To explore the effect and the probable mechanisms of JLD in the treatment of type 2 diabetes mellitus (T2DM) - associated cognitive impairment (TDACI).

The effect of JLD in combating TDACI was assessed in T2DM model mice by conducting Morris water maze (MWM) behaviour testing. Active components and their putative targets, as well as TDACI-related targets, were collected from public databases. Protein-protein interactions (PPIs), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses and molecular docking were then utilized to explore potential molecular network mechanisms. Finally, the main targets were verified in animal model experiments.

MWM test showed that JLD improved aspects of behaviour in T2DM model mice. JLD improved glucose intolerance, tissue insulin sensitivity, lipid metabolism and enhanced synapse-associated protein expression in hippocampus tissue. Network pharmacology revealed 185 active components, 337 targets of JLD, and 7998 TDACI related targets were obtained . PPI network analyses revealed 39 core targets. GO and KEGG analyses suggested that JLD might improve TDACI by regulating gene expression, apoptotic processes and inflammatory responses mainly via PI3K-AKT and AGE-RAGE signaling pathways. Molecular docking revealed strong binding of the main components to core targets. JLD reduced hippocampus tissue expression of the inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL6), core targets of treatment of TDACI.

The findings suggested that JLD has the potential to improve TDACI through multiple components, multiple targets and multiple pathways. JLD may be a promising treatment for diabetic cognitive impairment.

Heat shock protein family B (small) member 8 (HSPB8) is a 22 kDa ubiquitously expressed protein belonging to the family of small heat shock proteins. HSPB8 is involved in various cellular mechanisms mainly related to proteotoxic stress response and in other processes such as inflammation, cell division, and migration. HSPB8 binds misfolded clients to prevent their aggregation by assisting protein refolding or degradation through chaperone-assisted selective autophagy. In line with this function, the pro-degradative activity of HSPB8 has been found protective in several neurodegenerative and neuromuscular diseases characterized by protein misfolding and aggregation. In cancer, HSPB8 has a dual role being capable of exerting either a pro- or an anti-tumoral activity depending on the pathways and factors expressed by the model of cancer under investigation. Moreover, HSPB8 exerts a protective function in different diseases by modulating the inflammatory response, which characterizes not only neurodegenerative diseases, but also other chronic or acute conditions affecting the nervous system, such as multiple sclerosis and intracerebellar hemorrhage. Of note, HSPB8 modulation may represent a therapeutic approach in other neurological conditions that develop as a secondary consequence of other diseases. This is the case of cognitive impairment related to diabetes mellitus, in which HSPB8 exerts a protective activity by assuring mitochondrial homeostasis. This review aims to summarize the diverse and multiple functions of HSPB8 in different pathological conditions, focusing on the beneficial effects of its modulation. Drug-based and alternative therapeutic approaches targeting HSPB8 and its regulated pathways will be discussed, emphasizing how new strategies for cell and tissue-specific delivery represent an avenue to advance in disease treatments.

Recent research has established a strong link between metabolic abnormalities and an increased risk of dementia. In parallel, there is growing epidemiological evidence supporting the neuroprotective effects of antidiabetic medications against cognitive impairments. Among these, sodium-glucose co-transporter (SGLT2) inhibitors have emerged as pharmacological candidates with promising potential in alleviating the burden of age-related diseases, particularly neurodegenerative diseases (NDD). SGLT2 inhibitor therapies are FDA-approved medications routinely prescribed to manage diabetes. This novel class was initially developed to address cardiovascular disorders and to reduce the risk of hypoglycemia associated with insulin-secretagogue agents. It subsequently attracted growing interest for its beneficial effects on central nervous system (CNS) disorders. However, the molecular mechanisms through which these glucose-lowering therapies mitigate cognitive decline and limit the progression of certain brain degenerative diseases remain largely unexplored. Consequently, the neuroscientific community needs further studies that gather, analyze, and critically discuss the available mechanistic evidence regarding the neuroprotective effects of SGLT2 inhibitors. This review aims to critically examine the most relevant published findings, both in vitro and in vivo, as well as human studies evaluating the impact of SGLT2 inhibitors exposure on Alzheimer's disease (AD). It seeks to integrate the current understanding of their beneficial effects at the molecular level and their role in addressing the pathophysiology and neuropathology of AD. These insights will help extend our knowledge of how SGLT2 inhibitor therapies are associated with reduced risk of dementia and thus shed light on the link between diabetes and AD.

There is ongoing debate concerning the association of metformin with the risk of dementia in type 2 diabetes mellitus (T2DM). This study was conducted to evaluate the impact of metformin therapy on dementia in patients with T2DM.

PubMed, Embase, Cochrane Library, Web of Science and the ClinicalTrials.gov website were searched until 9 April 2024. Cohort studies investigating the effects of metformin therapy compared with other antidiabetic drugs or no therapy in T2DM were included. The hazard ratio (HR) and the 95% confidence interval (CI) were computed using the random effects model.

Twenty cohort studies (24 individual comparisons) involving 3 463 100 participants were identified. A meta-analysis revealed that people with T2DM who take metformin are linked to a lower incidence of all-cause dementia compared to non-user (n = 17, HR = 0.76, 95% CI = 0.65-0.91, p = 0.002, I2 = 98.9%) and sulfonylureas (n = 5, HR = 0.88, 95% CI = 0.85-0.90, p < 0.001, I2 = 9.7%), but not to thiazolidinedione (n = 2, HR = 0.53, 95% CI = 0.08-3.41, p = 0.503, I2 = 92.7%). Additionally, metformin showed favourable effects in non-specified T2DM (n = 19, HR = 0.75, 95% CI = 0.64-0.89), but not in newly diagnosed T2DM (n = 5, HR = 1.01, 95% CI = 0.81-1.27).

Metformin might correlate with a lower dementia incidence in people with T2DM. However, it is crucial to interpret these results with caution considering the high heterogeneity.

Circulating non-esterified fatty acids (NEFAs) have toxic effects on a variety of organs central to cardiometabolic disease and can cross the blood-brain barrier. Whether NEFAs associate with cognitive decline or dementia remains unknown. Circulating total NEFA levels were measured in 3242 participants without dementia among older adults of the Cardiovascular Health Study (CHS) and related to adjudicated dementia over 6 years (n = 456 cases) and annually assessed cognitive decline. For confirmation, we related circulating NEFAs to cognition assessed 10 years later among 4361 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). In CHS participants, each SD higher NEFA levels were associated with a hazard ratio (HR) for all-cause dementia of 1.11 (95 % CI: 1.01; 1.22). Baseline NEFA levels were also associated with more rapid decline in cognition over 6 years of follow-up. In MESA, circulating NEFA measurements were associated with lower cognitive scores measured 10 years later.'

Type 2 diabetes mellitus (T2DM) is a significant risk factor for mild cognitive impairment (MCI). Here, we identified a T2DM-specific effective connectivity (EC) network, the dynamic features of which could be used to distinguish T2DM patients with MCI from healthy controls (HC) and correlation with cognitive performance.

Local and multicentered T2DM patients and matched HC who underwent functional magnetic resonance imaging were recruited. Their static and dynamic effective connectivity were compared. The relationships between connectome characteristics and cognitive performance were also evaluated.

The nodes of the T2DM-related static causality network included the anterior central gyrus, tail of the parahippocampal gyrus, posterior superior temporal sulcus, posterior central parietal lobe, posterior central gyrus and V5 region of the occipital lobe. The V5 region of the visual cortex was the core node. In the multicentered dataset, compared with the HC group, the T2DM with MCI group had significantly greater fractional window and mean dwell time. Fractional windows of the state, which was dominated by the interaction of the nodes from SomMot_Network, Limbic_Network, Default_Network, in the T2DM-specific network increased with poorer cognitive performance in T2DM with MCI patients.

Our findings provide insights into the neurobiological mechanisms of the cognitive impairment of T2DM patients from a dynamic network perspective, which may ultimately inform more targeted and effective strategies to prevent MCI.

Diabetes mellitus is a major risk factor for frailty in older adults, and studies suggest that frailty risk may differ by diabetes treatment regimen. To investigate the association between diabetes medication use and frailty, we conducted an observational cohort analysis of older adults with diabetes enrolled in the ASPirin in Reducing Events in the Elderly (ASPREE) study. Diabetes at baseline (N = 2045) was defined as self-reported diabetes, fasting blood glucose levels > 125 mg/dL, or use of diabetes medication. Diabetes medication exposure at baseline was categorized as use of metformin only (monotherapy) (N = 545), metformin combined with other diabetes medications (N = 420), other diabetes medications only (N = 200), or no diabetes medications (N = 880). Frailty was defined using a modified Fried frailty phenotype (presence of ≥ 3 of 5 criteria) and a deficit accumulation frailty index (FI, score > 0.21/1.00). Mixed effects ordinal logistic regression models revealed the odds of frailty at baseline were highest for the other diabetes medications only group, but this difference remained consistent over follow-up. After adjustment for covariates, including baseline pre-frailty, no differences in the rates of Fried or FI frailty were observed among the diabetes medication exposure groups. These findings suggest that diabetes medication exposure in older adults with diabetes does not directly impact frailty risk.

Type 2 diabetes mellitus (T2DM) is a significant risk factor for cognitive impairment. Zinc deficiency contributes to T2DM development, while copper may exacerbate diabetes through prooxidant mechanisms. Higher zinc levels may protect against copper toxicity. This study investigates the association of plasma zinc and copper levels with mild cognitive impairment (MCI) in T2DM patients.

T2DM patients admitted to Tongji Hospital from 2012 to 2018 were classified into MCI (n = 136) and control (n = 136) groups, matched by age (± 3 years) and gender. Conditional logistic regression was used to assess the associations between plasma zinc, copper levels and MCI. A generalized additive model (GAM) evaluated the dose-response relationship between plasma zinc, copper levels and Mini-Mental State Examination (MMSE) scores.

The median of plasma metal levels in MCI and control groups were 831.31 μg/L and 936.29 μg/L for zinc, 932.07 μg/L and 860.47 μg/L for copper, and 0.91 and 1.11 for the zinc-to-copper (Zn/Cu) ratio. Compared to participants in the lowest tertile, the multivariable-adjusted odds ratios with 95% confidence intervals (CI) for MCI in the highest tertile were 0.33 (0.13, 0.79) for zinc, 3.56 (1.42, 8.94) for copper, and 0.37 (0.15, 0.93) for the Zn/Cu ratio. Plasma Aβ40 levels were significantly lower (p = 0.009) and plasma Aβ42/40 levels were significantly higher (p = 0.008) in MCI group compared with those in control group. Zinc concentration was positively associated with Aβ42. For per SD (327.71 μg/L) increase in plasma zinc levels, the percent change (95% CI) of Aβ42 were 2.90 (0.85, 4.99).

Higher plasma zinc levels and higher Zn/Cu ratio were associated with lower odds of MCI in T2DM patients, while higher copper levels increased the risk of MCI. This study provides insights on plasma zinc, copper, and Zn/Cu ratio and Aβ of MCI, further studies are needed to clarify the underlying mechanisms for novel therapies that could prevent or cure multiple T2DM-related cognitive impairments.

Diabetes mellitus is a global public health issue, often leading to organ damage, complications, and disabilities. Frailty is an age-related syndrome characterized by reduced physiological reserve and increased vulnerability to stressors, significantly affecting the prognosis of older diabetic patients. The prevalence of frailty is notably higher in older adults with diabetes than in those without. Therefore, a bibliometric analysis of research on diabetes-related frailty can provide deeper insights into the current state of this field and inform future research directions.

This study retrieved English-language publications on diabetes-related frailty from the Web of Science Core Collection (WOS) database, covering the period from 2005 to 2023. A total of 403 articles were included in the analysis. Statistical analysis and data visualization were conducted using Microsoft Excel, R Studio, VOS viewer, and Cite Space 6.3.R1. The analysis emphasized journals, authors, keywords, country collaborations, institutional collaborations, and references to elucidate trends and knowledge structures within the field of diabetes-related frailty research.

The number of publications on diabetes-related frailty has been steadily increasing each year, with research predominantly focused in developed countries, particularly the United States and Europe. The University of London has emerged as the institution with the highest volume of publications, while Alan J. Sinclair has been recognized as a significant contributor to this field. Key research hotspots include the complications associated with diabetes-related frailty, epidemiology, and quality of life. Additionally, a timeline analysis of references suggests that diabetic nephropathy is currently at the forefront of research in this area.

This comprehensive bibliometric analysis of diabetes-related frailty research underscores the necessity for improved international collaboration to further investigate the mechanisms underlying diabetes-related frailty and to devise more effective prevention and treatment strategies. Future research should emphasize the relationship between diabetic nephropathy and frailty, as well as the development of personalized intervention programs tailored for frail diabetic patients.

Diabetes-related cognitive dysfunction (DACD) is a comorbidity of type 2 diabetes that has a negative effect on patients' quality of life. Research has indicated that disruption of the gut microbiota (GM) may be linked to dementia with altered cognitive performance. Conversely, omega-3 polyunsaturated fatty acids (n-3 PUFAs) may reverse DACD. The present study aimed to assess the effects of an n-3 PUFA intervention and fecal microbiota transplantation (FMT) on high-fat and streptozotocin-induced DACD model rats. In DACD rats, n-3 PUFA treatment restored fasting blood glucose (FBG) levels and cognitive function, increased the expression of anti-inflammatory cytokines and downregulated the expression of proinflammatory cytokines in the cortex and colon. Additionally, the expression of the postsynaptic density protein-95 mRNA and protein varied with n-3 PUFA treatment. Treatment with n-3 PUFAs also increased the expression of tight junction proteins. Beneficial and short-chain fatty acid-producing bacteria were more abundant when rats were exposed to n-3 PUFAs. After FMT from the rats with DACD symptoms that were improved by the n-3 PUFA dietary intervention into another batch of DACD rats, we observed recovery in recipient DACD rats. These results indicated that the alleviation of DACD symptoms by n-3 PUFAs was attributed to gut microbiota remodeling.

This study evaluated the effects of choline alfoscerate on cognitive function and quality of life in T2DM patients with mild cognitive decrements.

In a double-blind, randomized, placebo-controlled trial, we recruited 36 individuals with T2DM and mild cognitive impairment which was assessed by the Mini-Mental State Examination (MMSE) score of 25-28, and randomly assigned them to receive either 1200 mg/day of choline alfoscerate or a placebo. Four additional questionnaires-the 36-Item Short Form Survey, the modified Informant Questionnaire on Cognitive Decline in the Elderly, the Korean version of Activities of Daily Living, and the Patient Health Questionnaire-were investigated at 6 and 12 months and analysed via mixed-effects models for repeated measures.

The mean age of study participants was 71.8 ± 5.3 years and 69.4% women. Six-month treatment with choline alfoscerate resulted in a non-significant increase in the MMSE score from 26.2 ± 1.3 to 26.9 ± 2.0, whereas the placebo group showed a non-significant decline from 26.6 ± 1.3 to 25.9 ± 2.3, resulting in a mean difference of +1.4 between the two groups (p = 0.059). At 12 months, the mean difference increased to +1.7 with statistical significance (p < 0.001). Physical health, as measured by the SF-36 survey, was significantly better in the choline alfoscerate group than in the placebo group.

Choline alfoscerate 1200 mg once daily treatment showed marginal improvement in cognitive function in T2DM patients with mild cognitive impairment at 6 months but leading to significance at 12 months compared to placebo, suggesting its potential as an adjunct therapy for managing early cognitive decline.

Lactobacillus casei Zhang (LCZ) has health benefits, such as the ability to improve blood glucose levels in individuals with type 2 diabetes mellitus (T2DM). However, little is known about the effects of LCZ on brain structural plasticity and cognitive function in T2DM. The aims of this study were to determine whether LCZ can prevent and alleviate brain damage and memory impairment in T2DM, and to understand the mechanisms underlying the effects of LCZ in T2DM.

Forty-one male Sprague-Dawley rats were divided into the saline control (CON, n = 14), T2DM (n = 14) and T2DM + LCZ (n = 13) groups. Magnetic resonance imaging (MRI) was used to evaluate alterations in brain structure among these three groups. The novel object recognition and Y-maze tests were conductedto assess cognitive function. Histological and immunohistochemical analysis, including Nissl staining, Golgi-Cox staining and glial fibrillary acidic protein immunostaining, were performed to explore the pathophysiological mechanisms underlying brain structural changes.

T2DM rats presented hyperglycemia, cognitive decline, hippocampal atrophy, and damage to hippocampal neurons and astrocytes. Compared with those in the T2DM groups, rats in the T2DM + LCZ group presented lower blood glucose levels, better cognitive function, a larger hippocampal volume, and more normal hippocampal neurons and astrocytes. There was no significant difference in these metrics between rats in the T2DM + LCZ and CON groups.

Hyperglycemia-induced damage to hippocampal neurons and astrocytes may lead to hippocampal atrophy and cognitive dysfunction in T2DM. LCZ can effectively prevent this damage by regulating blood glucose levels, preventing brain atrophy and cognitive impairment in T2DM rats. These findings provide a scientific basis for the clinical application of LCZ.

The correlation between diabetes and cognitive frailty is still controversial. The purpose of this study was to explore the related factors of cognitive frailty in older adults with type 2 diabetes, and to provide new ideas for realising healthy ageing of diabetic patients.

The survey was conducted at Mianyang Central Hospital affiliated to University of Electronic Science and Technology of China from January 15 to June 30, 2024. The subjects were older adults with type 2 diabetes aged 60 years or older. Cognitive frailty was assessed using Fried's phenotype and Mini-Mental State Examination. Statistical analysis and plotting were conducted using SPSS 25.0 and R 4.3.3. Least absolute shrinkage and selection operator (LASSO) regression was used to reduce the dimensionality of 30 clinical features collected, and the unimportant factors were initially screened out. The important factors with non-zero coefficients identified by LASSO regression were included in a multivariate logistic regression analysis to explore the factors influencing cognitive frailty in older diabetic patients.

This study included 301 older persons with type 2 diabetes. Among them, 91 (30.2%) cases of cognitive frailty occurred. Related factors for cognitive frailty in older adults with type 2 diabetes include: age (odds ratio (OR) = 6.417, 95% CI: 1.882-21.876, P = 0.003), hypomnesia (OR = 2,985, 95%CI: 1.143-7.797, P = 0.026), depression (OR = 9.926, 95%CI: 4.117-23.934, P < 0.001), diabetic retinopathy (OR = 6.489, 95%CI: 1.969-21.384, P = 0.002), history of diabetic ketoacidosis (OR = 12.024, 95%CI: 1.724-83.872, P = 0.012).

The prevalence of cognitive frailty in older persons with type 2 diabetes mellitus was higher. It was closely related to age, hypomnesia, depression, diabetic retinopathy and history of diabetic ketoacidosis. Early detection of the risk and effective intervention can reduce the incidence of adverse events and improve the quality of life of patients.

Alzheimer's disease (AD) is a neurological condition causing cognitive deterioration, leading to severe consequences. As the global prevalence of AD increases, new treatment approaches are needed to supplement current conventional therapies, as traditional treatments are not meeting the increasing demand for alternative treatments. It is increasingly evident that treating metabolic disorders like diabetes mellitus, obesity, and AD by blocking mechanistic target of rapamycin (mTOR) signalling is advantageous. Chronic mTOR activation may cause AD's metabolic, lysosomal, and mitochondrial dysfunction, tau hyperphosphorylation, amyloid plaque development, and disruption of the blood-brain barrier through endothelial cell malfunction. Chronic glucose loss through sodium-glucose transporter 2 (SGLT2) inhibitions can restore mTOR cycling, potentially halting or slowing AD pathogenesis. Chronic activation of mTOR is implicated in pathophysiological aspects of AD, such as metabolic dysfunction, tau hyperphosphorylation, amyloid plaque formation, and disruption of the blood-brain barrier. SGLT-2 inhibitors, commonly used in treating Type 2 Diabetes, have been shown to reduce mTOR activation and restore circadian regularity, a new finding in cognitive decline and metabolic disorders. Conversely, SGLT2 inhibitors decrease oxidative damage, inflammation, insulin signaling pathways, and proliferation of endothelial cells to enhance vascular tone, flexibility, and contractility. Along with reducing the formation of plaque containing amyloid and improving brain function, neural plasticity, acetylcholinesterase (AChE) activity, damage to the brain, and cognitive decline, they also regulate the mTOR pathway in the brain. Thus, repurposing SGLT-2 inhibitors, primarily used in diabetes treatment, presents a promising avenue for changing the way that AD is managed. The purpose of this review was to focus on the mTOR signalling cascade of SGLT 2 inhibitors to AD management in Type 2 Diabetes mellitus.

Metabolic syndrome (MetS) and mild cognitive impairment (MCI) are interconnected conditions sharing common pathological pathways, such as inflammation and oxidative stress, leading to the concept of "metabolic-cognitive syndrome." This highlights their mutual influence and potential overlapping therapeutic strategies. Although lifestyle modifications remain essential, nutraceutical supplementation has emerged as a promising adjunct for the prevention and management of these preclinical conditions. This review examines clinical and translational evidence on commonly used nutraceuticals targeting shared pathophysiological mechanisms of MetS and MCI. By addressing inflammation, oxidative stress, and metabolic dysfunction, these supplements may offer a valuable approach to mitigating the progression and consequences of both conditions. Understanding their efficacy could provide practical tools to complement lifestyle changes, offering a more comprehensive strategy for managing metabolic-cognitive syndrome.

Hypoglycemic pharmacotherapy interventions for alleviating the risk of dementia remain controversial, particularly regarding dipeptidyl peptidase 4 (DPP4) inhibitors vs metformin. Our objective was to investigate whether the initiation of DPP4 inhibitors, as opposed to metformin, was linked to a reduced risk of dementia.

We included individuals with type 2 diabetes over 40 years old who were new users of DPP4 inhibitors or metformin in the Chinese Renal Disease Data System database between 2009 and 2020. The study employed Kaplan-Meier and Cox regression for survival analysis and the Fine and Gray model for the competing risk of death.

Following a 1:1 propensity score matching, the analysis included 3626 DPP4 inhibitor new users and an equal number of metformin new users. After adjusting for potential confounders, the utilization of DPP4 inhibitors was associated with a decreased risk of all-cause dementia compared to metformin [hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.45-0.89]. Subgroup analysis revealed that the utilization of DPP4 inhibitors was associated with a reduced incidence of dementia in individuals who initiated drug therapy at the age of 60 years or older (HR 0.69, 95% CI 0.48-0.98), those without baseline macrovascular complications (HR 0.62, 95% CI 0.41-0.96), and those without baseline microvascular complications (HR 0.67, 95% CI 0.47-0.98).

In this real-world study, we found that DPP4 inhibitors presented an association with a lower risk of dementia in individuals with type 2 diabetes than metformin, particularly in older people and those without diabetes-related comorbidities.

The increasing prevalence of diabetes and its related cognitive impairments is a significant public health concern. With limited clinical treatment options and an incomplete understanding of the underlying mechanisms, traditional Chinese medicine (TCM) Naofucong is proposed as a potential neuroprotective agent against diabetic cognitive impairment (DCI). This study aims to investigate the therapeutic mechanisms of Naofucong in DCI. We hypothesize that Naofucong may improve cognitive function in diabetic rats by modulating the extracellular regulated protein kinases (ERK)/c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinases (MAPK) signaling pathway, enhancing insulin-degrading enzyme (IDE) expression, reducing amyloid-beta (Aβ) deposition, decreasing phosphorylated Tau (p-Tau) levels, and alleviating oxidative stress. Diabetes was induced in specific-pathogen-free male Sprague-Dawley rats using streptozotocin, and the rats were treated with oral Naofucong for 12 weeks. We assessed cognitive function and measured neuronal damage, oxidative stress injury, and the expression levels of IDE, Aβ, amyloid precursor protein (APP), p-Tau, and components of the ERK/JNK/p38 MAPK pathway. Diabetic rats showed significant declines in cognitive function, neuronal damage, oxidative stress, low IDE expression, Aβ accumulation, high APP expression, abnormal Tau phosphorylation, and overactivation of the ERK/JNK/p38 MAPK pathway. Naofucong treatment significantly reversed these symptoms. Our findings suggest that Naofucong improves cognitive impairment in diabetic rats by inhibiting the ERK/JNK/p38 MAPK pathway, upregulating IDE, reducing Aβ deposition, suppressing APP and p-Tau expression, and alleviating neuronal damage and oxidative stress. This research provides a reference for the clinical prevention and treatment of DCI using TCM Naofucong.

Diabetic encephalopathy is a chronic complication of diabetes that lacks an optimized treatment strategy. The present study sought to elucidate the potential molecular mechanism of Qi Fu Yin in improving diabetic encephalopathy through network pharmacology. The active components and target information of Qi Fu Yin were obtained from the TCMSP and Swiss target databases, while the target information of diabetic encephalopathy was sourced from Gene cards, OMIM, and Pharm Gkb databases. Enrichment analyses of KEGG and GO were conducted utilizing drug-disease common targets, while protein-protein interactions were predicted through the utilization of the STRING database platform. Subsequently, molecular docking was executed via Auto Dock Vina to authenticate the interaction between core components and core targets. The findings revealed that Qi Fu Yin exhibited 178 common targets with diabetic encephalopathy, and the enrichment analyses demonstrated that these targets were associated with lipid and atherosclerosis, AGE-RAGE signaling pathways, and other related pathways. The findings of the molecular docking indicated a favorable binding affinity between the active components of drug and the core targets, with EGF and quercetin exhibiting the most notable docking score. Additionally, the molecular dynamics simulation corroborated this high affinity. These results suggested that the active ingredients of Qi Fu Yin, including quercetin and kaempferol, may modulated the expression of genes such as IL10, TNF, EGF, and MMP2, thereby activating the AGE-RAGE signaling pathways and potentially serving as a therapeutic intervention for diabetic encephalopathy.Communicated by Ramaswamy H. Sarma.

Diabetic cognitive dysfunction (DCD) refers to the cognitive impairment observed in individuals with diabetes. Epidemiological studies have suggested that supplementation with n-3 polyunsaturated fatty acid (PUFA) or B vitamins may prevent the development of diabetic complications. Post hoc studies indicate a potential synergistic effect of n-3 PUFA and B vitamins in preventing cognitive impairment. However, the precise effect and underlying mechanism of this combination on DCD remain unclear. In case-control study, we compared fatty acid composition of erythrocyte membrane and serum homocysteine levels between diabetic individuals with and without DCD. We found that insufficient levels of n-3 PUFA, along with elevated serum homocysteine, significantly increase the risk of developing DCD. Treatment with a combination of fish oil, folate, and vitamin B12 improved cognitive impairment and aberrant neuronal morphology in streptozotocin-induced DCD mice. Folic acid and vitamin B12 enhanced the efficiency of exogenous docosahexaenoic acid (DHA) transportation to the brain by preventing the accumulation of homocysteine and S-adenosylhomocysteine, thereby inhibiting neuronal apoptosis in diabetic brains. Furthermore, folic acid and vitamin B12 supplementation can provide sufficient 5-methylcytosine for diabetic brains by promoting DNA methylation, while increased DHA levels maintain TET-mediated active DNA demethylation in diabetic brains through enhancing TET2 function. Overall, our study provides novel insights into molecular mechanisms underlying the synergistic preventive effects of the combined supplementation with fish oil, folic acid and vitamin B12 on DCD, suggests that combining n-3 PUFA and B vitamins could be a promising strategy for preventing DCD among individuals with diabetes.

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.

To evaluate the effects of exercise versus without-exercise group on global cognitive function, executive function, glycated hemoglobin A1c (HbA1c) and fasting plasma glucose in patients with type 2 diabetes mellitus and cognitive impairment.

A systematic search of Cqvip, SinoMed, Wanfang Data, CINAHL, Cochrane, Embase, Pubmed, Lippincott, Web of Science and Scopus was carried out. Randomized control trials were selected. The risk of bias was evaluated using the Cochrane Risk of Bias tool. The random-effects model was used to obtain the pooled estimates.

Eight trials with 884 participants were included. Exercise could significantly improve global cognitive function (standardized mean difference 0.82, 95% CI 0.53-1.12), executive function measured by the Trail-Marking Test part B (mean difference -20.43, 95% CI -36.20, -4.66), glycated hemoglobin A1c (%; mean difference -0.58, 95% CI -0.88, -0.29) and fasting plasma glucose (mg/dL; mean difference -17.61, 95% CI -32.67, -2.54).

Exercise can improve cognitive function, glycated hemoglobin A1c and fasting plasma glucose among type 2 diabetes mellitus patients with cognitive impairment. Additional studies with higher methodological quality are expected to draw more definite conclusions. This finding could provide a reference for clinical decision-making and guide future research initiatives. Geriatr Gerontol Int 2025; 25: 148-159.

Yi-guan-jian decoction (YGJ) is a traditional Chinese medicine prescription commonly used for treating syndromes associated with Yin deficiency in the liver and kidney, as well as Qi-obstructed in liver.

YGJ has shown potential alleviating cognitive dysfunction in type 2 diabetes mellitus (T2DM). However, the precise mechanisms are not yet fully understood. This study aims to reveal the mechanism by which YGJ alleviates cognitive dysfunction in T2DM.

Various doses of YGJ were administered to T2DM rats with cognitive dysfunction for 8 weeks. The positive control group received a combination of metformin and memantine. Cognitive function was assessed in T2DM rats using the Morris water maze test during treatment. Changes in gut microbiota and bile acids in the intestine were evaluated, and their interactions analyzed. Additionally, this study also evaluated the expressions of inflammatory markers (IL-1β,TNF-α, IL-16, IL-18 and CRP protein), Tau protein, neurotransmitter (5-HT and GABA), and bile acid receptor (FXR, PXR, VDR, and TGR5).

YGJ significantly alleviated insulin resistance and hyperlipidemia, reduce the levels of inflammatory factors in serum and hippocampus, and decreased mortality in T2DM rats. The Morris water maze test indicated that YGJ reduced the escape latency and increased platform crossing frequency, thereby improving cognitive function in T2DM rats. Furthermore, YGJ regulated the abundance of microorganisms associated with bile acid metabolism, including Romboutsia, Bacteroides, Turicibacter, Blautia, and Ruminococcus, thus regulating bile acid metabolism in T2DM rats. Additionally, YGJ also regulated bile acid metabolism by regulating intestinal FXR, PXR, VDR and TRG5 receptors.

YGJ can alleviate glucose homeostasis, insulin sensitivity, lipid metabolism, neuroinflammation, cognitive function, as well as remodel intestinal flora and BA composition in CDT2DM rats, which is a potential complementary and alternative therapy for the prevention and treatment of CDT2DM. These effects may be associated that YGJ regulates the structure of intestinal flora and BA metabolism, and inhibits intestinal BA receptors FXR, PXR, TGR5, and VDR.

Type 2 diabetes mellitus (T2DM) accelerates brain aging and disrupts brain functional network connectivity, though the specific mechanisms remain unclear. This study aimed to investigate T2DM-driven alterations in brain functional network connectivity and topology.

Eighty-five T2DM patients and 67 healthy controls (HCs) were included. All participants underwent clinical, neuropsychological, and laboratory tests, followed by MRI examinations, including resting-state functional magnetic resonance imaging (rs-fMRI) and three-dimensional high-resolution T1-weighted imaging (3D-T1WI) on a 3.0 T MRI scanner. Post-image preprocessing, brain functional networks were constructed using the Dosenbach atlas and analyzed with the DPABI-NET toolkit through graph theory.

In T2DM patients, functional connectivity within and between the default mode network (DMN), frontal parietal network (FPN), subcortical network (SCN), ventral attention network (VAN), somatosensory network (SMN), and visual network (VN) was significantly reduced compared to HCs. Conversely, two functional connections within the VN and between the DMN and SMN were significantly increased. Global network topology analysis showed an increased shortest path length and decreased clustering coefficient, global efficiency, and local efficiency in the T2DM group. MoCA scores were negatively correlated with the shortest path length and positively correlated with global and local efficiency in the T2DM group. Node network topology analysis indicated reduced clustering coefficient, degree centrality, eigenvector centrality, and nodal efficiency in multiple nodes in the T2DM group. MoCA scores positively correlated with clustering coefficient and nodal efficiency in the bilateral precentral gyrus in the T2DM group.

This study demonstrated significant abnormalities in connectivity and topology of large-scale brain functional networks in T2DM patients. These findings suggest that brain functional network connectivity and topology could serve as imaging biomarkers, providing insights into the underlying neuropathological processes associated with T2DM-related cognitive impairment.

In addition to peripheral neuropathy of various kinds, diabetes can also cause central neuropathy, which among other things can manifest itself as premature cognitive dysfunction, often linked to vascular dysfunction. Although the link between diabetes and cognitive dysfunction was discovered more than 100 years ago and has important clinical implications, this diabetes complication remains relatively unknown. Recent years have seen research that has clarified cerebral insulin resistance and defective insulin signaling as examples of pathogenic factors behind this cognitive impairment in diabetes.

We provide a narrative review of select and contemporary publications with relevance for the interface between diabetes/prediabetes and cognitive function.

Recently published studies show that physical activity can reverse insulin resistance in the brain as well as cognitive impairment and pathological appetite regulation. Pharmacological interventions with, for example, nasal insulin, GLP-1 receptor agonists, SGLT-2 inhibitors, or PPAR-γ agonists have also shown promising results.

Optimization of lifestyle factors (e.g. physical activity), as well as several pharmaceutical agents already in clinical use against diabetes, have shown promising results in improving cognitive function in diabetic patients. An important task for primary health care, where most patients with type 2 diabetes are diagnosed, treated, and followed, is to increase awareness and early detection of cognitive dysfunction in these patients for optimizing risk factor control.

Diabetes mellitus (DM), a chronic metabolic disorder that adversely affects the blood-brain barrier (BBB) and microglial function in the central nervous system (CNS), contributing to neuronal damage and neurodegenerative diseases. However, the underlying molecular mechanisms linking diabetes to BBB dysfunction and microglial dysregulation remain poorly understood. Here, we assessed the impacts of diabetes on BBB and microglial reactivity and investigated its mechanisms. We found diabetes severely disrupted the BBB integrity and microglial response to vascular injury. We also revealed a potential relationship between BBB disruption and impaired microglial function, whereby increasing BBB permeability led to a downregulation of microglial P2RY12 expression, thereby impairing microglial protection against cerebrovascular injury. Understanding these mechanisms may contribute to the developing of therapeutic strategies for diabetes-related neurological complications.

This study investigates the relationship between basal metabolic rate (BMR), body composition, obesity indices, and cognitive impairment (CI) in middle-aged and older type 2 diabetes mellitus (T2DM) patients, assessing their potential role in CI screening.

A cross-sectional study included 1243 T2DM patients over 45 years old. CI was assessed using the Montreal Cognitive Assessment. BMR and body composition indices were measured through bioelectrical impedance analysis. The associations and predictions related to CI were explored using multivariable-adjusted logistic regression, restricted cubic spline (RCS) models, and receiver operating characteristic (ROC) curve analyses. Mediation analysis explored the role of BMR adjusted by body surface area (BMR/BSA) in CI risk.

Patients with CI showed significantly lower BMR, BMR adjusted for height squared (BMR/Height²), BMR/BSA, appendicular skeletal muscle mass (ASM), and fat-free mass (FFM), alongside higher waist circumference (WC) and percentage of body fat. Logistic regression showed that participants in the fourth quartile of BMR, BMR/Height2, and BMR/BSA had approximately a 54% reduced risk of CI (odds ratio range 0.457 to 0.463). RCS analysis indicated a linear decrease in CI risk with increasing BMR metrics. ROC analysis indicated high predictive efficacy for CI with combined indicators, particularly BMR and FFM (area under the curve 0.645). Mediation analysis suggested that BMR/BSA played a significant mediating role in WC, ASM and FFM on CI risk, with a mediation proportion ranging from 45.73% to 50.87%.

Low energy expenditure assessed by BMR/BSA is an independent risk factor for increased CI risk in middle-aged and elderly T2DM patients. Central obesity, low muscle mass, and low energy expenditure significantly elevate CI risk in this population.

In this cross-sectional analysis, we explored how fluctuations in glycemic levels impact executive functions and psychosocial outcomes in patients with type 2 diabetes mellitus (T2DM). The goal was to understand the relationship between glycemic control and both neuropsychological and psychosocial health. We stratified participants into well-controlled and poorly controlled groups based on glycated hemoglobin (HbA1c) levels and variability, including a healthy control group for comparison. The study consisted of neuropsychological tests and psychosocial assessments. Results indicated that the poorly controlled T2DM group experienced significant executive dysfunction and scored lower on the Tower of London, Wisconsin Card Sorting, and Digit Span Tests, reflecting a broader impact on quality of life and resilience. These findings support the importance of maintaining stable glycemic levels for better executive and psychosocial outcomes and highlight the need for regular neuropsychological and psychosocial assessments in diabetes care.

The long-term high-fat, high-sugar diet exacerbates type 2 diabetes mellitus (T2DM)-related cognitive impairments. Phlorizin, a well-studied natural compound found in apples and other plants, is recognized for its bioactive properties, including modulation of glucose and lipid metabolism. Despite its established role in mitigating metabolic disorders, the neuroprotective effects of phlorizin, particularly against diabetes-related cognitive dysfunction, have not been fully elucidated. Therefore, the present study aimed to investigate the effect of dietary supplementation of phlorizin on high-fat and high-fructose diet (HFFD)-induced cognitive dysfunction and evaluate the crucial role of the microbiota-gut-brain axis. We found that dietary supplementation of phlorizin for 14 weeks effectively prevented glucolipid metabolism disorder, spatial learning impairment, and memory impairment in HFFD mice. In addition, phlorizin improved the HFFD-induced decrease in synaptic plasticity, neuroinflammation, and excessive activation of microglia in the hippocampus. Transcriptomics analysis shows that the protective effect of phlorizin on cognitive impairment was associated with increased expression of neurotransmitters and synapse-related genes in the hippocampus. Phlorizin treatment alleviated colon microbiota disturbance, mainly manifested by an increase in gut microbiota diversity and the abundance of short-chain fatty acid (SCFA)-producing bacteria. The level of microbial metabolites, including SCFA, inosine 5'-monophosphate (IMP), and D (-)-beta-hydroxybutyric acid (BHB) were also significantly increased after phlorizin treatment. Integrating multiomics analysis observed tight connections between phlorizin-regulated genes, microbiota, and metabolites. Furthermore, removal of the gut microbiota via antibiotics treatment diminished the protective effect of phlorizin against HFFD-induced cognitive impairment, underscoring the critical role of the gut microbiota in mediating cognitive behavior. Importantly, supplementation with SCFA and BHB alone mimicked the regulatory effects of phlorizin on cognitive function. Therefore, phlorizin shows promise as a potential nutritional therapy for addressing cognitive impairment associated with metabolic disorders. Further research is needed to explore its effectiveness in preventing and alleviating neurodegenerative diseases.

The aim is to provide new insights for researchers studying the pathogenesis of diabetic cognitive dysfunction and promoting the wider use of natural products in their treatment.

First, the Web of Science Core Collection was selected as the data source for a computerized literature search on oxidative stress and diabetic cognitive dysfunction (DCD). Next, Biblimetrix and VOSviewer performed statistical analysis focusing on publication countries, institutions, authors, research hotspots, and emerging directions in the field. Then, through the analysis of keywords and key articles, the forefront of the field is identified. Finally, we discussed the pathogenesis of DCD, the influence of oxidative stress on DCD and the antioxidant effect of natural products on DCD.

293 valid papers were obtained. Bibliometrics showed that oxidative stress, diabetes, Alzheimer's disease (AD), cognitive decline, insulin resistance and quercetin were the key words of the symbiotic network.

The antioxidant effects of natural products in improving DCD have been extensively studied in preclinical studies, providing potential for their treatment in DCD, but their evaluation in clinical trials is currently uncommon.

The maintenance of cognitive function is essential for quality of life and health outcomes in later years. Cognitive impairment, however, remains an undervalued long-term complication of type 2 diabetes by patients and providers alike. The burden of sustained hyperglycemia includes not only cognitive deficits but also the onset and progression of dementia-related conditions, including Alzheimer's disease (AD). Recent research has shown that the brain maintains an independent glucose "microsystem"-evolved to ensure the availability of fuel for brain neurons without interruption by transient hypoglycemia. When this milieu is perturbed, brain hyperglycemia, brain glucotoxicity, and brain insulin resistance can ensue and interfere with insulin signaling, a key pathway to cognitive function and neuronal integrity. This newly understood brain homeostatic system operates semi-autonomously from the systemic glucoregulatory apparatus. Large-scale clinical studies have shown that systemic dysglycemia is also strongly associated with poorer cognitive outcomes, which can be mitigated through appropriate clinical management of plasma glucose levels. Moreover, these studies demonstrated that glucose-lowering agents are not equally effective at preventing cognitive dysfunction. Glucagon-like peptide-1 (GLP-1) receptor analogs and sodium glucose cotransporter 2 inhibitors (SGLT2is) appear to afford the greatest protection; metformin and dipeptidyl peptidase 4 inhibitors (DPP-4is) also significantly improved cognitive outcomes. Sulfonylureas (SUs) and exogenous insulin, on the other hand, do not provide the same protection and may actually worsen cognitive outcomes. In the creation of a treatment plan, comorbid cognitive conditions should be considered. These efficacious treatments create a new gold standard of managing hyperglycemia-one which is consistent with the "complication-centric prescribing" mandates issued in type 2 diabetes treatment guidelines. The increasing longevity enjoyed by our populace places the onus on clinical care to play the "long game" in using targeted treatments for glucose control in patients with, or at risk for, cognitive decline to maintain cognitive wellness later in life. This article reviews critical emerging data for scientists and trialists and translates new enhancements in patient care for practitioners.

An abnormally organized brain spatial network is linked to the development of various central nervous system (CNS) disorders, including neurodegenerative diseases and neuropsychiatric disorders. However, the complicated molecular mechanisms of these diseases remain unresolved, making the development of treatment strategies difficult. A novel molecular imaging technique, called mass spectrometry imaging (MSI), captures molecular information on the surface of samples in situ. With MSI, multiple compounds can be simultaneously visualized in a single experiment. The high spatial resolution enables the simultaneous visualization of the spatial distribution and relative content of various compounds. The wide application of MSI in biomedicine has facilitated extensive studies on CNS disorders in recent years. This review provides a concise overview of the processes, applications, advantages, and disadvantages, as well as mechanisms of the main types of MSI. Meanwhile, this review summarizes the main applications of MSI in studying CNS diseases, including Alzheimer's disease (AD), CNS tumors, stroke, depression, Huntington's disease (HD), and Parkinson's disease (PD). Finally, this review comprehensively discusses the synergistic application of MSI with other advanced imaging modalities, its utilization in organoid models, its integration with spatial omics techniques, and provides an outlook on its future potential in single-cell analysis.

The glymphatic system is regarded as a key factor in the pathogenesis of neurodegenerative diseases. Given the heightened risk of cognitive impairment in patients with type 2 diabetes mellitus (T2DM), the possible alterations in the glymphatic system in T2DM patients remain to be explored. Diffusion tensor imaging (DTI) analysis along the perivascular space (ALPS) index can be utilized to model the glymphatic system in humans. Our aim was to explore the relationship between the ALPS index and cognitive function in patients with T2DM and whether this relationship is modulated by gray matter (GM) integrity anchored by the ALPS index.

All participants underwent evaluation using a comprehensive cognitive assessment scale to determine their neurocognitive status. The ALPS index was calculated based on DTI data, and the disparity in ALPS index values between patients with T2DM and healthy controls (HCs) was examined. Furthermore, multiple linear regression analysis was conducted in the T2DM group to identify the GM regions associated with the ALPS index, and the volumes of the GM partitions were extracted. The volume of GM partitions was used as the regulating variable, the ALPS index was used as the independent variable, and cognitive test scores were used as the dependent variable in our analysis.

The ALPS index differed significantly between the two groups, and the ALPS index in patients with T2DM was significantly lower than that in HCs. In addition, our analysis revealed a correlation between the ALPS index and GM volume in the insular region, consistent with the observed GM atrophy in the patient cohort. Moreover, a significant negative correlation was observed between the ALPS index in patients and performance on the Trail-Making Test-A (TMT-A), and this relationship was moderated by GM integrity. In patients with more severe GM atrophy, the ALPS index was more strongly correlated with cognitive function.

In this study, a decreased ALPS index was found in T2DM patients, indicating impaired glymphatic function in this population. Furthermore, a significant association was detected between the ALPS index and cognitive performance in T2DM patients, and this correlation was influenced by GM integrity. Therefore, the ALPS index has the potential to be used as a biomarker of cognitive impairment in diabetic patients. Further studies are needed to investigate the diagnostic and therapeutic implications of glymphatic dysfunction in T2DM patients with cognitive impairment.

The purpose of this study was to analyze the mechanism by which irisin affects β-cell pyroptosis in type 2 diabetes mellitus (T2DM). The in vivo T2DM model was established by raised with high-fat diet and intraperitoneally injection of streptozocin. Min6 cells were divided into four groups: negative control (NC), high glucose (HG), HG + irisin, and HG + irisin+3-MA. The cell viability was determined by CCK-8 assay. Dual-luciferase gene reporter assay was conducted to confirm the binding between miR-19b-3p and SOCS3. The expression level of FNDC5 and GSDMD was visualized using the immunofluorescence assay. The protein level of FNDC5, Beclin1, LC3II/I, NLRP3, cleaved-caspase-1, GSDMD-N, STAT3, p-STAT3, and SOCS3 was determined by Western blotting. The secretion of irisin, lactate dehydrogenase (LDH), and insulin was checked by ELISA. In vivo results showed that pathological changes in islet tissues with declined number of β cells, elevated FBG value, decreased FIN and HOMA-β value, elevated autophagy-associated proteins expressions, and activated NLRP3 signaling in T2DM mice, which were dramatically reversed by FNDC5 overexpression. Furthermore, the declined level of miR-19b-3p and p-STAT3, as well as the upregulation of SOCS3, was greatly rescued by FNDC5 overexpression. The in vitro data confirmed the binding site between SOCS3 and miR-19b-3p. SOCS3 was downregulated and p-STAT3 was upregulated in miR-19b-3p mimic-treated Min6 cells. In HG-stimulated Min6 cells, the elevated cell viability, increased production of insulin, decreased release of LDH, and inactivated NLRP3 signaling induced by irisin were abolished by miR-19b-3p inhibitor and STAT3 inhibitor. The increased level of autophagy-related proteins and activated SOCS3/STAT3 axis induced by irisin in HG-stimulated Min6 cells were abolished by miR-19b-3p inhibitor. The inhibitory effect of irisin against NLRP3 signaling in HG-stimulated Min6 cells was abrogated by 3-MA. In conclusion, irisin alleviated the pyroptosis of β cells in T2DM by inhibiting NLRP3 signaling through miR-19b-3p/SOCS3/STAT3 axis mediated autophagy.

Both metabolic syndrome (MetS) and cognitive dysfunction impair health-related quality of life (HRQOL). This study aims to determine whether individuals experiencing both MetS and cognitive dysfunction have lower HRQOL.

This cross-sectional study enrolled 567 participants who attended outpatient clinics at a medical center in northern Taiwan. MetS was diagnosed according to the modified criteria for the Asian population. Cognitive function was categorized as normal, mild cognitive dysfunction, and advanced cognitive dysfunction according to the score of the Montreal Cognitive Assessment, Taiwanese version. HRQOL was assessed using the SF-36v2® Health Survey (SF-36v2). The associations of the comorbidity status of MetS and cognitive dysfunction with HRQOL were analyzed using linear regression models, adjusting for age, sex, marital status, education level, income groups, and activities of daily living.

Out of 567 participants, 33 (5.8%) had MetS with mild cognitive dysfunction, and 34 (6.0%) had MetS with advanced cognitive dysfunction. Participants with both MetS and advanced cognitive dysfunction exhibited the lowest scores in the physical component summary and almost all scales of HRQOL. MetS exacerbated the inverse association between mild cognitive dysfunction and the mental component summary. For those with MetS, the scores on scales of role physical, bodily pain, vitality, and social functioning worsened as cognitive function deteriorated (all Ptrend<0.05).

As the severity of comorbidity between MetS and cognitive dysfunction varies, patients exhibited poorer performance in different aspects of HRQOL. Future research is needed to find solutions to improve HRQOL for patients with both MetS and cognitive dysfunction.

Recent evidence suggests that diabetes-related lower-extremity complications (DRLECs) may be associated with cognitive changes in people with diabetes. However, existing literature has produced inconsistent findings, and no systematic reviews have been conducted to investigate whether DRLECs impact the cognition of people with diabetes. This systematic review evaluated existing studies that investigated cognition in people with diabetes with DRLECs and without DRLECs.

Seven databases; MEDLINE, PubMed, CINAHL, EMBASE, Cochrane, PsycINFO and Web of Science were searched from inception until 22/8/2022 for studies that compared cognition in people with diabetes with and without DRLECs. Results were independently screened for eligibility and assessed for methodological quality by two authors, with key data extracted. Studies were eligible for meta-analysis if the studies reported similar cases, controls, and outcome measures.

Thirteen studies were included in the review, with eleven of medium methodological quality, one of high quality, and one of low quality. Four studies found significant differences in cognition between those with and without DRLECs, four found significant associations between diabetes-related lower-extremity complications and cognition, and five found no differences or associations. One small meta-analysis of eligible studies found that there was no statistically significant difference in cognition in people without, compared to with, peripheral neuropathy (Mean difference = -0.49; 95%CI: -1.59-0.61; N = 3; n = 215). Leave-one-out sensitivity analyses further confirmed that there was no significant difference in cognition among people with and without peripheral neuropathy (p > 0.05).

DRLECs may be related to cognition in people with diabetes, however, existing evidence is unclear due to variability in used methodologies that may challenge concluding the findings. Future high-quality studies investigating cognition among people with and without DRLECs are needed.

To investigate the relationship between the triglyceride and glucose (TyG) index and cognitive impairment (CI).

Five authoritative databases were systematically searched for potentially relevant studies on 'TyG index' and 'CI' from inception to 27 April 2024. Two representative databases from the United Kingdom and United States were also included. We used the PICOS criteria to select available articles. All data was combined to compute Odd Ratios (ORs).

15 studies were included in the meta-analysis (participants: 5604303). The pooled effect sizes demonstrate that individuals with a high TyG index exhibit a significantly elevated risk of CI compared to those with a low TyG index (OR = 2.16, 95%CI: 1.51; 3.08, p < 0.001). The subgroup analysis showed that inpatients with a high TyG index exhibited an increased risk of CI (OR = 4.56, 95%CI: 3.09; 6.74, p < 0.001). Furthermore, the risk of developing distinct types of CI differed significantly [CI: OR = 1.64, 95% CI: 1.29; 2.07, p < 0.001; Vascular Cognitive Impairment (VCI): OR = 5.39, 95% CI: 3.33; 8.70, p < 0.001].

A positive correlation exists between the TyG index and risk of CI, which has potential value in optimizing CI risk stratification among elderly people, especially those hospitalized.

https://www.crd.york.ac.uk/prospero/, identifier CRD42023450336.