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.
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 ].
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 ].
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 ].
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.
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.
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.
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.
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 ].
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 ].
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 ].
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 ].
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 ].
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.
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 ].
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 ].
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.
