The Mechanism and Treatment of Cognitive Dysfunction in Diabetes: A Review

Abstract

Diabetes mellitus (DM) is one of the fastest growing diseases in terms of global incidence and seriously affects cognitive function. The incidence rate of cognitive dysfunction is up to 13% in diabetes patients aged 65–74 years and reaches 24% in those aged >75 years. The mechanisms and treatments of cognitive dysfunction associated with diabetes mellitus are complicated and varied. Previous studies suggest that hyperglycemia mainly contributes to cognitive dysfunction through mechanisms involving inflammation, autophagy, the microbial-gut-brain axis, brain-derived neurotrophic factors, and insulin resistance. Antidiabetic drugs such as metformin, liraglutide, and empagliflozin and other drugs such as fingolimod and melatonin can alleviate diabetes-induced cognitive dysfunction. Self-management, intermittent fasting, and repetitive transverse magnetic stimulation can also ameliorate cognitive impairment. In this review, we discuss the mechanisms linking diabetes mellitus with cognitive dysfunction and propose a potential treatment for cognitive decline associated with diabetes mellitus.

 

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Keywords

cognitive dysfunction - diabetes - mechanism - treatment

Introduction

Diabetes mellitus (DM) is one of the most common chronic diseases occurring globally and is estimated to affect 693 million adults by 2045 [1]. It is associated with deficits in different cognitive areas and specifically contributes to accelerating cognitive decline [2]. Cognitive dysfunction includes mild cognitive impairment (MCI) and dementia [3]. Diabetic cognitive dysfunction (DCI) is one of the common complications of diabetes and mainly manifests as the loss of learning ability and memory and behavioral disorders [4], which have a serious influence on the quality of life [5]. It is difficult to reverse DCI once it occurs, and DCI can even develop into dementia [6]. Studies have indicated that diabetes is closely associated with cognitive dysfunction [7] [8] [9] [10] [11]. In general, cognitive impairment cannot be easily detected in the early stages but may gradually impair the ability to perform activities of daily life [12]. Studies have shown that in the majority of cases, the development of cognitive dysfunction in patients with diabetes is strongly related to age [13]. Cognitive decline can be aggravated in patients with diabetes and can even develop into MCI and dementia [14]. The occurrence of MCI was found to be related to long-term hyperglycemia [15]. Research has shown that the prevalence of cognitive dysfunction is up to 13% in diabetes patients aged 65–74 and reaches 24% in those aged over 75 years [16]. In a cohort study with a follow-up of 31.7 years, the findings demonstrated that at an early onset diabetes significantly increased the possibility of developing dementia. For every five years earlier the onset of diabetes was, the likelihood of dementia markedly increased. Conversely, no significant association was observed between late-onset diabetes and the subsequent development of dementia [17]. The characteristics of diabetes-related cognitive dysfunction vary in different stages, and the mechanisms are distinct. The mechanisms underlying diabetes-related cognitive dysfunction are complex and diverse, posing challenges in the treatment of this condition; moreover, a comprehensive discussion of the mechanisms of and therapies for diabetes-related cognitive dysfunction is lacking. This review aims to summarize the mechanisms of and therapies for diabetes-related cognitive dysfunction and provide a basis for the treatment of diabetes-related cognitive dysfunction.

 

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Mechanisms of cognitive dysfunction related to diabetes mellitus

Inflammation

Substantial evidence has shown that inflammation is involved in the occurrence of diabetes-related cognitive dysfunction [18] [19] [20]. Chronic hyperglycemia can activate the NOD-like receptor protein 3 inflammasome (NLRP3) and induce the inflammatory cascade, resulting in cognitive dysfunction [6]. Inhibition of NLRP3 in the brain can alleviate cognitive dysfunction in diabetic rats [21]. Microglia are immune cells in the brain that act as important regulators of neuroinflammation. Diabetes-related cognitive decline is associated with apoptosis of hippocampal neurons and microglia caused by microglial activation, with neuroinflammation caused by the overactivation of microglia being a major neuropathological feature of this condition [22] [23]. Hyperglycemia can easily lead to the dysfunction of glycolipid metabolism and aggravate the pathological microglia reactivity. The sterol regulatory element-binding protein cleavage activating protein (SCAP) increases NLRP3 expression and the release of inflammatory factors, thus aggravating the development progression of cognitive dysfunction [24]. Microglia are macrophages in the central nervous system. Various stimuli, such as cytokines, endotoxins, and hyperglycemia, can activate microglia, causing them to secrete inflammatory cytokines and remove debris during the central inflammatory response. Microglia express phosphoinositide 3-kinase (PI3K), which plays an important role in synaptic plasticity and inflammation through microglia. Increased activation of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway is involved in the regulation of oxidative stress, neuroinflammation, synaptic cell plasticity, apoptosis, etc. The brain-derived neurotrophic factor (BDNF) signaling pathway in microglia is also regulated by the PI3K/AKT pathway [25]. Microglia can be polarized toward two different phenotypes, the classical M1 phenotype and the alternative M2 phenotype [26]. M1 polarization of microglia exerts a proinflammatory effect by promoting the production of proinflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6). M2 polarization of microglia exerts an anti-inflammatory effect by promoting the phagocytosis of cellular debris or damaged neurons and the secretion of anti-inflammatory cytokines, such as IL-4 and IL-10 [27]. Whether microglia are polarized toward the proinflammatory or anti-inflammatory phenotype depends on the surrounding immune environment. Regulatory T cells (Tregs) play an important role in this process by exerting anti-inflammatory, immunosuppressive, and neuroprotective effects. Treg function is linked with microglial polarization in the brain. Impaired Tregs polarize microglia towards a proinflammatory phenotype, which subsequently leads to neuroinflammation and diabetes-related cognitive dysfunction [28] [29].

 

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Autophagy

Autophagy is a process of intracellular lysosomal catabolism and metabolism that regulates protein homeostasis and organelle turnover. Autophagy is also an intracellular degradation pathway that maintains intracellular homeostasis by removing damaged organelles, pathogens, and unwanted protein aggregates [30]. The hippocampus plays a key role in the regulation of learning and memory, and autophagy in hippocampal neurons improves memory and cognitive function [31]. Autophagy can modulate microglial activation, and in cellular and animal models, autophagy has been shown to contribute to different aspects of neuronal and microglial physiology, such as axonal homeostasis, synaptic repair, and neurogenesis. Diabetes-associated cognitive decline is connected with neuroinflammation and apoptosis of hippocampal neurons and microglia caused by microglial activation, which may be due to the suppression of autophagy [22]. As autophagy levels increase, cognitive function improves [6]. Autophagy also assists in the clearance of cytotoxic proteins accumulated in the brain. LC3B-II, ATG5, ATG7, and P62 are involved in the initiation and maintenance of autophagosome formation. In diabetes-related cognitive dysfunction, the expression of LC3BII, ATG5, and ATG7 is upregulated, while that of P62 is downregulated in the hippocampus, which suggests a protective effect of autophagy against diabetes-related cognitive dysfunction to a certain degree [32].

 

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Microbe-gut-brain axis

Cognitive dysfunction is an important comorbidity of diabetes [5] [14] [33]. Gut microbes have a symbiotic relationship with their hosts; they digest exogenous and indigestible foods, produce secondary metabolites that can affect host physiology, and metabolize endogenous substrates during prolonged fasting [34]. The gut microbiota is an emerging target for managing diabetes and maintaining cognitive function [35]. Signals can be transmitted via the microbe-gut-brain axis through multiple mechanisms. The production of pro- and anti-inflammatory cytokines is influenced by the gut flora, and these cytokines send signals to the brain through the circulatory system [36]. The gut-brain axis is a complex bidirectional communication system between the gastrointestinal tract and the central nervous system involving the endocrine, immune, and nervous systems [37]. The gut microbe metabolite acetate plays an important role in regulating cognitive function through the gut-brain axis. Synaptophysin, a synaptic vesicle membrane protein, affects the efficiency of synaptic vesicle cycling, the disruption of which impairs cognitive ability. Acetate from microorganisms can modulate hippocampal synaptophysin levels by stimulating the vagus nerve, which in turn improves cognitive function. Chronic acetate deficiency can result in a reduction in hippocampal synaptophysin levels and consequent cognitive decline [38]. Akkermansia muciniphila, a gut microbe, downregulates proinflammatory cytokines, especially IL-6 in the peripheral blood and hippocampus, and this change is correlated with improved cognitive function. An anti-IL-6 antibody was found to protect cognitive function in aged mice; however, the recombinant IL-6 protein was shown to abrogate the protective effect of Listeria monocytogenes on cognitive function [39].

 

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Insulin resistance

Insulin resistance is strongly associated with diabetes-related cognitive dysfunction [12] [40]. Insulin acts in the central nervous system and regulates behavior and metabolism, which are associated with cognitive function [16] [41]. Insulin regulates various biological processes by binding to and activating insulin receptors such as tyrosine kinase receptors [42]. Upon binding of insulin to an insulin receptor, the insulin receptor substrate (IRS) protein is activated, triggering the PI3K/AKT cascade, which plays a neuroprotective role in the brain, especially in the hippocampus [43]. During insulin resistance, the inability of the pancreas to supply adequate amounts of insulin results in a marked disruption of systemic glucose homeostasis, which is characterized by hyperglycemia and glucose intolerance (in the case of both impaired fasting glucose and impaired glucose tolerance) [44]. Insulin signaling pathways are primarily inactivated by serine phosphorylation of insulin receptors, which inhibits the PI3K/AKT signaling cascade and prevents glucose transporter protein 4 transport, in turn causing the overproduction of advanced glycation end products (AGEs) during hyperglycemia and leading to reduced cerebral blood flow. Reduced cerebral blood flow leads to vascular barrier disruption and consequent cognitive dysfunction. Insulin can cross the blood-brain barrier and play an important role in the regulation of central nervous system function; therefore, it has a significant effect on cognitive processes [45] [46]. In addition, insulin resistance affects mitochondrial function, leading to decreased ATP production and increased oxidative stress, which cause mitochondrial dysfunction, activation of inflammatory responses[40] [47], and ultimately cognitive dysfunction.

 

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Brain-derived neurotrophic factor (BDNF)

BDNF is a member of the neurotrophic factor family and plays a key role in neuronal differentiation and growth, as well as synaptic connectivity [48]. A low BDNF level is associated with diabetes-related cognitive dysfunction, while its elevated levels can improve cognitive function [49]. In the central nervous system, BDNF is abundantly expressed in the hippocampus, where it is associated with memory and cognition. It increases neuroplasticity and neurogenesis through its cognate tyrosine kinase receptor TrkB [50]. However, AGEs can inhibit the BDNF-TrkB pathway in T2DM [51], nullifying this compensatory neuroprotective effect and rendering patients with T2DM more susceptible to neurodegeneration, ultimately resulting in impaired cognitive function.

Fig. 1 A flowchart of cognitive dysfunction in diabetes mellitus.

 

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Oxidative stress

Oxidative stress is closely associated with diabetes-related cognitive dysfunction [52] [53] [54]. In normal cell metabolism, glucose oxidation is the most common source of energy production [55], and oxidative stress is prone to occur when oxidants and antioxidants are out of balance. Hyperglycemia reduces antioxidant levels and increases the production of free radicals. Oxidative stress results in high oxygen consumption, and reactive oxygen species (ROS) produced in response to hyperglycemia disrupts antioxidant homeostasis in the brain, thus causing brain tissue cell damage [56] [57]. Diabetes increases oxidative stress, levels of ROS, lipid peroxide, and NADPH oxidase, and inhibits the hippocampal Nrf2/HO-1/ NQO1 signaling pathway to further decrease antioxidant capacity[58]. Oxidative stress increases the activity of acetylcholinesterase [57] and impairs the plasticity of neurons and synapses [59]. Oxidative stress also increases the production of mitochondrial ROS, reduces the levels of antioxidant SOD and GSH, and causes non-enzymatic glycosylation of proteins and glucose oxidation [60]. Through the above mechanisms, cognitive dysfunction can develop in diabetic patients.

 

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Diabetic Neurodegeneration

Diabetic neurodegeneration can affect brain structure and function, resulting in cognitive dysfunction. Cognitive function relies on the communication between neurons through synapses [61]; however, morphological and structural changes in brain neurons have been observed in experimental animal models of diabetes mellitus [62]. In different stages of the disease, neurons show varying signs of degeneration, such as cell body enlargement, nuclear enlargement, a reduction in the number of organelles, mitochondrial swelling, endoplasmic reticulum expansion, fracture and vacuole formation, and increased plasma electron density in axons and dendrites [62]. Moreover, patients with diabetes-related cognitive decline may have severe and diffuse degeneration of grey matter, white matter, and neurons [63]. The firing of action potentials and the release and recycling of neurotransmitters in the brain require high levels of energy [63] [64]. Microvascular and macrovascular diseases in diabetic patients may lead to reduced blood flow to the brain, which in turn affects the energy supply to brain tissue and impairs nerve function. During the degeneration of the central nervous system in patients with diabetes, areas of the brain closely related to cognitive function, such as the hippocampus, are severely damaged [65] [66]. The hippocampus is a key brain region for learning and memory, and electrophysiological studies have shown that diabetes reduces synaptic plasticity in areas of the hippocampus, which affects cognitive functions such as memory, learning, and attention.

 

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Pharmacological treatment of diabetes-related cognitive dysfunction

Hypoglycemic agents

Metformin

Discovered 300 years ago in a traditional herbal medicine, metformin was redeveloped in the 1940s as an antimalarial drug [67]. The use of metformin in the treatment of diabetes was first reported by French physician Jean Sterne in 1957; after rigorous scrutiny, metformin was approved for use in the United States in 1995 [68]. Metformin improves cognitive function through multiple mechanisms [69] [70]. Metformin induces the polarization of microglia to the beneficial anti-inflammatory M2 phenotype, reduces the formation of pathologic microglial clusters, decreases proinflammatory cytokine levels, and increases autophagy in the hippocampus, thus improving cognitive function [71]. It is also able to improve cognitive function by increasing insulin sensitivity [47]. Samaras et al. [72] showed that older patients with diabetes treated with metformin had slower cognitive decline and a lower risk of dementia. Metformin has been shown to decrease the α diversity of gut bacteria and increase the abundance of Lactobacillus mucilaginous, L. royale, L. salivarius, and Bacillus paracasei, which decreases with age. Metformin-mediated production of A. muciniphila was shown to improve cognitive function in aged mice by modulating host inflammation-related pathways through a reduction in the level of the proinflammatory cytokine IL-6 [39]. Metformin can also increase BDNF levels in the brain, thereby improving cognitive function [73].

 

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Glucagon-like peptide-1 (GLP-1)

GLP-1 receptor agonists (GLP-1RAs) improve vascular, microglial, and neuronal function [74]. They exert neuroprotective effects by attenuating neuroinflammation and modulating the PI3K/AKT pathway [75] [76]. Liraglutide, a GLP-1 analog [77] [78] [79] with 97% homology to human GLP-1, was shown to inhibit inflammatory factor (e. g., TNF-α, IL-1β, and IL-10) production [80] and attenuate neuroinflammation [81]. Liraglutide was found to attenuate neuronal and synaptic ultrastructure damage in the CA1 region of the hippocampus. Furthermore, liraglutide promotes the expression of the autophagy markers microtubule-associated protein 1 light chain 3 (LC3)-II and beclin 1. In vitro, liraglutide increases the level of phosphorylated AMP-activated protein kinase (p-AMPK) and decreases the level of phosphorylated mammalian target of rapamycin (p-mTOR). Liraglutide promotes autophagy through the AMPK/mTOR pathway [82], suggesting its potential in promoting autophagy in diabetic mice, in turn ameliorating cognitive decline [82] [83].

 

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Sodium-glucose cotransporter 2 (SGLT2)

SGLT2 inhibitors are relatively new hypoglycemic agents with anti-inflammatory properties that increase macrophage polarization, inhibit NLRP3 inflammasome activation [84], and ameliorate cognitive dysfunction [85]. Engeletin could significantly increase BDNF levels in the brain, leading to the improvement of cognitive function [84] [86]. Engeletin was also shown to protect microglia and improve cognitive function [87]. Furthermore, engeletin can block nuclear factor (NF)-κB, c-Jun N-terminal kinase (JNK) and signal transducers and activators of transcription 1 and 3 (STAT1/3) phosphorylation through the IκB kinase/NF-κB, mitogen-activated protein kinase 7/JNK, and Janus kinase 2/STAT1 pathways, exerting an anti-inflammatory effect to improve cognitive function [88].

 

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Nonglycemic agents

Fingolimod

Sphingosine receptors (S1PRs) are associated with the progression of neurodegenerative diseases. Neuroinflammation is a common pathology of T2DM and cognitive impairment. Inhibition of S1P1 activity decreases the phosphorylation of the M1 markers extracellular signal-regulated kinase 1/2, p38, and JNK MAPKs but increases the phosphorylation of M2 marker AkT; these molecules participate in pathways downstream of S1P1 activation [89]. Fingolimod (an S1PR1 modulator) reduces microglial polarization and ameliorates cognitive dysfunction [90] [91]. Studies indicate that that fingolimod ameliorates cognitive deficits by modulating microglial polarization in T2DM through the inhibition of proinflammatory cytokine production [92].

 

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Melatonin (MLT)

MLT is a major secretory product of the pineal gland that can improve cognitive function [93] [94]. MLT has been shown to inhibit microglial cell activation and reduce the levels of proinflammatory cytokines. In one study, MLT could significantly reduce the levels of toll-like receptor 4 (TLR4), p-Akt, and mTOR, suggesting that blockade of the TLR4/Akt/mTOR pathway may be a potential mechanism underlying the anti-inflammatory and anti-apoptotic effects of MLT. MLT reduces plasma insulin levels, restores peripheral insulin sensitivity, and ameliorates insulin resistance, thus normalizing blood glucose levels and consequently improving cognitive function [95]. It could also reduce the levels of TLR4, p-Akt, and p-mTOR in the hippocampus of T2DM mice through the TLR4/Akt/mTOR pathway, thus promoting cell autophagy and improving cognitive function [22]. In addition, MLT restores mitochondrial autophagy and improves cognitive function by reversing aberrant expression of lysosomal signaling pathway proteins and pathological phagocytosis of microglia and facilitating the fusion of autophagosomes with lysosomes via Mcoln1 [96].

 

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Nonpharmacologic treatment of diabetes-related cognitive dysfunction

Self-management

Basic personal care activities require less cognitive capacity than complex instrumental activities of daily living, such as self-management of diseases, which is among the activities that allow for independent living in the community. Self-management of diabetes requires proper planning as well as correct and timely execution of tasks such as blood glucose monitoring, taking regular medication regularly, modifying diet and lifestyle, and establishing appropriate blood glucose levels [97]. In a 2018 systematic review of eight studies, 64 types of executive dysfunction, memory impairment, and learning deficits were associated with poor self-management in patients with diabetes-related cognitive dysfunction and dementia. Poor self-management of the disease was directly correlated with worse cognitive dysfunction in these patients [98]. Another systematic review showed that developing the right attitude towards self-management of diabetes is effective in improving cognitive function [99]. These results highlight the importance of self-management in the treatment of diabetes-related cognitive dysfunction.

 

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Intermittent fasting (IF)

IF is a cyclical diet that has become very popular for its ability to reduce weight [100] and potentially improve memory [101] [102]. IF alters T cells in the gut, resulting in a decrease in the production of inflammatory cells and an increase in the number of regulatory T cells; IF also leads to an increase in intestinal bacterial abundance and activation of microbial metabolic pathways that regulate systemic immune responses [103]. IF can improve cognitive function by: (1) reversing the disruption of the intestinal barrier and the changes in the intestinal microbiome caused by diabetes mellitus, thereby improving the integrity of the intestinal tract and the intestinal barrier [34], and also reducing plasma LPS levels, in turn inhibiting the neuroinflammatory response; (2) increasing insulin sensitivity in mice by decreasing fasting blood glucose and fasting insulin levels; (3) inhibiting NF-κB activation, decreases JNK/p38 phosphorylation and downregulates the expression of Iba-1, a well-known marker of microglial activation, and attenuating inflammatory responses; and (4) altering the microbial diversity in diabetic mice by increasing the abundance of Lactobacilli and reorganizing the intestinal microbiota, leading to alterations in the serum levels of microbial metabolites and consequently alleviating cognitive dysfunction associated with diabetes through the gut-brain axis [104].

 

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Repetitive transcranial magnetic stimulation

Brain stimulation is currently considered a highly effective treatment for cognitive dysfunction. Noninvasive brain stimulation has a significant effect on cognition [105]. One such method, repetitive transcranial magnetic stimulation (rTMS), is an evolving noninvasive brain stimulation technique [106] [107] that is effective in improving cognitive function [108] [109]. A meta-analysis showed that noninvasive brain stimulation such as rTMS can transiently and noninvasively modulate neuronal activity and cortical excitability, thus improving cognitive function [110] [111]. High-frequency rTMS of the left dorsolateral prefrontal cortex and right dorsolateral prefrontal cortex improves memory capacity through activation of BDNFs, and the high-frequency rMTS of the right inferior frontal gyrus increases executive capacity [112]. TMS at 20 Hz effectively reduces microglial activation through the PI3K/Akt/NF-κB signaling pathway and decreases the levels of proinflammatory cytokines (such as IL-6 and TNF-α), thus relieving neuroinflammation, neuronal loss, apoptosis, and improving synaptic plasticity and cognitive function in mice [113] [114].

 

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Conclusions

Diabetes-related cognitive dysfunction is a serious complication of diabetes that imposes a heavy burden on families and society. It also poses a challenge to healthcare systems and affects socioeconomic status. Understanding the mechanism underlying diabetes-related cognitive impairment is a prerequisite for its treatment. This review explores the mechanisms of and treatments for diabetes-related cognitive dysfunction to provide a basis for clinicians to better treat diabetes-related cognitive dysfunction.

 

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Data availability statement

The data is available on request from the authors.

 

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Conflict of Interest

The authors declare that they have no conflict of interest.

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Publication History

Received: 06 August 2024

Accepted after revision: 21 November 2024

Accepted Manuscript online:
21 November 2024

Article published online:
13 January 2025