病（T3DM）” 這一術語，以強調胰島素在大腦能量供應中的關鍵角色。
大腦是一個高能量需求器官，線粒體透過氧化磷酸化（OXPHOS）提供足夠能量以滿足其需求。葡萄糖是神經元的主要能量來源，可透過醣解與 OXPHOS 產生超過 95% 的三磷酸腺苷（ATP）。雖然僅靠醣解也能產生 ATP，但僅有兩分子 ATP，不足以滿足神經元的能量需求，且此過程會導致活性氧（ROS）積累。因此，任何損害神經元正常 OXPHOS 過程的因子，皆可能引起能量耗竭，進而觸發神經元死亡，最終導致神經退行性疾病的發生。研究指出，在認知受損前，AD 患者腦中神經元的葡萄糖代謝路徑就已發生改變。這意味著，在 AD 的進展過程中，神經元會經歷一個代謝重編程過程，從 OXPHOS 轉向醣解。此外，至少在早發性 AD 患者腦中 ATP 產量下降的比例為 7%，晚發性 AD 為 20%，而進階 AD 為 35%–50%。顯著的是，神經元的能量合成下降發生在認知衰退與 AD 病理特徵出現之前。隨著病程進展，這意味著能量合成功能喪失可能是 AD 的早期典型病理變化之一。然而，由於腦代謝的複雜性，這些發現應謹慎解讀，因為代謝轉換可能隨時間變成不適應性的，並啟動一系列複雜的補償反應，進一步促進 AD 的進展。
鑑於腦部胰島素水準降低或胰島素受體信號缺損與認知功能障礙及神經退化疾病之間的關聯，涉及中樞胰島素信號、葡萄糖利用與神經元能量穩態的機制——尤其是神經元能量代謝的代謝重編程——正成為具潛力的研究與干預方向。在本綜述中，我們探討誘導 T3DM 的潛在機制，以及胰島素阻抗如何驅動神經元代謝重編程，同時總結處理 T3DM 的治療策略。
胰島素阻抗與 AD
AD 是癡呆最常見的成因，佔所有癡呆病例的 60–80%。它是一種以腦中澱粉樣斑塊與 tau 纏結累積為特徵的神經退行性疾病，導致漸進性的認知衰退。作為一種進展性、起始潛伏的神經退行性障礙，AD 正迅速成為全球醫療、社會與經濟的重大負擔。根據 2022 年世界阿茲海默症報告，到 2050 年受 AD 影響的人數預計將超過一億，給全球醫療體系帶來巨大壓力。
已有多種被廣泛接受的假說試圖解釋 AD 的發病機制，包括澱粉樣級聯假說、膽鹼能假說、tau 過度磷酸化假說、神經發炎假說，以及金屬離子調控失衡假說。然而，疾病的精確機制仍不清楚。當前 AD 的治療，如 Donepezil、Rivastigmine、Galantamine 等，是美國 FDA 批准的乙醯膽鹼酯酶抑制劑，用來緩解症狀。2003 年，非競爭性 N‑甲基-d-天冬氨酸（NMDA）受體拮抗劑 Namenda 也獲 FDA 批准。Namzaric（Donepezil + Namenda 組合）於 2014 年獲批。然而，這些治療主要針對記憶喪失與混亂等認知症狀，並不改變疾病進展或處理基本的神經退化過程。近年來，FDA 核准新的 AD 治療方法，包括 Biogen/Esai 所開發的 Aducanumab 和 Lecanemab。然而，Aducanumab 的臨床試驗僅在高劑量組展現效力，而 Lecanemab 有明顯副作用，如與澱粉樣物相關的影像異常（包括腦水腫與腦出血）。雖然這兩款藥物皆旨在清除腦內澱粉樣斑塊，其副作用與臨床效能仍需廣泛監測。鑒於 AD 的複雜性，探索其致病機制與辨識潛在治療靶點至關重要。
腦部能量供應與胰島素阻抗
儘管人類大腦僅佔體重約 2%，但卻消耗約全身總能量需求的 20%。神經元主要依靠氧化代謝，以葡萄糖為主要能量來源並利用 OXPHOS 提供足夠能量以維持突觸傳遞與神經元功能。因而，葡萄糖提供成人大腦所消耗熱量的大部分。大部份葡萄糖被氧化以產生大量 ATP，以維持膜離子梯度與其他與突觸傳導有關的細胞過程。維持葡萄糖穩定需靠荷爾蒙與神經調控，支持大腦與外周組織的正常運作。葡萄糖不僅是神經與非神經細胞的主要能量來源，也是一種信號分子。例如，AMP 活化蛋白激酶（AMPK）對細胞內 AMP/ATP 或 ADP/ATP 比例變化有響應，進而調節 mTORC1 活性。此信號通路協調細胞生長、增殖、代謝與存活與其營養環境。故葡萄糖調控機制對確保足夠供應以滿足中樞與外周代謝需求至關重要。胰島素是調節血糖吸收與促進同化代謝的重要荷爾蒙，有助於肝醣、脂肪、蛋白質的合成。在正常情況下，對胰島素敏感的器官或組織（如大腦、骨骼肌、肝臟、脂肪組織）需較低濃度的內源或外源胰島素即可誘導生理反應。但若存在胰島素阻抗，這些組織需要更高濃度的胰島素才能產生反應。這種情形導致胰島素在葡萄糖攝取與利用上的效率下降，臨床上稱為胰島素阻抗。胰島素阻抗被視為多種現代疾病（包括代謝症候群、非酒精性脂肪肝病（NAFLD）、動脈粥樣硬化、T2DM 及神經退行性疾病）的驅動因素。
胰島素與其信號通路
胰島素在從營養利用向能量儲存轉換中扮演關鍵調控角色。胰島素由胰島 β 細胞合成，用以調節血糖濃度。它由兩條多肽鏈經二硫鍵連接，總共 51 個胺基酸。胰島素通過結合胰島素受體（InsR，一種跨膜糖蛋白受體，由兩個 α 和兩個 β 亞單元組成）發揮作用。此互動啟動下游信號傳導級聯反應（見圖 1）。當胰島素結合 InsR 的 α 亞單元時，引發構象改變，使 β 亞單元在細胞質區域自體磷酸化多個酪氨酸殘基。這些磷酸化殘基被諸如胰島素受體底物（IRS）等適配蛋白的磷酪氨酸結合（PTB）區域辨識。在六種哺乳類 IRS 蛋白（IRS‑1 至 IRS‑6）中，IRS‑1 與 IRS‑2 通常被視為胰島素信號系統的關鍵節點，與胰島素阻抗的發展密切相關。特別是在肥胖、壓力與發炎情境下，在 IRS‑1 上發生廣泛的絲氨酸磷酸化，透過各類激酶介導。
大腦作為一個對胰島素敏感的器官
大腦發展與神經生殖區域的調控在很大程度上依賴胰島素。胰島素透過調控神經幹細胞的增殖、分化與存活促進神經生成。正常的胰島素信號不僅對維持電路調控與突觸可塑性至關重要，也在控制神經與星狀膠質細胞的代謝與線粒體功能中扮演角色。目前已確定大多數組織包括大腦都表達 InsR，對胰島素敏感。有證據表明，InsR 在神經元與膠質細胞中皆有表達，各腦區的表達水準不同。InsR 在下丘腦、海馬、腦皮質與嗅球等與代謝調控與認知功能密切相關區域特別豐富。值得注意的是，神經元與膠質細胞表達不同的 InsR α 亞型。神經元表達 InsR‑A 亞型，而膠質細胞主要表達 InsR‑B 亞型。與 InsR‑B 相比，InsR‑A 對胰島素具有較高的親和力，其受體內吞速率約為 1–2 倍。動物研究顯示，有選擇性破壞神經元 InsR，特別是在下丘腦中，會增加脂肪量與外周胰島素阻抗。相反地，恢復下丘腦的胰島素作用能預防糖尿病。
在正常生理條件下，胰島素可透過受體介導的轉運機制穿過血腦障壁（BBB），此轉運速率可被肥胖、發炎與 AD 等因素調控。使用內皮細胞特異性 InsR 敲除小鼠的研究證實，內皮 InsR 對胰島素穿越 BBB 以及在海馬、下丘腦與前額葉皮質的下游胰島素信號至關重要。此外，也有證據指出大腦可獨立產生胰島素。胰島素前體在胰腺合成，於內質網中由特定前激素轉化酶切割 C‑肽段，最終形成成熟胰島素。面對血糖升高，β 細胞透過胞吐作用釋放胰島素。人類與兔子擁有單一胰島素編碼基因，而啮齒動物有兩條。其中，Ins II 似為在神經元中表達的主要胰島素基因。在培養的兔子神經元與膠質細胞中，僅神經元將胰島素分泌至培養基中。有限證據顯示這些前激素轉化酶均勻分布於大腦各區域。然而，在視上核與室旁核中能處理前胰島素的神經元表達這些酶，部分支持大腦內胰島素產生的概念。
AD 與 T3DM
在過去二十年中，T2DM 已發展成一種複雜、多因子且異質性疾病。全球大約 90–95% 的糖尿病病例屬於 T2DM。臨床上，若存在相對性胰島素缺乏（由於胰腺 β 細胞功能異常）與外周胰島素阻抗，則被診斷為 T2DM。
胰島素信號失調與多種神經系統疾病相關。更重要的是，在 AD 中，腦部的胰島素缺乏與胰島素阻抗分別對應第 1 型糖尿病（T1DM）與 T2DM 的特徵。因此，兩者在 AD 中並存，促使學者將 AD 概念化為一種以大腦為主的糖尿病，即所謂 “T3DM” 。
流行病學資料顯示 T2DM 與 AD 等神經疾病的共病發生率很高。胰島素失調與葡萄糖代謝異常被視為 AD 的風險因素。研究表明，T2DM 使得 AD 的風險增加 50–100%。1990 年代，鹿特丹研究指出，糖尿病者與年齡配對的非糖尿病對照相比，更可能罹患癡呆（比值比 1.9，95% CI 1.2–3.1）。血糖濃度升高不僅增加癡呆風險，也加速輕度認知障礙（MCI）向 AD 的轉變。使用 ^18F‑FDG/CT 的正子發射斷層攝影顯示，MCI 患者的腦部葡萄糖代謝顯著下降，暗示在症狀出現之前便有代謝衰退作為一個潛在病理標誌。
MCI 與全身性代謝功能失調與胰島素阻抗密切相關，包括 T2DM、代謝症候群、多囊卵巢綜合症與 NAFLD。此外，無 T2DM 的個體若有外周胰島素阻抗，也被視為三年內罹患 AD 的風險因素。值得注意的是，腦內胰島素阻抗可能獨立於 T2DM 而發生，可能促進或甚至觸發 AD 的關鍵病理事件，如 β‑澱粉樣斑塊形成與 tau 磷酸化。這一發現與 AD 患者腦中胰島素信號分子水準的變化一致，也與在此類病例中經鼻胰島素施用改善記憶的觀察相呼應。最後，胰島素阻抗是 AD 的常見特徵，與澱粉樣斑塊負荷增加、海馬體積減少、認知功能下降及皮質葡萄糖代謝下降相關，均與記憶回想能力下降相關。總而言之，胰島素信號缺陷與全身性胰島素阻抗可能在 AD 的發病中扮演重要角色。
導致 T3DM 的潛在機制
Aβ 是一種被認為是 AD 標誌性與 T3DM 啟動因子的內源性神經毒物。結構上，Aβ 具有親水性 N 端與疏水性 C 端。因此，Aβ 片段的釋放最初使得 Aβ 單體自發聚合為可溶性 Aβ 寡聚體（AβOs），隨後聚合為不可溶的原纖維，再進一步聚集形成澱粉樣斑塊，也稱為老年斑。與 Aβ 單體與原纖維相比，AβOs 的桶狀結構對細胞膜具有較高親和力，使其更容易與各種膜受體相互作用，其中以 InsR 和 NMDAR 最為突出。除與膜受體結合外，AβOs 還可通過破壞線粒體功能來誘導胰島素阻抗。
膜受體影響
首先，AβOs 與胰島素競爭結合 InsR，導致 InsR 內吞並使細胞膜上 InsR 的親和力與數量減少，從而阻礙胰島素信號。這種受阻主要指受體親和力與數目下降，或受體結構異常妨礙胰島素–受體結合。通常，胰島素活化 InsR 酪氨酸激酶，進而聚合並磷酸化各種底物接駁蛋白，如 IRS 蛋白家族成員。在四種哺乳類 IRS 蛋白中，IRS‑1 與 IRS‑2 被視為胰島素信號系統的關鍵節點，其功能異常與胰島素阻抗密切相關。機理上，下游結合核苷酸結合寡聚化區域 1（NOD1）效應子與胰島素受體通路的交互可能透過削弱 IRS 功能來抑制胰島素信號。事實上，儘管 T2DM 模型中 InsR 水準下降約 90%，但 InsR 與下游信號缺陷二者皆與胰島素阻抗發展有關。
證據顯示，將原代海馬神經元暴露於 AβOs in vitro，可誘發失去胰島素敏感性、IRS‑1 抑制性磷酸化，以及使樹突膜上的 InsR 表達下降。APP/PS1 小鼠也在海馬區展現胰島素信號受損，表現為 IRS‑1 在絲氨酸 616 位點的磷酸化上升。IRS‑1 在關鍵絲／蘇氨酸殘基上的異常磷酸化會加速磷酸化後 IRS‑1 蛋白的降解，從而減弱胰島素信號強度。IRS‑1 的異常磷酸化導致胰島素結合 InsR 的敏感性下降，並使部分 IRS‑1 從膜轉移至細胞質，這是胰島素阻抗的主要分子基礎。機理上，AβOs 可透過異常激活 TNF‑α / JNK 通路誘導 IRS‑1 的絲氨酸磷酸化並誘發線粒體氧化壓力。類似地，TNF‑α / JNK 通路在 T2DM 中也被激活，促進外周胰島素阻抗、β 細胞凋亡與氧化壓力增加。
此外，AβOs 可導致 NMDAR 的異常活化。在 AD 中，AβOs 誘導的抑制胰島素受體信號作用可透過 memantine 阻斷。生理情況下，突觸 NMDAR 活性通過抑制 FOXO1 在海馬區發揮抗氧化作用。然而在 AD 中，功能異常的 NMDAR 活性與胰島素阻抗可能導致 FOXO1 核轉位，最終增加 ROS 生成。這可能進一步惡化胰島素信號受損與神經元功能障礙。另一種可能性是，AβOs 觸發過量 NMDAR 活化與 Ca²⁺ 流入，使 IRS‑1 上的酪氨酸磷酸酶活性上升，從而削弱胰島素信號。這些可能性與上述 IR 調控機制一致，並提示神經元活動異常與胰島素信號間存在潛在生理反饋迴路。
線粒體功能
AβOs 可通過外線粒體膜跨運子（TOM）與內膜跨運子（TIM）特異性轉運，或透過線粒體相關內質網膜（MAM）進入線粒體，從而破壞線粒體功能並促進 T3DM 的發生。實際上，Aβ 前驅體蛋白（APP）與 Aβ 已被證明與線粒體共定位，甚至在富含脂筏的 MAM 區域生成。此外，線粒體功能障礙能透過過量產生 ROS 部分誘導胰島素阻抗。在此情況下，胰島素阻抗被認為源於線粒體生成過多燃料（如 NADH、FADH₂），而能量需求並未相應增加，導致線粒體釋放 H₂O₂。
線粒體脊狀結構受損與 ROS 產生
線粒體脊狀結構是內線粒體膜的皺褶。電子傳遞鏈（ETC）複合體嵌入於內膜，將脊狀結構形態與線粒體功能聯繫起來。電子顯微鏡顯示，AβOs 對鼠類 N2a 細胞造成嚴重的線粒體脊狀結構破壞。相符的，死後報告指出 AD 患者神經元線粒體的脊狀結構破壞率顯著上升。脊狀結構增加了內膜的表面積，有利於更有效的有氧代謝。然而，脊狀受損削弱 ETC 複合體的完整性，損害電子傳遞與質子轉運。這導致電子與質子的外洩、ATP 生成下降與 ROS 增加。一方面，ROS 可透過直接作用於涉及葡萄糖攝取的蛋白，誘導胰島素阻抗。細胞氧化還原狀態偏向氧化，降低絲／蘇氨酸磷酸酶整體活性，強化對壓力敏感的絲／蘇氨酸激酶活性，從而抑制胰島素信號，促進胰島素阻抗。另一方面，線粒體 ROS 可活化發炎體，引發發炎反應級聯。許多被發炎活化的信號通路涉及絲／蘇氨酸激酶，如 JNK，可損害胰島素信號。然而，線粒體在炎症中的精確調控作用仍未明確，但它提供了一個潛在機制，說明線粒體功能障礙如何影響胰島素作用。
線粒體動態
線粒體動態對維護線粒體健康、生物能功能、品質控制與細胞活力極為關鍵。在生理條件下，線粒體持續進行分裂（fission）與融合（fusion），結果導致形態變化，有助於維持整體線粒體網絡穩定。Aβ 產生增加與 AβOs 與動態相關蛋白 1（Drp1）的相互作用，是線粒體碎裂、動態異常與突觸損傷的關鍵因素。此外，AβOs 可直接透過 Akt 活化誘導 Drp1 在 Ser616 位置的磷酸化，促進線粒體碎裂並引發下游事件，包括 ROS 產生。
在高脂飲食之老鼠模型中，肝臟的線粒體融合蛋白 2（Mfn2）表達下降，伴隨胰島素信號受損。相比之下，Mfn2 過度表達可補償高脂飲食誘導的胰島素信號破壞。肝臟特異性 Mfn2 敲除小鼠出現胰島素敏感性下降，且伴隨更強的線粒體分裂。在骨骼肌中，線粒體分裂增加亦與脂肪誘導的胰島素阻抗相關。事實上，在肥胖與 T2DM 中，肌肉中線粒體尺寸與 Mfn2 表達下降，並與胰島素敏感性受損相關。這些結果皆支持線粒體動態破壞在胰島素阻抗與 T2DM 中扮演關鍵角色。
線粒體—內質網（ER）應激耦合
MAM 是內質網與線粒體交互的專門亞細胞區域，促進 Ca²⁺、脂質與代謝物在二者間的有效交換，以維持細胞代謝與完整性。這些區域具脂筏特性，有利於 APP 的 γ‑分泌酶活性強化，凸顯 MAM 作為 Aβ 生成靠近線粒體的潛在位置。Tubbs 等人在 OB/OB 小鼠與飲食誘導胰島素阻抗模型中顯示，MAM 的完整性對胰島素信號至關重要。他們顯示，基因或藥理學抑制環孢素 D（CypD）會破壞肝細胞中 MAM 的完整性，進而改變胰島素信號。相反地，過度表達 CypD 可增強 MAM 的完整性並改善糖尿病鼠肝細胞的胰島素信號。Shinijo 等人發現，用棕櫚酸處理的 HepG2 細胞，其 ER 向線粒體的 Ca²⁺ 傳輸顯著下降，ACSL4（一種 MAM 標記）水準下降，暗示 MAM 破壞在線粒體阻抗中扮演重要角色。此外，過度表達 Mfn2 部分恢復 MAM 接觸位點並改善棕櫚酸誘導的胰島素阻抗，促進 Akt Ser473 磷酸化。這些結果凸顯線粒體融合/分裂過程與 ER 間互動在調控胰島素阻抗中的可能作用。
神經元代謝重編程
代謝重編程指細胞為適應生理或病理需求變化而調整其能量產生路徑的過程。這一概念在癌症生物學中尤為重要，如所謂的 Warburg 效應：癌細胞即便在氧氣充足下，也主要依賴有氧醣解而非更有效率的 OXPHOS。隨著我們對腫瘤及幹細胞代謝理解的進步，代謝重編程已不再僅僅等同於 Warburg 效應，而是泛指任何細胞代謝機制的變化。
在神經元中，葡萄糖透過醣解或戊聚糖磷酸途徑（PPP）代謝，隨後進入 TCA 循環與 OXPHOS，生成水、二氧化碳與 ATP。丙酮酸脫氫酶複合體（PDC）在醣解與 TCA 間的交叉點扮演關鍵角色，控制來自碳水化合物的碳是否進入線粒體。此外，PDC 受兩種主要酶調控：丙酮酸脫氫酶激酶（PDK）與丙酮酸脫氫酶磷酸酶（PDP）。這些酶調控 PDC 活性，透過對 E1α 亞單元上 Ser293、300、232 的磷酸化（抑制）與去磷酸化（活化）來控制。
神經元主要利用葡萄糖作為能量來源，透過持續醣解與與 OXPHOS 關聯之 TCA 循環幾乎完全氧化。然而，在某些條件下（如低血糖），神經元可代謝穀氨酸與谷氨醯胺以產生能量。目前對於神經元在胰島素阻抗期間的代謝變化研究相對較少。
胰島素阻抗與代謝重編程
臨床上，代謝症候群是一種由多種代謝異常聚集而成的病理狀態，其根本原因為胰島素阻抗，表現為葡萄糖利用效率下降。胰島素阻抗導致能量代謝補償性轉換，總稱為代謝重編程，突顯胰島素阻抗與能量代謝之緊密聯繫。代謝組學資料顯示，相對於對照組，T2DM 患者血清中有較高的丙酮酸、乳酸與檸檬酸水準，提示醣解作用增強與 TCA 迴路功能受擾。類似地，Sas 等人發現 T2DM 患者尿液中醣解產物（如乳酸、磷酸烯醇丙酮酸、2,3-二磷酸甘油酸與甘油醛-3-磷酸）濃度顯著升高，同時 TCA 迴路中間體如丙酮酸、檸檬酸、琥珀酸、延胡索酸與蘋果酸亦升高。然而，隨著疾病進展，這些水準逐漸下降。此外，腦脊髓液（CSF）分析顯示 T2DM 患者有獨特的代謝異常，包括丙氨酸、亮氨酸、纈氨酸、酪氨酸、乳酸與丙酮酸水準升高，而組氨酸水準降低。這些發現突顯胰島素阻抗相關的代謝失調。以下綜述幾種可能機制，說明胰島素阻抗誘導代謝重編程（見圖 4）。
潛在機制：胰島素阻抗與 PDK 活化
PDKs 抑制 PDC 活性，從而調控代謝路徑。在四種 PDK 同工酶中，PDK4 的激酶活性最高。糖尿病中 PDC 調控異常涉及 PDK2 與 PDK4 兩者。這兩者在 T2DM 患者與高脂飲食動物模型中顯著上調。藥理抑制 PDK4（如二氯乙酸）已被證明可改善高血糖。與脂肪酸為能量來源的狀態（如糖尿病、飢餓）也上調 PDK4 表達。轉錄組學與單細胞測序資料顯示，Pdk4 在 AD 模型與 AD 患者腦中上調，是 T2DM 與 AD 之間的潛在共享基因。
胰島素通過下游靶點如 FOXO 與 PGC‑1α 調控 PDK2 與 PDK4 表達。研究表明，在高脂飲食小鼠中，胰島素阻抗激活 PGC‑1α 與 ERRα，這二者結合至 PDK4 啟動子，提高其 mRNA 與蛋白表達。此外，胰島素也透過 PI3K/Akt 路徑抑制 PDK2 與 PDK4 表達，該途徑通過磷酸化 FOXO 來實現。進一步研究表明，胰島素通過下調三個啟動子元件（含糖皮質激素反應元件、FOXO1 結合位點與 ERR 元件）來減少 PDK4 基因表達。其他調控 PDK 表達者包括生長激素、脂聯素、腎上腺素與羅格列酮，在組織特異性上具有差異效應。PDK4 是 PDC 活性、丙酮酸氧化與葡萄糖穩態的重要調控因子。PDK4 敲除模型顯示血糖、肝臟糖質新生降低。在飢餓與糖尿病狀態下，PDK4 在主要組織中普遍上調，以響應胰島素缺乏與皮質激素、自由脂肪酸增加。然而，目前將 PDK4 直接與 AD 聯繫的實驗證據仍然有限。
ROS 誘導的代謝重編程
在胰島素阻抗中，葡萄糖利用效率降低與氧化損傷密切相關。胰島素阻抗通過多種機制促進氧化壓力，包括晚期糖基化終產物（AGEs）、內質網應激與發炎。過量的 ROS 生成損害線粒體功能，抑制 OXPHOS 活性，同時加劇胰島素阻抗，形成惡性循環。
胰島素阻抗透過以下途徑促進 ROS 生成：高血糖誘導非酵素性蛋白與脂質糖化產生 AGEs，AGEs 與受體（RAGE）交互刺激氧化壓力。此外，胰島素阻抗常伴隨內質網應激，表現為蛋白折疊異常。這激活未折疊蛋白反應（UPR），通過 JNK 通路促進 ROS 生成。慢性低度發炎進一步升高 ROS，因為發炎細胞因子如 TNF‑α、IL‑6 可透過激活絲／蘇氨酸激酶（使 IRS 磷酸化）損害胰島素信號，並吸引巨噬細胞至脂肪組織局部，放大區域 ROS 水準。
此外，ROS 作為分子信號可促進從 OXPHOS 向醣解的轉變，經由穩定低氧誘導因子‑1α（HIF1α）來實現。HIF1α 驅動無氧醣解並抑制 OXPHOS。羥脯氨酶（PHD）是對氧化壓力敏感的 HIF‑1α 抑制因子。在常氧條件下，PHD 可使 HIF‑1α 的脯氨酸與天冬氨酸殘基水解氧化而降解。然而，過量 ROS 可使 PHD 失活（透過氧化性二聚化），從而在常氧條件下穩定 HIF‑1α。這導致細胞從 OXPHOS 向無氧醣解轉變。結果是乳酸積累，丙酮酸與 ATP 生成顯著下降。一方面，丙酮酸供給不足破壞 TCA 迴路恆定；另一方面，這種轉變導致能量耗竭，損害細胞存活能力，尤其是對高能量需求的細胞。
過量 ROS 也可氧化修飾醣解與 OXPHOS 關鍵酶。對 AD 腦組織的氧化還原蛋白質體學分析顯示，醣解酶（如醛縮酶、三磷酸異構酶、甘油醛‑3‑磷酸脫氫酶、磷酸甘油酸變位酶 1、α‑烯醇酶）在受影響腦區被氧化修飾。此外，在 MCI 與 AD 患者腦線粒體中，也觀察到 TCA 循環中的琥珀酸脫氫酶、肌酸激酶與 ATP 合成酶的氧化損傷。再者，線粒體 DNA 的氧化損傷可能降低能量生成，研究指出 Sirtuin 3 的缺陷可加劇 AD 線粒體的氧化損傷。實際上，線粒體功能障礙與胰島素阻抗密切相關。
胰島素阻抗與線粒體品質下降
線粒體品質控制（MQC）指維持線粒體在細胞內完整性、功能性與數量的過程。一方面，線粒體品質下降與丙酮酸向線粒體的運輸受損有關，削弱 TCA 循環；另一方面，在線粒體 ATP 生成不足的情況下，呈現胰島素阻抗的細胞常轉向醣解作為替代能源。MQC 的關鍵組成包括線粒體生合成、分裂、融合與自噬。
胰島素信號已知涉及 Akt 的活化，進而導致 mTORC1 的組裝。mTORC1 在調控蛋白質、脂質與脂肪酸合成，以及線粒體代謝方面扮演關鍵角色。透過其對 PGC‑1α 與核呼吸因子 1 和 2（NRF1/2）的調控，mTORC1 對線粒體氧化代謝與生合成至關重要。當胰島素活化 mTORC1 時，mTORC1 刺激核編碼的線粒體蛋白生成，將其整合至 TCA 循環、脂肪酸 β 氧化與電子運輸鏈等代謝途徑中。
另一個複合體 mTORC2 也涉及 mTOR，且介導 Akt 的活化，負調控 FoxO1。FoxO1 促進血氧合酶‑1（HO‑1）的轉錄，在神經元中觸發能量代謝從 OXPHOS 向醣解轉變。當 MQC 下降時，細胞經歷假性缺氧狀態，儘管氧氣充足但低氧利用率，這會活化 HIF1α。FoxO1 與 HIF‑1α 形成調控迴路，上調醣解相關酵素如己糖激酶（HK）、磷酸果糖激酶與丙酮激酶，從而提升醣解代謝。此外，HIF‑1α 促進乳酸脫氫酶（LDH）表達，將丙酮酸轉為乳酸，使即使在線粒體氧化能力下降時仍可進行醣解。
MQC 下降減少可用於 OXPHOS 的功能性線粒體數量，削弱細胞氧化葡萄糖以生成 ATP 的能力。隨著線粒體 ATP 輸出降低，細胞的 AMP/ATP 比率上升，激活 AMPK。AMPK 促進醣解、抑制合成代謝（如蛋白質合成），並增強分解代謝途徑（包括自噬與線粒體自噬）。這些過程可進一步減少線粒體含量，同時透過促進葡萄糖攝取與醣解通量來暫時補償能量赤字，卻也強化向醣解的代謝轉換。此外，AMPK 還促進線粒體分裂，干擾線粒體動態。有研究指出，在胰島素阻抗反應中，海馬內線粒體分裂增加。高血糖水平與胰島素信號受損造成能量失衡，導致能量生產與需求不匹配。這引發能量赤字與線粒體動態失調，特徵為融合蛋白表達下降與分裂蛋白上升。雖然這種適應可增加線粒體數量，但也導致線粒體破碎、功能障礙。在高脂飲食誘導小鼠模型中，抑制 Drp1 過度活性可協助恢復線粒體動態並防止胰島素阻抗。例如，在 OB/OB 小鼠分離出的原代海馬神經元中，減少 Drp1 活性可改善與肥胖誘導缺陷相關的 ATP 生成。使用 Drp1 抑制劑 mdivi‑1 處理恢復海馬突觸可塑性，連結過度線粒體分裂與與胰島素阻抗相關的認知缺陷。
在胰島素阻抗情境中，對受損線粒體的清除（線粒體自噬）對胰島素敏感細胞至關重要。然而，持續的線粒體損傷可導致 PINK1 (PTEN-inducible kinase 1)‑Parkin 路徑持續活化，持續標記受損線粒體進行降解。這種過度活化的自噬可能降低線粒體品質，因為難以有效地清除功能不佳線粒體，抑制 OXPHOS。過度與不足的自噬皆對神經元存活不利。研究顯示，沉默 Parkin 或抑制 PINK1 翻譯可恢復線粒體 OXPHOS。儘管大多數研究指出 AD 中神經元自噬受抑制，但部分研究表明低劑量 Aβ₁₋₄₀ 會觸發線粒體品質下降與自噬活化，使 ATP 生成下降。值得注意的是，代謝疾病中線粒體自噬的變化可能具有時間依賴性，可能早期被激活而後期受抑制。考慮到 Aβ 在退化神經纖維的自噬體中積累，作為 AD 腦內毒性肽的主要細胞內庫存，未來研究應謹慎解讀這些發現。
治療策略
目前，T2DM 與 AD 的治療主要是對症與靶向特定途徑，對疾病預防與控制面臨重大挑戰。此外，現有藥物治療的嚴重副作用促使科學家尋求替代療法。眾所周知，胰島素阻抗是 T3DM 的典型特徵，其與糖尿病、胰島素阻抗與認知衰退之間具有重疊但又獨特的病理特徵。利用 AD 小鼠模型的研究表明，改善腦部胰島素信號能緩解疾病症狀。因此，已有多種方法被探討用以處理 AD 中的胰島素信號缺陷，包括外源性胰島素補充、提升胰島素敏感性、改善線粒體功能以增強 OXPHOS、以及採用補充性或替代性干預方案。基於 ClinicalTrials.gov 的臨床資料彙整一表，以利對 T3DM 的治療策略進行恰當分析（見表 1）。
針對胰島素阻抗
胰島素輸注
雖然健康個體的血漿與腦脊髓液（CSF）胰島素水平存在陡坡差，但從血漿到 CSF 的胰島素運輸速度緩慢。即便藥理性地在四小時內提高血漿胰島素水平，CSF 胰島素濃度仍低於典型空腹血漿胰島素水平。這表明，透過外周胰島素補充逆轉腦部胰島素阻抗具有挑戰性。雖然系統性高劑量胰島素療法是治療 T2DM 的可行臨床方案，但對於處理 AD 患者或非糖尿病者的腦部胰島素阻抗則不適合，因低血糖風險太高。
有趣的是，少量研究報告指出，在保持血漿葡萄糖於空腹基線水平下，靜脈胰島素輸注可顯著改善 AD 患者記憶。然而，提高外周胰島素的水平可能消耗腦內胰島素降解酶（胰島素降解酶為分解腦內 Aβ 的關鍵酶），這可能對 Aβ 降解產生負面影響，抵消預期療效。因此，補充外周胰島素以促進腦部胰島素信號並不是理想方案。為了解決這一問題，研究者探討經鼻胰島素給藥，該途徑可繞過血腦障壁，透過海綿竇毛細血管進入腦循環。初步研究顯示，經鼻胰島素可能有助於改善認知功能與 AD 生物標誌物。
胰島素增敏劑
腦部胰島素阻抗的程度因人而異，難以量化。單純提高腦部胰島素水準可能強化胰島素與其受體結合，卻可能導致 InsR 下調並加重胰島素阻抗。作為經鼻胰島素的替代方案，胰島素受體增敏劑可透過各種機制增強胰島素—InsR 結合或其下游作用。目前，二甲雙胍與噻唑烷二酮（TZDs）被視為治療 AD 與其他型態癡呆症的有希望候選者。一項薈萃分析指出，這些胰島素增敏劑在糖尿病患者中可將癡呆的合併相對風險降低 22%。作為單一療法時，二甲雙胍與 TZDs 分別可降低癡呆風險 21% 與 25%。此外，GLP‑1 受體激動劑 liraglutide 已被證明可透過 InsR/IRS‑1/Akt 路徑恢復海馬胰島素反應性，改善 APP/PS1 轉殖小鼠的工作記憶。雖然該藥物在六個月治療中改善了腦部葡萄糖攝取，但在淀粉斑塊沉積或認知功能方面未見與安慰劑組的差異。目前，liraglutide 仍處於臨床前研究階段。
針對代謝重編程
靶向 PDK
越來越多證據表明，與神經疾病相關的能量代謝改變在其分子病理生理機制中扮演核心角色。細胞質醣解與線粒體 OXPHOS 之間的功能聯繫將 PDC 置於線粒體代謝核心。無論因自然老化或後天疾病，PDC 活性受損皆呈現類似病理模式，凸顯 PDC 與其調控激酶作為神經疾病的關鍵治療靶點。
二氯乙酸（DCA）為一種丙酮酸類似物與特定 PDK 抑制劑，可促進代謝從醣解向 OXPHOS 轉變，促進線粒體中丙酮酸氧化。DCA 投與已被證明可降低血清與 CSF 中升高的乳酸水準。此外，DCA 被報導可緩解腹痛、頭痛與類似中風症狀，並改善認知功能。
除了 DCA，其他若干 PDK 抑制劑已顯示可提高 PDC 活性並恢復 ATP 水準，包括 SDZ048‑619、AZD7545（選擇性 PDK2 抑制劑）、二異丙胺二氯乙酸（PDK4 抑制劑）與苯丁酸。這些化合物顯著改善 PDC 活性。同樣，LDHA 小分子抑制劑 FX11 可透過減少乳酸生成來間接抑制 PDK，從而緩解因糖尿病神經病變誘發的發炎與慢性疼痛。這些 PDK 抑制劑與降低乳酸積累或中和其效應的方法，提供了探索促進葡萄糖氧化作為神經疾病治療靶點的基礎。
靶向線粒體
線粒體 OXPHOS 酶在代謝重編程中扮演關鍵角色，因其可調控 ATP 生成、ROS 信號、氧化還原平衡與生合成前體的可得性。透過調控 OXPHOS 酶活性，細胞可重構其代謝途徑以應對生理需求、適應壓力或在異常狀態下在分解與合成間切換。輔酶 Q10（CoQ10）為 ETC 的關鍵構件，在促進 ATP 生成的同時充當線粒體抗氧化劑。多項研究將 CoQ10 視為 AD 的潛在治療靶點，可穩定因神經毒素與氧化壓力受損的線粒體，並在 Tg19959 與 APP/PS1 小鼠中改善記憶與行為表現。改良型線粒體抗氧化劑 MitoQ 擁有改善的細胞攝取性與對負電荷線粒體的親和力。MitoQ 處理已被證明可防止 3×Tg AD 小鼠的認知衰退與氧化壓力，延長壽命、改善 ETC 功能並保護線粒體心磷脂含量。
由於 ROS 是 OXPHOS 的副產物，減少 ROS 積累同時維持 ATP 生成是研究重點。 α‑硫辛酸（LA）為 PDC 與 α‑酮戊二酸脫氫酶（α‑KGDH）的必需輔酶，已被證明可增強線粒體功能、活化抗氧化反應、減少 ROS 生成並改善胰島素敏感性。LA 可穿越血腦障壁，減輕 Aβ 誘導之神經元損傷，並誘導 Akt 表達，其神經保護效應部分透過 PKB/Akt 信號途徑介導。同樣地，β‑羥丁酸作用於線粒體複合體 I，降低 ROS 水準、誘導腦線粒體 ATP 生成並改善 AD 患者記憶。
多酚類植物次級代謝物具有抗氧化特性，存在於水果、蔬菜、茶與紅酒中。多酚或單體酚補充在 AD 預防與治療中被廣泛研究。例如，白藜蘆醇（存在於紅酒與葡萄中）與表沒食子兒茶素沒食子酸酯（EGCG，存在於綠茶）可活化 AMPK 與 Sirtuin 1，進而上調 PGC‑1α（線粒體生合成主調控因子）。這種活化促進新的線粒體生成並改善細胞能量代謝。白藜蘆醇與 EGCG 的組合被證明可調節線粒體生合成並恢復 OXPHOS 功能。此外，如沒食子酸（抑制 LDH）等多酚，可透過抑制丙酮酸向乳酸轉換來抑制乳酸生成，從而提升 OXPHOS 效率。
幹細胞與再生醫學
幹細胞與再生醫學策略透過改善胰島素信號、減少發炎、發揮自分泌/旁分泌效應，有望在 AD 中促進代謝重編程。腦源性神經營養因子（BDNF），作為幹細胞分泌的神經營養因子，結合 TrkB 受體，活化 IRS1/2、PI3K 與 Akt 通路。BDNF 已被證明在 db/db 小鼠中以劑量依賴方式降低血糖並提升胰島 β 細胞胰島素水準。然而，神經營養因子遞送並非神經退化疾病中幹細胞療法的主要益處。雖然神經營養因子遞送在逆轉神經退化方面效果有限，但可提升幹細胞移植的治療效果。
健康的腦血管系統對將胰島素運送至腦細胞至關重要。幹細胞可促進神經血管修復，改善胰島素與葡萄糖的輸送，以支持 AD 中的代謝重編程。幹細胞亦可向大腦轉移健康線粒體。研究顯示，線粒體轉移不僅恢復生物能狀態，也能重編程受體細胞的代謝狀態，使其能適應壓力或環境變化。這一方法凸顯針對線粒體功能障礙的治療策略在疾病背景中的潛力。
其他治療途徑
運動是調控外周胰島素阻抗的最強效工具之一，近年來成為預防 AD 與認知衰退的研究熱點。體力活動已被證明可降低 AD 風險。動物研究指出，運動可改善腦部胰島素敏感性、改善線粒體功能、降低氧化壓力並減少神經元 tau 過度磷酸化與聚集。此外，為期三個月的有氧運動計畫被發現可透過提升腦部酮體運輸來促進神經生成與認知功能，以有效改善腦能量代謝。
飲食干預是調節外周胰島素阻抗與 AD 的有效方式。其中最具代表性的是 DASH 飲食（Dietary Approaches to Stop Hypertension）。遵循 DASH 飲食已被證明可改善空腹胰島素水準，與較佳認知表現相關。此外，一項隨機對照試驗指出，認知正常成人與 MCI 個體若遵循高脂、高單醣飲食或低飽和脂肪、低糖等熱量等值飲食四週，結果不同。高脂高糖飲食使健康成人 CSF 胰島素濃度下降，使其向 AD 患者常見模式轉變；而低脂低糖飲食使 MCI 患者胰島素濃度提升至與健康對照組相當水準。
此外，熱量限制對包括肥胖、T2DM、心血管疾病、癌症與神經退化性腦病在內的多種慢性病有顯著益處。一項含 545 名參與者、12 項 RCT 的薈萃分析指出，間歇性禁食可顯著降低 BMI 與空腹葡萄糖水平。動物研究進一步指出，間歇性禁食可透過提升海馬胰島素信號與抑制 Aβ 沉積改善記憶。其潛在機制涉及週期性代謝轉換，當禁食時，身體從肝臟葡萄糖代謝轉向脂肪酸衍生酮體生成。肝臟葡萄生成過程中，TCA 中間體被重導向糖質新生。因而，乙酰 CoA 積累並被導入酮體生成路徑。這些酮體輸出肝外，在腦中被代謝為乙酰 CoA，抑制 PDC，保留丙酮酸作為關鍵醣解中間體，進一步抑制醣解速率，減少葡萄糖代謝。酮體也可調控多種與健康與老化相關的蛋白與分子（如 PGC‑1α、纖維母細胞生長因子、NAD⁺、sirtuins、PARP1、ADP-核糖環化酶），這些因子與神經退化疾病病理密切相關，突顯代謝重編程的治療潛力。
結論與展望
隨著代謝疾病研究深入，代謝重編程已不再侷限於腫瘤領域。令人信服的證據指出，異常葡萄糖代謝是 AD 病理與進展的關鍵組分。然而，葡萄糖代謝缺陷的機制，以及其對細胞功能與存活的下游不良影響尚處於早期階段。本綜述分析了胰島素阻抗與 AD 的分子連結，探討胰島素阻抗如何驅動神經元的代謝重編程，並總結針對胰島素阻抗與能量代謝的治療策略。
儘管已有進展，幾個關鍵問題仍待解決。首先，AβO 如何與 InsR 相互作用？這如何影響下游胰島素信號？目前的理解僅限於臨床觀察。由於 AβO 的管狀結合界面空間受限，具靈活性的小分子干預具有潛力，未來研究應整合化學、計算與生物學方法來探討。第二，如何準確量化腦部胰島素水準？現有臨床方法主要依靠功能性磁共振成像（fMRI）測定全腦腦血流（CBF）作為腦部胰島素敏感性的代理，但其時間解析度低且成本高。識別特定生物標誌物以簡化臨床評估並提升敏感性刻不容緩。最後，任何在大腦中的代謝重編程事件（病理或療法誘導）必須小心進行。神經元與膠質細胞對代謝極為敏感，可能對 AD 進展產生有益或有害效果。
總之，理解胰島素阻抗、代謝重編程與 AD 之間的連結仍是一項複雜挑戰，但這些努力對於推動早期診斷、有效預防與治療干預具有重大前景。
二、SEO 最佳化文章（以上譯文為基礎）
Meta Title（網頁標題建議）
第 3 型糖尿病與腦神經元代謝重編程：機制、成因與治療策略
Meta Description（網頁描述建議）
探討 T3DM（第 3 型糖尿病）如何在腦部造成胰島素阻抗與線粒體功能失調，進而誘發神經元代謝重編程，並彙整對應的潛在治療策略，如經鼻胰島素、PDK 抑制劑與線粒體保護劑。
正文架構（四大章節）
H2: T3DM（第 3 型糖尿病）與阿茲海默症的關聯
介紹胰島素阻抗不僅限於外周，而可發生於大腦神經元內，稱為 T3DM
描述 AD 患者常見之腦部胰島素信號缺陷、葡萄糖代謝衰退等典型現象
論述 T2DM、肥胖與 AD 間的流行病學關聯與共同病理脈絡
H2: 胰島素受體受損與線粒體功能失調的機制
Aβ 寡聚體（AβOs）如何競爭結合 InsR、導致受體內吞與 IRS‑1 串聯磷酸化
AβOs 對 NMDAR、鈣離子過度流入、FOX O1 轉位與氧化壓力的影響
線粒體脊狀結構受損、過量 ROS、動態異常（分裂／融合失衡）與 MAM 耦合失調的角色
H2: 代謝重編程：從 OXPHOS 向醣解的轉換
描述代謝重編程的概念與其在癌症、幹細胞中的經典例子
PDC—PDK 調控丙酮酸通路的關鍵機制
胰島素阻抗如何透過 PDK 上調、ROS 穩定 HIF1α、AMPK 激活加速向醣解轉變
線粒體品質控制下降、過度或不足的線粒體自噬對代謝重編程的影響
H2: 治療策略：靶向胰島素敏感性與線粒體修復
經鼻胰島素：繞過血腦屏障，直接補充腦部胰島素以改善信號通路
胰島素增敏劑：二甲雙胍、TZDs、GLP‑1 類藥物在中樞神經的應用潛力
PDK 抑制劑：如 DCA、AZD7545、FX11 等促使代謝回歸 OXPHOS
線粒體保護劑與抗氧化劑：CoQ10、MitoQ、α‑硫辛酸、多酚（白藜蘆醇、EGCG）
幹細胞與再生醫學：透過促進神經修復、移轉健康線粒體與改善血管功能
生活方式干預：運動、間歇性禁食、DASH 飲食等如何改善胰島素敏感性與大腦代謝
小結與未來方向
總結 T3DM 在 AD 中的核心角色，強調理解 AβO 與 InsR 交互作用、量化腦部胰島素水平、代謝重編程的雙刃特性為未來挑戰。展望在早期標誌物、精準干預與代謝療法上的潛在突破。
大腦在挨餓？當血糖進不了神經細胞，記憶力恐怕會先「斷電」
大腦在挨餓？當血糖進不了神經細胞，記憶力恐怕會先「斷電」
在我們日常生活中，「餓」是一個很直觀的感受。但你有沒有想過，大腦也會「餓」？而且這種餓，不是吃太少，而是吃再多，能量也進不了腦細胞。
近年來，越來越多神經科學研究指出：在阿茲海默症（Alzheimer’s disease, AD）發展之前，大腦就已經出現能量代謝異常。這不只是記憶力退化的結果，可能就是病程的起點。本文帶你一探「大腦代謝重編程」的前線科學，了解它如何影響你的記憶力、思考力，甚至老化速度。
🧠 大腦是人體最「耗電」的器官
🧠 大腦是人體最「耗電」的器官
大腦的重量只占身體約 2%，但它卻消耗了將近 20% 的葡萄糖。
神經細胞不像肌肉或肝臟那樣儲存能量，它必須時時刻刻仰賴血液中的葡萄糖與氧氣，來維持訊息傳遞、記憶儲存與神經活性。
其中，有一種大家熟悉卻常忽略的關鍵角色：胰島素訊號。
胰島素不只調節血糖，也負責協助葡萄糖進入細胞進行代謝。以往我們以為大腦不太需要胰島素，但現在已知，大腦不僅有胰島素受體，還有自己的胰島素製造能力，特別是在海馬迴與額葉皮質這些與學習記憶相關的區域。
⚠️ 當能量進不來，大腦怎麼辦？
⚠️ 當能量進不來，大腦怎麼辦？
最新研究指出，許多阿茲海默症患者在臨床症狀出現前，就已經在腦部出現葡萄糖代謝下降的現象。這種現象稱為代謝重編程（metabolic reprogramming）。
簡單來說，就是神經細胞原本使用高效率的「有氧代謝」方式，轉向低效率但快速的「糖解作用」。
🔁 代謝重開機的過程如下：
🔁 代謝重開機的過程如下：
胰島素訊號變弱 → 葡萄糖進不來 → 神經細胞缺乏能量
線粒體功能下降 → 無法有效產生ATP（能量）
神經細胞轉向糖解 → 產生乳酸、能量減少
自由基增加、氧化壓力升高 → 神經細胞進一步受損
雖然這是一種短期的「自救機制」，但長期下來，反而讓神經元處在高壓、高毒性的環境，最終走向凋亡。
🔬 最新研究：失智可能從「能量危機」開始
🔬 最新研究：失智可能從「能量危機」開始
2025 年發表於《Molecular Medicine》的研究綜述指出，在阿茲海默症的發展過程中，神經細胞會因為無法正常利用葡萄糖，而被迫改變代謝策略。
這些變化包括：
線粒體損傷、氧化磷酸化下降
乳酸堆積與酸化環境
自由基與發炎反應增加
Pyruvate dehydrogenase kinase（PDK）活化，抑制能量生成
大腦細胞啟動過度的粒線體自噬（mitophagy）
這一連串的惡性循環，不僅讓神經元逐漸喪失功能，也可能加速 Aβ 澱粉樣蛋白的堆積與 tau 蛋白磷酸化，造成更明顯的神經退化。
🧬 胰島素訊號、線粒體與失智風險的三角關係
🧬 胰島素訊號、線粒體與失智風險的三角關係
1. 胰島素訊號失調
1. 胰島素訊號失調
研究發現，β-類澱粉蛋白（Aβ）寡聚體會與胰島素受體競爭，甚至誘發胰島素受體內化，導致胰島素訊號減弱，進一步使葡萄糖利用下降。
2. 線粒體功能受損
2. 線粒體功能受損
線粒體是細胞的發電廠，但也容易被 Aβ、氧化壓力攻擊。一旦線粒體失能，神經細胞的能量供應將大受影響，並產生大量自由基。
3. 神經元啟動代謝替代模式
3. 神經元啟動代謝替代模式
為了彌補能量不足，神經元被迫啟動糖解途徑。但這條路徑產能有限、會產生乳酸與發炎訊號，反而讓環境更惡化。
🧩 能量斷線會發生什麼事？
🧩 能量斷線會發生什麼事？
根據腦部影像研究，阿茲海默症患者的額葉與海馬迴，常在病程初期就出現代謝低下。
這可能會導致：
記憶力下降：特別是短期記憶與人名記憶
專注力與學習力下降：思緒不集中、學習新資訊困難
語言能力變差：找不到詞、表達困難
方向感與時間感混亂：走錯路、忘記約定時間
這些改變並非單純老化，而可能反映出大腦能量的深層危機。
💡 我們可以做些什麼？
💡 我們可以做些什麼？
雖然目前尚未有明確藥物能逆轉這種代謝異常，但已有不少策略正在研究與實踐中。
✅ 飲食與生活型態調整
✅ 飲食與生活型態調整
控制高糖與高升糖指數飲食：避免血糖大起大落，減少大腦負擔
運動：提升胰島素敏感性、改善線粒體功能
優質睡眠：幫助大腦清除代謝廢物
壓力管理：慢性壓力會影響荷爾蒙與代謝系統
✅ 科學研究中的潛在策略
✅ 科學研究中的潛在策略
經鼻胰島素療法：繞過血腦障壁、直接提升大腦胰島素濃度
活化線粒體生合成的營養素或藥物：如 PGC-1α 調節劑
自由基清除與抗發炎劑：減少氧化傷害
奈米技術的藥物傳遞：幫助藥物進入中樞神經系統
🔍 常見問題 Q&A
🔍 常見問題 Q&A
Q1：我血糖正常，也會發生大腦餓的問題嗎？
Q1：我血糖正常，也會發生大腦餓的問題嗎？
是的，這不完全與血糖濃度有關，而是細胞是否「能夠有效使用」血糖。就像餐桌上有食物，但沒人能拿到。
Q2：是不是只要控制飲食就沒事？
Q2：是不是只要控制飲食就沒事？
飲食是重要的一環，但壓力、睡眠、運動、基因等都會影響大腦代謝功能，需要整體調整。
Q3：有沒有可以提早偵測的方法？
Q3：有沒有可以提早偵測的方法？
目前研究正在開發腦部葡萄糖代謝的影像檢查、血中代謝生物標記等，未來可能用來早期偵測大腦代謝異常。
🧭 結語：照顧腦，不只是記憶力的事
🧭 結語：照顧腦，不只是記憶力的事
我們常說「記憶力不好」，但這背後可能是更深層的能量危機。
當大腦處在長期的能量不足、線粒體功能失調、氧化壓力增加狀態下，許多神經退化性變化會悄悄啟動。
認識「大腦代謝重編程」這件事，不只是為了避免失智，更是為了讓我們的大腦，在每一天都保有清晰、有力的運作能力。
未來的預防醫學，或許不只是問你「記不記得」，而是問：「你的腦，有沒有吃飽？」
大腦能量與代謝異常：50個常見問答（FAQ）
大腦能量與代謝異常：50個常見問答（FAQ）
1. 大腦真的會「餓」嗎？
1. 大腦真的會「餓」嗎？
是的，大腦雖然消耗大量能量，但當葡萄糖無法進入神經細胞時，即使血糖正常，神經元也會因缺乏能量而進入「飢餓狀態」。
2. 大腦主要靠什麼能量來源？
2. 大腦主要靠什麼能量來源？
大腦主要依賴葡萄糖作為能量來源，經由有氧代謝（氧化磷酸化）產生足夠ATP供應神經訊號傳遞與細胞維持。
3. 為什麼神經細胞會無法使用葡萄糖？
3. 為什麼神經細胞會無法使用葡萄糖？
當胰島素訊號失調或神經細胞對胰島素反應降低時，葡萄糖就無法順利進入神經元進行代謝。
4. 胰島素對大腦有什麼作用？
4. 胰島素對大腦有什麼作用？
胰島素不僅協助葡萄糖進入細胞，也參與神經可塑性、記憶形成及神經元存活等功能。
5. 大腦為什麼會改變代謝方式？
5. 大腦為什麼會改變代謝方式？
當正常的有氧代謝受阻，大腦會啟動「代謝重編程」，轉向效率較低但能快速產能的糖解作用來維持基本功能。
6. 什麼是代謝重編程？
6. 什麼是代謝重編程？
代謝重編程是細胞面對能量危機時，改變能量產生方式的過程，通常伴隨乳酸堆積、能量減少、氧化壓力上升等現象。
7. 糖解作用對大腦是好還是壞？
7. 糖解作用對大腦是好還是壞？
短期內可維持能量供應，但長期會造成酸化環境、產生過多廢物，並加速神經細胞受損。
8. 這種大腦能量失衡與失智有什麼關聯？
8. 這種大腦能量失衡與失智有什麼關聯？
研究發現，大腦葡萄糖代謝下降可能早於阿茲海默症臨床症狀，是失智症病程的前兆之一。
9. 線粒體在這個過程中扮演什麼角色？
9. 線粒體在這個過程中扮演什麼角色？
線粒體是細胞的能量工廠，當它們功能受損時，會造成能量產出下降與自由基增加，加速神經退化。
10. 自由基是什麼？對大腦有什麼影響？
10. 自由基是什麼？對大腦有什麼影響？
自由基是代謝產生的不穩定分子，過量會造成氧化壓力，破壞細胞結構與功能，導致神經發炎與退化。
11. 有哪些跡象可能代表大腦代謝異常？
11. 有哪些跡象可能代表大腦代謝異常？
包括記憶力下降、專注力變差、語言能力退化、方向感混亂等，這些都是能量不足導致神經訊號傳遞異常的表現。
12. 這些變化可以透過檢查早期發現嗎？
12. 這些變化可以透過檢查早期發現嗎？
部分研究使用腦部正子攝影（如FDG-PET）可以偵測早期的葡萄糖代謝下降，未來也可能發展血液或腦脊髓液中的代謝標記。
13. 經鼻胰島素療法是什麼？
13. 經鼻胰島素療法是什麼？
這是一種繞過血腦障壁、直接讓胰島素進入大腦的治療方式，目前正於臨床研究中，初步顯示對記憶改善有潛力。
14. 哪些生活習慣會影響大腦代謝健康？
14. 哪些生活習慣會影響大腦代謝健康？
高糖飲食、缺乏運動、慢性壓力、睡眠不足都可能影響大腦對能量的利用效率與代謝功能。
15. 飲食可以幫助改善嗎？
15. 飲食可以幫助改善嗎？
是的，選擇低升糖指數食物、避免過度精緻糖分攝取，有助於穩定血糖與胰島素反應，減少大腦負擔。
16. 運動對大腦代謝有幫助嗎？
16. 運動對大腦代謝有幫助嗎？
有，規律運動能提升胰島素敏感性、促進線粒體功能，改善大腦的能量使用效率。
17. 這種代謝異常會發生在每個人身上嗎？
17. 這種代謝異常會發生在每個人身上嗎？
不一定，但與年齡、基因（如APOE4）、生活習慣有關，尤其中年開始就可能逐步出現跡象。
18. 這算是一種中醫認為的「虛耗」嗎？
18. 這算是一種中醫認為的「虛耗」嗎？
可以這樣理解，中醫可能以「氣虛、腦力不足」描述這類能量失衡的狀態，現代科學則從細胞能量代謝解釋這種現象。
19. 有沒有辦法讓大腦更有效率地利用能量？
19. 有沒有辦法讓大腦更有效率地利用能量？
除了提升胰島素訊號與改善線粒體健康外，也可透過睡眠、冥想、間歇性斷食等方式優化能量利用。
20. 為什麼這件事重要？
20. 為什麼這件事重要？
因為記憶退化、思考遲鈍可能不是老化必然，而是「大腦正在挨餓」的警訊。認識並改善代謝健康，就是保護大腦的第一步。
21. 大腦代謝異常是否會影響情緒？
21. 大腦代謝異常是否會影響情緒？
會的，能量不足可能導致神經傳導物質失衡，引發焦慮、憂鬱等情緒症狀。
22. 長期高血糖是否會影響腦部功能？
22. 長期高血糖是否會影響腦部功能？
會，高血糖會破壞微血管與神經，並促使發炎與氧化壓力上升，影響記憶與學習能力。
23. Aβ蛋白與代謝異常有什麼關係？
23. Aβ蛋白與代謝異常有什麼關係？
Aβ寡聚體可能干擾胰島素受體，並誘發胰島素訊號中斷，是代謝失調與神經退化間的重要橋樑。
24. Tau蛋白與代謝功能有何關聯？
24. Tau蛋白與代謝功能有何關聯？
研究指出，能量代謝異常會促進Tau蛋白異常磷酸化，加速神經纖維糾結形成。
25. 大腦可以自己產生胰島素嗎？
25. 大腦可以自己產生胰島素嗎？
部分研究發現大腦某些區域具備類似胰島素合成的機制，但功能仍在研究中。
26. 什麼是線粒體自噬（mitophagy）？
26. 什麼是線粒體自噬（mitophagy）？
是細胞清除損壞線粒體的過程，有助於維持細胞能量品質，但過度活化可能導致功能性線粒體減少。
27. 有沒有營養素對腦部代謝特別有幫助？
27. 有沒有營養素對腦部代謝特別有幫助？
如Omega-3脂肪酸、維生素B群、左旋肉鹼、白藜蘆醇等被研究為可能促進神經代謝的營養補充選項。
28. 酮體對大腦能量有幫助嗎？
28. 酮體對大腦能量有幫助嗎？
在葡萄糖供應受限時，酮體可作為替代能量來源，被視為潛在補償路徑。
29. 慢性壓力如何影響大腦代謝？
29. 慢性壓力如何影響大腦代謝？
壓力荷爾蒙會影響胰島素反應與葡萄糖代謝，長期下來可能導致代謝異常與神經炎症。
30. 如何知道自己是否有大腦代謝異常？
30. 如何知道自己是否有大腦代謝異常？
目前仍以症狀評估為主，未來可能透過代謝標記或影像工具輔助早期判斷。
31. 間歇性斷食是否對大腦代謝有益？
31. 間歇性斷食是否對大腦代謝有益？
初步研究顯示間歇性斷食可提升胰島素敏感性、活化線粒體與細胞自噬，有機會改善神經代謝。
32. 睡眠與大腦能量有什麼關係？
32. 睡眠與大腦能量有什麼關係？
睡眠有助清除代謝廢物，修復線粒體與神經細胞，是維持大腦代謝平衡的重要因素。
33. 神經細胞在「餓」的狀態下會發生什麼？
33. 神經細胞在「餓」的狀態下會發生什麼？
能量供應不足會導致突觸失能、訊號中斷、記憶儲存與提取能力下降，嚴重時細胞凋亡。
34. 老化一定會導致大腦代謝變差嗎？
34. 老化一定會導致大腦代謝變差嗎？
老化確實會降低胰島素敏感性與線粒體效率，但透過生活調整可減緩這些變化。
35. 可以用藥物改善大腦代謝嗎？
35. 可以用藥物改善大腦代謝嗎？
目前仍在研發階段，包括提升中樞胰島素反應、保護線粒體功能等藥物策略。
36. 是否有特定族群需要特別注意大腦代謝問題？
36. 是否有特定族群需要特別注意大腦代謝問題？
如中年族群、有代謝症候群、家族失智病史者應特別關注腦部代謝健康。
37. 什麼是MAM（線粒體相關內質網膜）？
37. 什麼是MAM（線粒體相關內質網膜）？
MAM是內質網與線粒體接觸的區域，負責鈣離子傳遞與代謝協調，其功能失衡與神經退化有關。
38. 神經發炎與能量代謝有何關聯？
38. 神經發炎與能量代謝有何關聯？
能量不足或代謝產物累積可促發神經發炎反應，進一步破壞神經元與訊號通路。
39. 大腦是否有替代能量來源？
39. 大腦是否有替代能量來源？
在葡萄糖代謝不足時，大腦可轉用乳酸、酮體、部分胺基酸作為替代能量來源。
40. 代謝異常會不會影響腦神經再生能力？
40. 代謝異常會不會影響腦神經再生能力？
會，能量不足會限制神經幹細胞分化與突觸形成，影響大腦修復與學習能力。
41. 這種現象會不會發生在青少年身上？
41. 這種現象會不會發生在青少年身上？
雖較少見，但高糖飲食、熬夜、久坐也可能影響青少年大腦代謝與發展。
42. 是否可透過呼吸練習改善大腦代謝？
42. 是否可透過呼吸練習改善大腦代謝？
有研究顯示腹式呼吸、冥想可降低壓力荷爾蒙、穩定代謝環境，有助於大腦能量調節。
43. 大腦代謝異常與注意力缺陷（如ADHD）有關嗎？
43. 大腦代謝異常與注意力缺陷（如ADHD）有關嗎？
部分研究探討能量代謝與神經傳導物質之間的關聯，但仍需更多證據證實。
44. 可以做哪些檢查來評估腦代謝？
44. 可以做哪些檢查來評估腦代謝？
目前包括功能性腦影像（如FDG-PET）、代謝血清標記、神經心理測驗等輔助工具。
45. 中醫怎麼看待大腦能量不足？
45. 中醫怎麼看待大腦能量不足？
中醫常以「腦髓空虛」、「腎精不足」等觀點描述神經功能與代謝相關症狀，主張整體調補調理。
46. 電腦用太久會讓大腦代謝變差嗎？
46. 電腦用太久會讓大腦代謝變差嗎？
久坐不動會影響全身代謝與血流，包括大腦血氧與葡萄糖利用效率。
47. 阿茲海默症患者是否都會有大腦代謝異常？
47. 阿茲海默症患者是否都會有大腦代謝異常？
絕大多數AD患者在早期就已經出現葡萄糖代謝下降，尤其在海馬迴與額葉皮質區域。
48. 有什麼飲食模式可提升大腦代謝？
48. 有什麼飲食模式可提升大腦代謝？
如地中海飲食、MIND飲食、抗發炎飲食都與大腦健康與代謝功能改善有正面關聯。
49. 小朋友大腦也可能代謝失調嗎？
49. 小朋友大腦也可能代謝失調嗎？
發育期間若營養不良、血糖控制差，也可能影響腦部能量供應與學習發展。
50. 預防這種情況的關鍵是什麼？
50. 預防這種情況的關鍵是什麼？
從中年就開始注意飲食、運動、睡眠與壓力管理，提早維持大腦代謝穩定，是保養腦力的根本策略。
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